Frequently Asked Questions

What are the requirements for license renewal? Licenses Expire Contact Hours Required Biennially on or before November 1 of the even or odd years. 30

How do I complete this course and receive my certificate of completion? Go to Pharmacy.EliteCME.com and follow the prompts. You will be able to print your certificate immediately upon completion of the course.

How much will it cost? Cost of Courses Course Title Contact Hours Price Overview of Arizona Pharmacy Law - Mandatory 3 $12.00 Best Practices for Prescribing Opioids in Chronic Non-Cancer Pain 3 $12.00 Complications of Chronic Kidney Disease 2 $8.00 Diabetic Medications and Insulin Pump Therapies 6 $24.00 Drug Administration 2 $8.00 Law and Ethics: What the Pharmacy Professional Should Know 3 $12.00 Methicillin-Resistant Staphylococcus Aureus: Prevention and Treatment 2 $8.00 Pain Management Awareness for Pharmacists 2 $8.00 Patient Safety and Medication Errors 3 $12.00 Pharmacist Responsibilities in the Management of Controlled Substances 1 $4.00 Shingles Disease Process and Vaccination for Pharmacists & Pharmacy Technicians 2 $8.00 Sterile Drug Preparation 1 $4.00  BEST VALUE  SAVE $21.00  Entire 30-hour Course 30 $99.00

Are you an Arizona board-approved provider? State board’s rules/statutes state that any course approved by the Accreditation Council for Pharmaceutical Education (ACPE) is accepted. All of our courses are accredited by ACPE.

Are my credit hours reported to the Arizona board? No. The board performs random audits at which time proof of continuing education must be provided. Your hours will be electronically reported to CPE Monitor within 10 business days.

Is my information secure? Yes! Our website is secured by Thawte, we use SSL encryption, and we never share your information with third-parties.

What if I still have questions? What are your business hours? No problem, we have several options for you to choose from! Online at Pharmacy.EliteCME.com you will see our robust FAQ section that answers many of your questions, simply click FAQ in the upper right hand corner or e-mail us at [email protected] or call us toll free at 1-888-666-9053, Monday - Friday 9:00 am - 6:00 pm, EST.

Important information for licensees Always check your state’s board website to determine the number of hours required for renewal, and the amount that may be completed through home-study. Also, make sure that you notify the board of any changes of address. It is important that your most current address is on file.

Arizona State Board of Pharmacy Contact Information Arizona State Board of Pharmacy Arizona State Board of Pharmacy Mailing Address Physical Address P.O. Box 18520 1616 W. Adams St., Suite 120 Phoenix, AZ 85005 Phoenix, AZ 85007

Phone: (602) 771-2727 | Fax: (602) 771-2749 Website: https://pharmacy.az.gov/

Pharmacy.EliteCME.com Page i Table of Contents CE for Arizona Pharmacy Professionals All 30 Hrs ONLY CHAPTER 1: OVERVIEW OF ARIZONA PHARMACY LAW (MANDATORY) Page 1 $99 State laws and regulations governing pharmacy practice are extremely important in the day-today work of a pharmacy associate. From the license needed to work in the pharmacy to the floor space necessary for each employee, laws and regulations govern every aspect of daily pharmacy operation. As a pharmacy employee, it is imperative to maintain a working knowledge of state pharmacy laws, and continue to learn about new laws that have been passed as well. Overview of Arizona Pharmacy Law Final Exam Page 9 What if I Still Have CHAPTER 2: BEST PRACTICES FOR PRESCRIBING OPIOIDS IN CHRONIC Questions? NON-CANCER PAIN Page 10 No problem, we have several options for you to choose from! At the conclusion of this course, you will be able to assess patients for the appropriateness Online at Pharmacy.EliteCME. of treatment with opioid analgesics. You will understand how to start opiate therapy, change com you will see our robust FAQ dosages, and discontinue treatment with opioid analgesics. section that answers many of Best Practices for Prescribing Opioids in Chronic Non-Cancer Pain your questions, simply click FAQ Final Exam Page 30 in the upper right hand corner or e-mail us at [email protected] CHAPTER 3: COMPLICATIONS OF CHRONIC KIDNEY DISEASE Page 31 or call us toll free at 1-888-666- 9053, Monday - Friday 9:00 am Chronic kidney disease (CKD) is often used as a broad term to describe many levels of decreased - 6:00 pm, EST. kidney function, from mildly decreased renal output to severe kidney failure. This course is for all pharmacists and pharmacy technicians with a need to better understand kidney function and how chronic kidney disease affects it. Complications of Chronic Kidney Disease Final Exam Page 37

CHAPTER 4: DIABETIC MEDICATIONS AND INSULIN PUMP THERAPIES Page 38 Visit Pharmacy.EliteCME.com to view our entire course library and With a wide variety of medications available for the treatment of diabetes, pharmacists must familiarize themselves with the tools available to treat this growing public health problem. This get your CE today! course serves to review the medications available for the treatment of diabetes, as well as the current recommendations for choosing pharmacologic treatment. Diabetic Medications and Insulin Pump Therapies Final Exam Page 59

CHAPTER 5: DRUG ADMINISTRATION Page 60 PLUS... Lowest Price Guaranteed As healthcare providers with a wealth of knowledge on the use of medications, pharmacists are perfectly poised to reduce the frequency of medication administration errors. This chapter will Serving Professionals Since 1999 explain medication administration and how to put best practice standards in place to help reduce medication administration errors and increase patient safety. Drug Administration Final Exam Page 67

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©2018. All Rights Reserved. Materials may not be reproduced without the expressed written permission or consent of Elite Professional Education, LLC. The materials presented in this course are meant to provide the consumer with general information on the topics covered. The information provided was prepared by professionals with practical knowledge in the areas covered. It is not meant to provide medical, legal or professional advice. Elite Professional Education, LLC recommends that you consult a medical, legal or professional services expert licensed in your state. Elite Professional Education, LLC has made all reasonable efforts to ensure that all content provided in this course is accurate and up to date at the time of printing, but does not represent or warrant that it will apply to your situation or circumstances and assumes no liability from reliance on these materials.

Page ii Pharmacy.EliteCME.com Table of Contents CE for Arizona Pharmacy Professionals

CHAPTER 6: LAW AND ETHICS: WHAT THE PHARMACY PROFESSIONAL SHOULD KNOW Page 68

Many federal and state laws govern the practice of pharmacy, and these laws are constantly changing. It is important for pharmacy professionals to familiarize themselves with both the federal and state regulations governing their daily responsibilities in the pharmacy, and keep up to date on new laws as well as amendments to existing laws. Law and Ethics: What the Pharmacy Professional Should Know Final Exam Page 76

CHAPTER 7: METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: PREVENTION AND TREATMENT Page 77

Staphylococcus aureus (S. aureus) is a gram positive coccus that occurs in grapelike clusters. It is a common pathogen involved in community and health care acquired infections. Identification of patients at high risk for infection helps improve care. Timely and appropriate antibiotics in the setting of MRSA infection is imperative due to the high rate of morbidity and mortality. Methicillin-Resistant Staphylococcus Aureus: Prevention and Treatment Final Exam Page 83

CHAPTER 8: PAIN MANAGEMENT AWARENESS FOR PHARMACISTS Page 84

Pain can be defined in general terms as an unpleasant emotional and sensory experience that is associated with potential or actual damage to tissue. It is critical to note that in some cases, people may be unable to verbalize the pain they are experiencing, but still require appropriate therapy for its treatment. Pain Management Awareness for Pharmacists Final Exam Page 89

CHAPTER 9: PATIENT SAFETY AND MEDICATION ERRORS Page 90

Over the past decade, medication safety has been a big concern for pharmacists who dispense or administer medications to patients. It is imperative to understand the legalities, responsibilities and accountability that we have to patients while participating in any component of the medication administration process. Pain Safety and Medication Errors Final Exam Page 98

CHAPTER 10: PHARMACIST RESPONSIBILITIES IN THE MANAGEMENT OF CONTROLLED SUBSTANCES Page 99

This course is designed to provide an overview of the Controlled Substances Act and allow practicing pharmacists the opportunity to test their knowledge by evaluating relevant case studies and applying information they have learned in this course to answer questions specific to those cases. Pharmacist Responsibilities in the Management of Controlled Substances Final Exam Page 104

CHAPTER 11: SHINGLES DISEASE PROCESS AND VACCINATION FOR PHARMACISTS AND PHARMACY TECHNICIANS Page 105

Herpes zoster, commonly known as shingles, affects approximately one out of every three Americans in their lifetime, resulting in an estimated 1 million cases in the United States each year. Upon completion of this course, you will understand the characteristics of varicella zoster virus, including primary infection and secondary reactivation of the latent virus, complications and treatment. As well as describe the efficacy, contraindications and precautions, adverse reactions and administration of Zostavax and Shingrix. Shingles Disease Process and Vaccination for Pharmacists and Pharmacy Technicians Final Exam Page 110

CHAPTER 12: STERILE DRUG PREPARATION Page 111

Sterile compounding of pharmaceutical products is a fundamental practice of pharmacy that is highly regulated due to the potential for harm to patients. This course reviews the standards of sterile compounding as discussed in USP Chapter <797>. Compliance with these standards is critical to remain compliant with state and federal compounding regulations. Sterile Drug Preparation Final Exam Page 115

Pharmacy.EliteCME.com Page iii Chapter 1: Overview of Arizona Pharmacy Law (Mandatory)

3 Contact Hours

Page 1 Pharmacy.EliteCME.com any issues related to the practice of pharmacy, the manufacturing, substances. Compliance inspections can be conducted to determine if wholesaling or supplying of drugs, devices, poisons or hazardous any violations have occurred and may also secure samples or specimens substances, the use of pharmacy technicians and support personnel and of any drug, device, poison or hazardous substance after paying or the lawful performance of its duties. offering to pay for such sample, or they may detain or embargo a drug, To properly enforce pharmacy rules and laws, the Board of Pharmacy device, poison, or hazardous substance in accordance with section 32- or its agents have free access at all reasonable hours to any pharmacy, 1994. manufacturer, wholesaler, nonprescription drug permittee or other The Board of Pharmacy is also responsible for providing notice at least establishment in which drugs, devices, poisons, or hazardous substances once every three months of any changes to prescribing authority of any are manufactured, processed, packed, or held, or enter any vehicle being prescriber licensed to practice in Arizona. used to transport or hold such drugs, devices, poisons or hazardous Pharmacy setup and security Pharmacies in Arizona must have a dispensing, compounding, and drug NOTE: Pharmacy size regulations must be addressed and discussed stocking area that is at least 300 feet. If the minimum pharmacy size is with the Board of Pharmacy when applying for a permit to operate a used, no more than three personnel may work at the same time. Each pharmacy. additional staff member requires an additional 60 feet of floor space. Controlled substances can be kept in a separate safe or locked cabinet This is to allow pharmacists adequate space to monitor the activities of or distributed throughout the stock of prescription medications; it is pharmacy personnel and ensure efficient workflow. up to the pharmacy to decide what best suits its needs to maximize Each employee working at the same time should have at least 3 feet of efficiency and minimize theft. The pharmacy must be surrounded from counter space, and it must be at least 16 inches deep and 24 inches long floor to ceiling by a permanent barrier with secure entry points. Is to be sure all of them have space to spread out their work to minimize should be designed in a way that the pharmacist is the only person who error potential. can gain entry to the restricted area where prescription on medications Counter space should be contained by a barrier at least 66 inches tall and controlled substances are stored, and only a pharmacist with a key to prevent unauthorized persons from seeing the pharmacy counter, is permitted to enter the storage area, except in an extreme emergency. potentially violating a patient’s privacy. The floor space along the All prescription medications and medical devices must be stored in a dispensing and compounding counter must be at least 36 inches wide. clean, organized space that is well lit, well ventilated, dry, and maintains adequate temperatures for medication storage. A separate drug storage New pharmacies must have a separate patient counseling area to allow area outside of the pharmacy may be used if necessary; however, it patients privacy during consultation. must be enclosed from floor to ceiling by a secure barrier that only the pharmacist can access with a key. Who can prescribe medications in Arizona? In the state of Arizona, many different types of practitioners can prescribe medications to patients. Some of these prescribers have limits Veterinarian Independent prescribing authority limited to to their prescription authority, such as treatment limited to certain scope of practice – prescribing authority is body parts or limit to the prescription of controlled substances. It is limited to treatment of animals. very important to be aware of the various types of prescribers and their Physician Can prescribe non-controlled medications authority limits to ensure prescriptions are filled within the limits of the assistant without limits. Controlled substances can only be law. prescribed with board approval. Schedule IV-V drugs may be prescribed but no more than five Type of Prescription authority times within a six month period. Schedule III prescriber drugs can be prescribed, only with a supervising Medical doctor Independent prescribing authority, not limited by physician’s written consent. the scope of practice. Can prescribe Schedule III- Registered nurse Can prescribe non-controlled and controlled IV but no more than five times within 6 months practitioner medications with board approval, independent and can prescribe Schedule V, not to exceed one prescribing authority. year. EMT/paramedic Does not have any prescribing authority. Doctor of Independent prescribing authority, not limited by osteopathy scope of practice. Can prescribe Schedule III-IV Chiropractor Does not have any prescribing authority. but no more than five times within 6 months and Naturopathic May prescribe non-controlled medication and can prescribe Schedule V, not to exceed one year. doctor any Schedule III, IV or V medications. May not Dentist Independent prescribing authority limited to prescribe any intravenous medications, cancer scope of practice – prescribing authority is chemotherapeutics or antipsychotics. The only limited to treatment of mouth, teeth and gums. Schedule II drug they can prescribe is morphine. Podiatrist Prescribing authority is limited to their scope of Optometrist May prescribe drugs, non-controlled drugs practice which is treatment of lower extremities, with board approval and the only controlled primarily feet and ankles. Can prescribe non- substances they can prescribe is Schedule III controlled medications with board approval as analgesics. Must be TPA certified and approved well as controlled substances, again, with board by their State Board. approval. Can also prescribe Schedule III-IV, not Pharmacist Can start, alter, or discontinue medication to exceed more than 5 times, in a 6 month period therapy under a collaborative agreement with and Schedule V drugs can be prescribed, not to a supervising physician. May also administer exceed one year. most immunizations without a prescription after earning certification. Prescription requirements in Arizona Prescriptions filled in the state of Arizona must comply with several to pharmacies, as well as the components of prescriptions. All regulations put in place by the Board of Pharmacy. Different prescriptions must be dispensed under the direct supervision of a regulations apply to the various methods of transmitting prescriptions

Pharmacy.EliteCME.com Page 2 pharmacist licensed by the Arizona Board of Pharmacy. Prescriptions Controlled substances may not be filled even if it is approved by filled by a pharmacy in Arizona must meet the following requirements: medical practitioner; prescriptions of controlled substances from any ●● Prescriptions must be written by a prescriber with prescribing foreign country are prohibited. authority in Arizona as noted in the chart in the previous section. Prescriptions should be completed by the prescriber with the patient’s Prescriptions written outside of the limitations of the prescriber’s name, the name and strength of the medication ordered, quantity authority are not considered to be valid. to dispense, directions for use, number of available refills, date the ●● An electronically transmitted prescription order, containing the prescription was written, and the signature of the doctor. Controlled prescribing medical practitioner’s electronic or digital signature, is substance prescriptions also should have the DEA number of the acceptable but must be promptly transcribed in writing and filed by prescriber noted on the face of the prescription and the prescribers the pharmacist. address. ●● Written prescription orders with the practitioner’s electronic or manual signature is acceptable. A prescription order that contains A pharmacist shall ensure that the following information is recorded only an electronic signature must be applied to paper that uses on the back of a prescription order when it is refilled: the date refilled, security features that will ensure the order is not subject to any form the quantity dispensed, and the name or approved abbreviation of of copying or alteration. the manufacturer or distributor if the prescription order is written ●● For an oral prescription order, the medical practitioner’s name and generically or a substitution is made, and the name or initials of the telephone number must be on the prescription along with the name dispensing pharmacist. and initials of the dispensing pharmacist. Adulteration of prescription medications dispensed in Arizona is ●● For a faxed prescription order, a medical practitioner or their agent prohibited. This includes manufacturing prescription products where may transmit a prescription order for a Schedule III, IV, or V the products may consist of any filthy, putrid, or decomposed matter. controlled substances, prescription-only drug, or nonprescription This includes manufacturing prescription products under unsanitary drug to a pharmacy by facsimile (fax) under the following conditions where contamination is likely, dispensing products that conditions: contain dangerous colorants or toxic additives that are not part of the ○○ The prescription is faxed only to the pharmacy of the patient’s original drug product, or altering the purity of the original drug product, choice. resulting in a weaker drug product. This is a severe violation of the law ○○ The fax prescription order contains all the information required. that can result in suspension or removal of a pharmacist’s license. ●● The patient may send prescription orders via fax or email if the Misbranding of prescription products is also prohibited by federal and original prescription hard copy is presented to the pharmacy upon state law. Knowingly misrepresenting the labeling of a prescription drug pickup of the medication, and has the prescriber’s manual signature. product resulting in inaccurate statements of quantity or quality is a All prescriptions filled in Arizona must have a paper version that must violation of the law. To avoid misbranding, prescriptions must contain be filed and kept in a readily retrievable location for at least seven years. appropriate directions for use and warnings to protect the health and Effective as of July 22, 2014, a pharmacist, or an intern under a safety of the patient. An example of misbranding is when a prescriber pharmacist’s supervision, may fill a new written prescription order for asks the pharmacist to dispense a placebo pill in the container of a drug or device, as long as it was issued by a medical practitioner, who prescription medication. This is a violation of the law and can result is licensed by the appropriate licensing board of a foreign county. The in severe disciplinary action including suspension or removal of a pharmacist, manager, or proprietor must keep a separate record of these pharmacist’s license. prescriptions, and keep them for seven years, also. Generic substitution and DAW Prescriptions filled in Arizona should be dispensed, as they are substituted prescriber did not specify that the brand name product in the Orange for a brand name product, the price for both the brand name written, if the Book. If a generic product is substituted for a brand name product, prescriber writes on the prescription any variation of and generic product the price for both the brand name and generic product must be given must be given to the patient if the prescription is the terms “DAW” to the patient if the prescription is not billed to an insurance plan. A (dispense as written), or do not “substitute,” or “medically necessary.” generic product may not be substituted for a brand name product if If these terms are not present on the face of the prescription, a generic the manufacturer does not print an expiration date on the product’s product substituted for the brand name prescribed. packaging, or if the manufacturer does not have a program for the recall The generic product substituted for the brand name written must FDA- of unsafe or flawed products. The patient may choose to have the brand approved and listed as bioequivalent to the brand name dispensed if the name dispensed if the prescriber did not specify that the brand name is “medically necessary.” Refills and valid time frame for filling prescriptions All prescriptions filled in Arizona have a valid time frame in which the may only be refilled within this time frame. Prescriptions for schedule original prescription and available refills may be filled, depending on III-V controlled substances are valid for six months from the written the type of medication ordered. Prescriptions filled in Arizona for non- date, and may be refilled up to five times. Schedule II prescriptions are controlled substances are valid for one year from the written date, and valid for 90 days from the written date and may not be refilled. Dispensing controlled substances without prescription In the state of Arizona, certain controlled substances can be dispensed of the person purchasing the product, the quantity and name of the without a prescription under specific conditions. Patients who are at product purchased, the date the purchase was made, and the name or least 18 years old can purchase certain controlled substances from a initials of the pharmacist overseeing the sale. pharmacist if all of the following criteria are met: ●● The bottle must be labeled with the pharmacy’s name and address, ●● It must be requested for legitimate medical treatment. date product was dispensed, serial number, prescriber’s name, ●● No more than 240 cubic centimeters or 48 dosage units of any patient’s name, directions for using the product, and any warning controlled substances containing opium, or 120 cubic centimeters statements necessary. If a controlled substance, it must also include or 24 dosage units of any other controlled substances may be the federally required warning: “Caution: federal law prohibits the dispensed to the same person within 48 hours. transfer of this drug to any person other than the patient for whom it ●● No more than 120 dosage units of any product that contains only was prescribed.” ephedrine may be dispensed within 30 days. Pseudoephedrine is regulated in Arizona because it is a common ●● Any patient who is not known to the pharmacist must provide product used in the manufacture of methamphetamine. Regulations identification and proof of age. have been put in place to deter people from purchasing large amounts ●● A record book must be used to collect information about the person purchasing the controlled substance, including name and address Page 3 Pharmacy.EliteCME.com of pseudoephedrine for methamphetamine production to decrease the ●● All products containing pseudoephedrine must be kept behind production of this drug in Arizona. the counter or in a locked cabinet, and can only be sold under the In most instances, Arizona state regulations on pseudoephedrine sales supervision of a licensed pharmacist. are less restrictive than federal laws, so federal laws must be followed ●● There are strict limits to how much pseudoephedrine can be in Arizona. These regulations include: purchased at once. No more than 9 grams of pseudoephedrine may ●● All sales must be recorded in a logbook. be purchased by a single person within a 30-day period, and no ○○ The logbook may be electronic or on paper. more than 3.6 grams may be purchased per person per day. This is ○○ It must be readily retrievable and maintained for at least two to decrease the availability of pseudoephedrine and limit its use in years. the production of methamphetamine. ○○ It must record the name and address of the person purchasing ○○ Mail order or Internet retailers are limited to shipping no more pseudoephedrine, the date and time the sale was made, the name than 7.5 grams of pseudoephedrine within a 30-day period. and quantity of the product purchased, and include the signature ○○ These rules do not apply to prescriptions written for of the purchaser. pseudoephedrine – only for over-the-counter sales without a ●● A state-issued photo identification card, driver’s license, or passport prescription. must be presented at time of purchase. Patient counseling Patient counseling must occur on all new prescriptions dispensed to names, directions for use, contraindications as appropriate, and adverse adverse effects. Counseling must be conducted by a licensed pharmacist effects. The patient or his or her representative should be given time under the direct supervision of a licensed pharmacists, and should to ask questions and receive appropriate answers. Counseling is not include an overview of the medication, including its brand and generic required on refills unless there is a change in directions or dosage. Transferring prescriptions Regulations for transferring prescriptions between pharmacies are 4. Date of original dispensing. enforced by the Board of Pharmacy. 5. Number of valid refills remaining and the date of the last refill. Prescriptions may be transferred between pharmacies within the state 6. Name and identification code, number, or address, telephone of Arizona. The transfer of original prescription order information for number, and original prescription number of the pharmacy from a non-controlled substance drug must be communicated between two which the prescription is transferred. licensed pharmacists, or a licensed pharmacist and a licensed pharmacy 7. Name of the transferring pharmacist or pharmacy or graduate intern. or graduate intern, or between two licensed pharmacy, or graduate 8. Name of the receiving pharmacist or pharmacy or graduate intern. interns. Prescriptions for Schedule III, IV, or V- a controlled substance may only When a prescription is transferred out of a pharmacy, it must be be transferred (communicated) between two licensed pharmacists, and invalidated by the transferring pharmacy by writing VOID on the face may only be transferred one time, regardless of the number of refills of the original prescription hard copy, or if electronically transferred, remaining. ensuring it is invalidated in the pharmacy’s dispensing computer system The word “void” is written on the face of the invalidated original to avoid duplicate copies of prescriptions. prescription order unless it is an electronic or oral transfer and The following information needs to be recorded by the transferring the transferred prescription order information is invalidated in the pharmacy professional: transferring pharmacy’s computer system. The name, address, and DEA 1. The name and ID code, number, or address and telephone number number of the pharmacy to which the prescription is transferred, the of the pharmacy to which the prescription is transferred. name of the receiving pharmacist, the date of transfer, and the name of 2. The name of the receiving pharmacist or pharmacy or graduate the transferring pharmacist is written on the back of the prescription intern. order or entered into the transferring pharmacy’s computer system. 3. The date of transfer. For the receiving pharmacist, the same information is recorded as 4. The name of the transferring pharmacist or pharmacy or graduate with the non-controlled substances discussed previously and both intern is written on the back of the prescription or entered into the pharmacists must record the DEA number of the other pharmacy on the transferring pharmacy’s computer system. transfer order. The following information is recorded by the receiving pharmacist or Prescriptions may be transferred into Arizona from out of state if they pharmacy or graduate intern on the transferred prescription order: meet all of the above requirements for prescription. More on this can 1. The word “transfer.” be found on the state board website under laws and statutes, https:// 2. Date of issuance of the original prescription order. pharmacy.az.gov/resources/rules-statutes 3. Original number of refills authorized on the original prescription order. Pharmacy licensure All pharmacies, drug wholesalers, drug storage facilities, and drug 1. A permit to sell non-prescription medications in the original manufacturers in Arizona must be licensed with the Board of Pharmacy, package. Businesses that hold this permit are not required to sell and these licenses must be renewed every other year. Pharmacies not their products at one fixed location. located in Arizona that deliver medications to patients in Arizona must 2. A pharmacy permit can be issued and is necessary to operate a full also be registered with the state Board of Pharmacy in Arizona. service pharmacy. Application for a permit to operate a pharmacy, drug wholesaler, drug 3. Limited service pharmacy permits may be issued to pharmacies that storage facility, or drug manufacturing plant must include the following: are only practicing a limited portion of pharmacy practice, such as a ●● The name of the person responsible for the operation of the facility, closed-door pharmacy that only offers patient counseling and does including any licensed pharmacists responsible for its operation. not dispense medications. ●● The location of the facility to be licensed, including physical street 4. Full service wholesale drug permits may be issued to wholesalers address. that stock prescription and nonprescription medications. ●● A description of the activities to be performed at the facility. 5. Nonprescription drug wholesale permits can be issued to wholesalers that only want to stock nonprescription medications. If a company with several facilities is seeking licensure, a separate 6. Drug manufacturer permits may be issued to facilities involved in application must be completed for each location desiring licensure. the creation of prescription and nonprescription drug products. There are several types of permits that may be issued by the Board of Pharmacy. These include:

Pharmacy.EliteCME.com Page 4 7. A drug packager or pre-packager permit may be issued to Permits can be revoked if it is discovered that a medical provider a person or business registered with the Food and Drug is receiving compensation from a pharmacy for prescribing certain Administration (FDA) and authorized by the FDA to change the products. If a permit-holder’s business is closing or otherwise ceasing original manufacturer’s packaging of a drug product to re-sell to operate, the permit should be surrendered immediately, the Board of the repackaged product to a business that is authorized to sell Pharmacy must be notified, and all drug products and signage should be repackaged medications. removed or destroyed. 8. A compressed medical gas distributor or supplier permit can be issued to facilities interested in selling or distributing compressed medical gasses, such as oxygen. Fingerprint requirements The Arizona State Board of Pharmacy no longer accepts fingerprint Is there a fee to obtain a Fingerprint Clearance Card? cards. If you are applying for licensure as a pharmacy technician trainee, Currently, the fee for volunteers is $65.00 and the fee for all others is pharmacy technician, intern or pharmacist, you must now submit a valid $67.00. The electric application adds an additional convenience fee of Arizona fingerprint clearance card WITH your application. If you have $7.95, which includes fingerprinting at an approved vendor location. a valid Arizona fingerprint clearance card, submit of a copy with your The paper application may require payment of an additional fee for application. If you do not have a valid Arizona fingerprint clearance fingerprinting services, dependent on which service the applicant card, you must obtain one before applying for licensure. To obtain an chooses to perform the fingerprinting. Fees are subject to change at any Arizona Fingerprint Clearance Card, you may apply online at http:// time. fieldprintarizona.com. Select “Regular Application – Paid Employee,” How long will it take to get my Fingerprint Clearance Card? then select “Board of Pharmacy – Licensure.” The statutory reference The average processing time can vary from week to week based on needed is A.R.S. § 32-1904. For questions, contact the Arizona the number of applications received and whether or not the applicant Department of Public Safety at 602-223-2279. DPS hours are Monday has a criminal record requiring research. If research is not required, through Friday, 8:00 am to 5:00 pm. Applicants who are not in Arizona processing will take approximately two to four weeks for an electronic must contact DPS for an application packet. application, and four to six weeks for a paper application. Processing Below are some frequently asked questions about this new rule, can take up to 90 days for applications which require research. retrieved from the Arizona Department of Public Safety website, www. Can I check the status of my application? azdps.gov You may check the status of your electronic or paper application Who is required to have a level one fingerprint clearance card? online at: https://webapps.azdps.gov/public_inq_acct/acct/ The Arizona Revised Statutes (ARS) require members of many ShowClearanceCardStatus.action. You may also check the status by professions to have an active fingerprint clearance card prior to, or as calling 602-223-2279, although wait times may apply. a condition of, licensure, certification or employment. The Statutes How long is my Fingerprint Clearance Card good for? currently list 47 reasons why a person may need a fingerprint clearance A fingerprint Clearance Card is valid for six years. card. The Applicant Clearance Card Team (ACCT) calls these “sponsors.” Your licensing, certifying, or authorizing agency, board, or What will my fingerprints be used for? employer (sponsor) can better advise if you need a fingerprint clearance Your fingerprints will be used to obtain both a state and federal criminal card and which Statute provides the reason for the requirement. history records check. Pharmacist licensure and continuing education requirements for pharmacists Pharmacists can obtain their licenses from the Arizona Board of training program of 400 hours before they are eligible to resume Pharmacy. To be eligible for a pharmacist license, applicants must practice as a pharmacist. graduate from an accredited school of pharmacy recognized by the Pharmacists who serve as the pharmacist-in-charge at a pharmacy must board, successfully complete a practical experience program supervised report this position to the Board of Pharmacy. The pharmacist in charge by a licensed pharmacist, pass the pharmacist licensure exam and state is considered the responsible manager of the pharmacy. If this position jurisprudence exam, pay a pharmacist application fee to the Board of is terminated, the pharmacist must report this change to the Board of Pharmacy, and be of good moral character. Pharmacy as well. All pharmacists must renew their licenses every other year, and all Pharmacists who wish to serve as preceptors to pharmacy interns must pharmacist licenses expire on October 31. To be eligible for renewal, register for a preceptor license with the Board of Pharmacy. These pharmacists must complete three continuing education units or CEUs pharmacists are responsible for practical instruction of the intern, and (30 hours) every two years, with at least 0.3 CEUs (three hours) on are to act as a teacher and mentor to the student. Preceptors are also able the topic of pharmacy law. Proof of continuing education completion to verify intern hours worked by the pharmacy intern. To be eligible for should be retained for five years, and credits may not be carried over to a preceptor license, the applicant must be a licensed pharmacist with the next renewal period. an unrestricted license and must have at least one year of experience Failure to renew a pharmacist license by October 31 of a renewal year actively working as a licensed pharmacist. Pharmacists with preceptor may result in additional fees. Pharmacists who have not been practicing licenses working in a community setting may only be a preceptor to two pharmacy for more than one year must complete a board-approved pharmacy interns per calendar quarter. Pharmacy intern responsibilities Pharmacy interns can work in a pharmacy under a licensed pharmacist Intern hours may be registered after the beginning of the first year once they become registered and licensed with the Board of Pharmacy. of professional pharmacy education, and after the pharmacy intern To be eligible for an intern license, applicants must be enrolled in an receives a Board of Pharmacy-issued intern license. Intern licenses are accredited school of pharmacy recognized by the Board of Pharmacy. issued for five years, and may be issued for an additional year with Graduate intern licenses may be issued to applicants who have board approval. Intern licenses are not eligible for renewal, as the intern graduated from a school of pharmacy approved by the board. license is used for students studying to become pharmacists. Students A total of 1,500 intern hours must be recorded with the Board of who do not complete their education within six years must explain to Pharmacy before an intern is eligible for licensure as a pharmacist. the Board of Pharmacy that they intend to continue working toward No more than 500 hours may be recorded per quarter (three months). completing their education and becoming a pharmacist for a renewal to Pharmacy interns can only register hours worked if working under a be issued. preceptor, a licensed pharmacist registered with the Board of Pharmacy The pharmacy intern may perform the following tasks under the with a preceptor license. immediate supervision of a licensed pharmacist:

Page 5 Pharmacy.EliteCME.com ●● Dispense and sell medications, medical devices, and poisons to ○○ Dispensing and compounding medications. patients. ○○ Clinical pharmacology. ●● Compound medications. ○○ Providing information on medications to patients and health ●● Perform duties of a pharmacist, as long as a licensed pharmacist care providers. directly supervises them. ○○ Record keeping and completing federal and state-mandated ●● Pharmacy interns are to be trained in the practice of pharmacy reports. during their intern hours worked. This includes: ○○ Maintaining compliance with the law. ○○ The manufacture and sale of medications and medical devices. Pharmacy technician responsibilities Pharmacy technicians, pharmacy technician trainees, and certified ●● Record information in the refill record or patient profile; pharmacy technicians must be registered and licensed with the Board ●● Type and affix a label for a prescription medication or enter of Pharmacy to work in a pharmacy, and license must be renewed every information for a new or refill prescription medication into a other year. computer, if a pharmacists verifies the accuracy and initials in Before beginning work in a pharmacy, pharmacy technicians and trainees handwriting or by another method approved by the Board or its must sign and date a statement showing they have reviewed the Board designee the finished label prepared by the technician before the of Pharmacy procedures for pharmacy technicians, the job description prescription medication is dispensed to the patient. for their position in the pharmacy, and the pharmacy’s handbook of ●● Reconstitute a prescription medication, if a pharmacist checks the the policies applicable to pharmacy technicians. These policies should ingredients and procedure before reconstitution and verifies the final include information on employer expectations for pharmacy technicians, product after reconstitution. activities that technicians may perform, how to report and avoid ●● Retrieve, count or pour a prescription medication, if a pharmacist medication errors, how to maintain confidentiality of patient information, verifies the contents of the prescription medication against the security procedures, federal and state regulations, dispensing procedures, original prescription medication container or by an alternative drug and maintaining the pharmacy inventory and storage. identification method approved by the Board or its designee. ●● Prepackage drugs in accordance with R4-23-402 (A); People interested in working as a pharmacy technician must be 18 ●● Measure, count, pour, or otherwise prepare and package a drug or older, possess a high school diploma or GED certificate, and be of needed for hospital inpatient dispensing, if a pharmacists verifies decent moral character. For interested persons to be eligible to apply the accuracy, measuring, counting, pouring preparing, packaging for a pharmacy technician license, the person must complete a training and safety of the drug before the drug is delivered to a patient care program for pharmacy technicians that meets state-specific standards, area. and take the Pharmacy Technician Certification Board exam (PTCB ●● After completing a pharmacy technician drug compounding training exam) and pass with a satisfactory score. Pharmacy technicians in program developed by the pharmacy permittee or pharmacist-in- training must apply for a pharmacy technician trainee license to charge under R4-23-1105(C), assist a pharmacist, graduate intern, complete their training in a pharmacy. or pharmacy intern in compounding prescription medications and Pharmacy technicians in training (Pharmacy Technician Trainees) sterile or nonsterile pharmaceuticals in accordance with written must apply for a pharmacy technician trainee license to complete their policies and procedures, if the preparation, accuracy and safety of training in a pharmacy. Pharmacy technicians in training are required to the final product is verified by a pharmacists before dispensing. provide a copy of a U.S. birth certificate and high school diploma.The Technicians must wear a nametag with their name and title while difference between a trainee and a technician is the pharmacy technician working as a pharmacy technician. has completed both a training program, and passed the PTCB exam with a passing score, acquiring a wall card. Pharmacy technician training programs may be conducted at the pharmacy where the technician will work, or off-site at a training After completing a pharmacy technician training program and passing school. Training programs must teach the technician the tasks they will the PTCB exam, pharmacy technicians may apply for a pharmacy be required to perform in their employment and discuss the policies technician license with the Board of Pharmacy. The license application and procedures and activities that may be completed by a pharmacy must include demographic information for the person applying, technician as implemented by the Board of Pharmacy. Technicians must any felony offense or drug-related offences committed or pending, be assessed on their knowledge of these tasks and retrained if they do information on whether the person applying has ever had a revoked not demonstrate competency. or suspended pharmacy license or a denied pharmacy technician application, the pharmacy name and location where the applicant will The pharmacist-in-charge who is training the pharmacy technician must work, the verified signature of the person applying, the date, and the keep a record of the progress of the trainee and sign off on a document license fees for the license issuance and wall hanging license to be when the technician has completed the training program successfully. displayed in the pharmacy. Documentation of successful completion of the training program must be saved for possible inspection by the Board of Pharmacy, and a copy Due to a change in statute, the Board of Pharmacy will begin must be provided to the technician as well. requiring fingerprint clearance cards in August of 2016. To facilitate the changeover from fingerprint cards, to fingerprint clearance cards, Technicians who wish to compound prescription medications must the Board of Pharmacy stopped accepting fingerprint cards on July successfully pass a training program onsite at the pharmacy where they 15, 2016. Pharmacy technician licenses must be renewed every other are employed, or off-site at a pharmacy technician training school. The year, and renewal must be completed by filling out a renewal form and training program must address the following guidelines: including the necessary renewal fees. All pharmacy technician licenses ●● The tasks the pharmacy technician will be required to perform, as must be renewed every two years. well as indication of how or when the pharmacist-in-charge will assess the pharmacy technician’s competency. Pharmacy technicians may perform the following tasks when working ●● Preparation of the area to be used for compounding of prescription under the supervision of a licensed pharmacist: medications. ●● Record on the original prescription order the prescription serial ●● Preparation of the components used. number and the date dispensed; ●● Aseptic technique to be used for the preparation of prescription ●● Initiate or accept verbal or electronic refill authorization from a products in a sterile environment. medical practitioner or medical practitioner’s agent and record, on ●● How to properly package and label prescription products. the original prescription order or by an alternative method approved ●● Proper cleanup of the medication compounding area, including by the Board or its designee, the medical practitioner’s name, procedures for hazardous waste cleanup. patient name, name and quantity of prescription medication, specific refill information and the name of the medical practitioner’s agent, The technician’s training progress must be documented by the if any; pharmacist-in-charge, and program completion must be recorded and

Pharmacy.EliteCME.com Page 6 signed by the pharmacist in charge. Documentation of the completion NOTE: Only pharmacy technicians who have successfully completed a of training programs must be maintained for possible inspection by the medication compounding training program may compound prescription Board of Pharmacy. medications for final verification by a pharmacist! Pharmacy technician continuing education requirements In Arizona, pharmacy technicians need to obtain a license from the For a pharmacy technician licensed less than 24 months the continuing Board of Pharmacy to work in a pharmacy. To maintain their license, education contact hours are calculated by multiplying 0.83 hours times technicians must complete 20 hours of continuing education every other the number of months between the date of initial licensure and the year, which will only be accepted from an Approved Provider. To be licensee’s next renewal date. eligible for license renewal, two hours of continuing education must be NOTE: Address changes and changes in employer for any licensed on the topic of pharmacy law. Proof of continuing education completion pharmacy employee must be reported to the Board of Pharmacy within should be retained for five years, and credits may not be carried over to 10 days. the next renewal period. Pharmacists administering immunizations In the state of Arizona, pharmacists who are certified to give in an emergency situation under the supervision of a licensed, certified immunizations may immunize adults as recommended by the adult pharmacist. immunization schedule or international travel recommendations issued Once graduate interns or pharmacists are certified to administer by the U.S. Centers for Disease Control. These immunizations may be immunizations, the certification must be maintained with the Board of issued without a prescription. Pharmacy and kept in the pharmacy for review by patients or the Board Certified pharmacists may immunize children aged 6-18 years with of Pharmacy if needed. Immunization certifications must be renewed flu immunizations or immunizations necessary during a public health every five years. To be eligible for renewal, a renewal application must emergency without a prescription order. Other immunizations may be be sent to the Board of Pharmacy including a current certificate in given with a prescription order from the patient’s prescriber. basic cardiopulmonary resuscitation and completion of 0.5 continuing Pharmacists must be trained and certified in immunization delivery education units (5 hours) on the administration of immunizations. before they are eligible to apply for a certificate to immunize patients. Immunizations given must have accurate records maintained at the The training program must include the following information: pharmacy. Each immunization given must have documentation that ●● Immunology and the immune response involved in immunization of includes: patients. ●● The patient’s name, address and birth date. ●● Names of available vaccines, dose, side effects, immunization ●● The date the immunization was given and the injection site. schedule, and how immunity occurs with each available vaccine. ●● The name of vaccine given as well as the dose, lot number, and ●● How to respond to emergencies that occur from the administration expiration date. of a vaccine, including how to administer epinephrine or ●● The name and address of the patient’s primary care physician. diphenhydramine to slow the effects of an allergic reaction to a ●● The name of the pharmacist or graduate intern who gave the vaccine. immunization. ●● How to administer intramuscular and subcutaneous injections. ●● A record of consultation with the patient that determined the patient ●● Proper record keeping requirements and reporting requirements for was eligible for vaccination. adverse effects and prescriber notification. ●● The date and time vaccination information was sent to the patient’s primary care provider. NOTE: The training program developed by the American Pharmacists ●● Consultation information given to the patient, including the title and Association (APhA) meets the requirements for immunization training date of the vaccine information sheet (VIS). programs in Arizona. ●● A copy of the parent consent form for vaccines given to minors. Pharmacists who have passed the immunization training program are Certain vaccines require a prescription for a pharmacist to immunize eligible for an immunization certificate from the Board of Pharmacy as an adult. These include the Japanese encephalitis vaccine, the rabies long as they have a current unrestricted pharmacist license in Arizona vaccine, yellow fever vaccines, and typhoid vaccines. After receiving and have a current certification in basic cardiopulmonary resuscitation a prescription order for these vaccines, a pharmacist is allowed to (CPR). Pharmacists must apply for their immunization certificate with immunize the patient. All other vaccines may be administered to an the Board of Pharmacy and receive board approval before administering adult patient without a prescription, according to the recommendations immunizations to patients in Arizona. published by the U.S. Centers for Disease Control. Graduate interns may administer vaccinations after completion of a Documentation of vaccinations given to patients must be sent to the certification course and certification by the Board of Pharmacy, but only patient’s primary care physician within 48 hours of immunization. under the supervision of a licensed, immunization-certified pharmacist. Records must be kept in a readily accessible place for at least seven Graduate interns may also administer epinephrine or diphenhydramine years for possible inspection by the Board of Pharmacy. Conclusion Arizona state pharmacy laws dictate the daily operations of pharmacies found on the Arizona Board of Pharmacy’s website at http://www. and pharmacy employees. It is important to stay up-to-date on new azpharmacy.gov/. A copy of the current Arizona state pharmacy law pharmacy laws that govern daily practice to serve patients within the book can be found at http://www.azpharmacy.gov/pdfs/law%20 limits of the law and obtain continuing education credits to maintain book%208-9-2012.pdf licensure. Information on new pharmacy laws in Arizona can be 2016 STATUTE CHANGES AND REVISIONS Some changes were enacted regarding the pharmacist’s ability to were part of A.R.S. 32-1970 (HB2355) and R4-23-407-.01. These dispense an opioid antagonist without a prescription. These changes initiatives are summarized below. R4-23-407.1. Dispensing an Opioid Antagonist The definition of “opioid antagonist” is defined as any drug approved by opioid antagonist and is used in instances of opioid-related overdoses the U.S. Food and Drug Administration that binds to opioid receptors – an acute condition in which the opioid overdose causes a decreased and which officially blocks or inhibits the receptor and prevents the level of consciousness, pinpoint pupils and respiratory depression. body from responding to the opioid. “Naloxone hydrochloride” is an Other symptoms include seizures, muscle spasms, coma and/or death.

Page 7 Pharmacy.EliteCME.com An opioid overdose requires medical assistance from any number of law enforcement personnel, fire department personnel, school district “community members” who are in a position to assist an individual employees and personnel of a facility or center that provides services to at risk of experiencing an opioid-related overdose. Community individuals at risk of experiencing an opioid-related overdose. members include emergency first responders, peace officers or other Written policies required Before allowing an opioid antagonist to be dispensed, a pharmacy ●● A review on the confidentiality, security and privileged nature or permit holder must have written policies and procedures regarding the documentation of opioid antagonists dispensed under A.R.S. 32- documentation of opioid antagonists including the quantity dispensed, 1970. directions for use and (if available) the patient’s name, address, Before dispensing an opioid antagonist, a licensed pharmacist must: telephone number and birth date. In lieu (or in addition to) of this ●● Complete an opioid prevention and treatment training program information, the name, address, telephone number and birth date of a that includes how to recognize the symptoms of an opioid-related family member in a position to assist the individual at risk of an opioid- overdose, how to respond to a suspected opioid-related overdose, related overdose, OR the name, address, telephone number and entity how to administer all preparations of an opioid antagonist and the at which employed of a community member in a position to assist the information needed by an individual to whom an opioid antagonist individual at risk of an opioid-related overdose, as well as the name of is dispensed. the individual providing the education as required under subsection (B) ●● Comply fully with the policies and procedures developed under (2). subsection B (which is detailed in the section above, “Written The education that is provided to the individual to whom the opioid Policies Required.” antagonist is dispensed must include: A pharmacist who has completed an opioid prevention and treatment ●● How to prevent an opioid-related overdose, as well as how to training program may administer an opioid antagonist to an individual recognize an opioid-related overdose; the pharmacist believes is experiencing an opioid-related overdose, and ●● How to safely administer an opioid antagonist safely to an is exempt from civil liability under the terms of A.R.S. 36-2267(B). individual experiencing an opioid-related overdose, as well as It is also noted that dispensing an opioid antagonist to a “community precautions regarding potential side effects and possible adverse member” (as defined above) is not wholesale distribution, as is defined events associated with administration of the opioid antagonist. in A.R.S. 32-1981. ●● A reiteration of the importance of seeking emergency medical assistance for the individual experience the opioid-related overdose, before or after administering the opioid antagonist; HB2355: Article 4: Opioid Antagonists: Prescribing and dispensing; immunity; good faith statement; definition As outlined in the above section R4-23-407.1, the revisions in the the person who is experiencing an opioid-related overdose; c.) to a following statutes pertain to naloxone hydrochloride and other opioid community organization that provides services to persons who are at antagonists that are approved by the United States Food and Drug risk for opioid-related overdoses; or d.) any other person who is in Administration. HB36-2266 states that a healthcare provider (Arizona- a position to assist a person at risk of experiencing an opioid-related licensed physician, nurse practitioner or any other health professional overdose. who has prescribing authority and who is acting within their scope Upon the dispensing of this opioid antagonist, the administering of practice) may, either directly or by a standing order, prescribe or health professional who either prescribes or dispenses it must instruct dispense naloxone hydrochloride or any other opioid antagonist for use the individual to whom the opioid antagonist is being dispensed to according to the protocol specified by the physician, nurse practitioner request emergency services as soon as is practical, either before or after or other health professional to either: a.) an individual who is at risk administering the opioid antagonist. of experiencing an opioid-related overdose; b.) a family member of Criminal prosecution and civil damages exemptions HB2355 notes that except in cases of gross negligence, willful or entity who is able to receive an opioid antagonist under the section misconduct or intentional wrongdoing, the healthcare provider who in of the applicable Arizona Statutes. The healthcare professional outlined good faith prescribed or dispensed an opioid antagonist will be immune in Section 32-1979 or 36-2266 of the Arizona Statutes is, in addition, from professional liability and criminal prosecution for any decision not liable for any civil or other damages as the result of any act or made, act, omission or injury that resulted from the act if the healthcare omission by the person rendering the care or as the result of any act professional acted with reasonable care and in good faith. This update or failure to act to arrange further medical treatment or care for the also allows for the requirement by the healthcare professional of the person experiencing the overdose, unless the person while rendering provision of a factual basis for a reasonable conclusion that the person the care acts with gross negligence, willful misconduct or intentional or entity meets the description in subsection A, and is that of a person wrongdoing. 2015 Legislative review Following is a summary of 2015 legislative changes that affect 2. License renewals for medical practitioners who hold active regulatory agencies. Unless otherwise noted, all new legislation takes licenses in Arizona. effect on July 3, 2015. The purpose of the statute is to facilitate the Board of Pharmacy ●● Senate Bill 1370: This bill adds a new statute to Title 32 (§32¬3219) with registering and providing access to the Controlled Substance and applies to “medical practitioner” regulatory boards. Beginning Prescription Monitoring Program (CSPMP). The medical practitioner December 31, 2015, these boards are required to submit information regulatory board will be required to provide the Board of Pharmacy to the Arizona State Board of Pharmacy notifying the Board of with “any information necessary” to facilitate the database registration Pharmacy of: and access. Once the Board of Pharmacy receives the necessary 1. New licensees who intend to apply for a DEA permit. information, it can then register medical practitioners who hold DEA permits with the CSPMP and provide them access to the database.

Pharmacy.EliteCME.com Page 8 Additionally, a medical practitioner regulatory board is required to ●● HB 2086: This bill adds A.R.S. §32-1978, which makes it a crime notify new licensees who intend to apply for a DEA permit of their to sell to a minor (or for a minor to purchase) dextromethorphan responsibility to register with and be granted access to the CSPMP (Delsym®) without a prescription. database. References Arizona State Board of Pharmacy. (July, 2015) Rules and statutes. Retrieved July, 2015 from Arizona state-board-of-pharmacy administered or pharmacy or graduate intern-administered immunizations. State Board of 4. Berman, Suzi. RPh (April 2012). Director of Pharmacy for Arizona State Board of Accessed July 23, 2015 https://pharmacy.az.gov/ resources/license-permit-registration/immunization- Pharmacy tamper resistant prescription Pharmacy website https://pharmacy.az.gov/resources/rules- registration statutes pads memo. Accessed at https://pharmacy.az.gov/blog-terms/faqs on July 24, 2015. Arizona State Board of Pharmacy. (July, 2016). Arizona Revised Statutes and Arizona Administrative Arizona State Board of Pharmacy. (July 2015). New fingerprint requirement. Accessed July 27, 2015 Codes. Retrieved January 23, 2017. https://pharmacy.az.gov/ 5. Arizona State Board of Pharmacy. (July, 2015). 2015 legislative changes in Arizona Department of Public Safety. (2016). Fingerprint Clearance Cards. Retrieved January 23, pharmacy. Volume 36, No.1 Newsletter. Accessed 2017 from http://www.azdps.gov/services/fingerprint/ Arizona State Board of Pharmacy. (July, 2015). Immunization rule, Arizona Administrative Code, R4-23-411, pharmacists-on July 28, 2015 http://www.nabp.net/publications/newsletters/arizona- OVERVIEW OF ARIZONA PHARMACY LAW Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. The Arizona State Board of Pharmacy consists of how many 7. A(n) ______, containing the prescribing members? medical practitioner’s electronic or digital signature, is acceptable a. 9. but must be promptly transcribed in writing and filed by the b. 6. pharmacist. c. 12. a. Electronically transmitted prescription order. d. None of the above. b. Fax. 2. How long must all prescriptions filled in Arizona have a paper c. Pill bottle. version that must be filed and kept in a readily-retrievable location? d. Hand-written note. a. Three years. 8. Arizona state regulations on pseudoephedrine sales are ______b. Five years. than federal laws. c. Seven years. a. More restrictive. d. Ten years. b. The same. 3. No more than how many dosage units of any controlled substances c. Less restrictive. containing opium may be prescribed to the same person within 48 d. More limiting. hours? 9. Which of the following statements regarding federal regulations for a. 24 dosage units. the sale of pseudoephedrine are NOT true: b. 48 dosage units. a. The sale must be entered into a logbook that is electronic or on c. 36 dosage units. paper. d. 12 dosage units. b. A state-issued photo identification card, driver’s license, or 4. The difference between a trainee and a technician is what? passport must be presented at the time of purchase. a. The pharmacy technician has completed both a training program c. The maximum purchase of pseudoephedrine that may be and passed the PTCB exam with a passing score. purchased by a single person within a 30-day period is no more b. An associate’s degree. than 20 grams. c. Additional training in compounding. d. All products containing pseudoephedrine must be kept behind d. None of the above. the counter, or in a locked cabinet, and can only be sold under the supervision of a licensed pharmacist. 5. Who must keep a record of the progress of the trainee and sign off on a document when a technician has completed the training 10. Pharmacies that are NOT located in Arizona, but who still deliver program successfully? mediations to patients in Arizona, ______registered with the a. The Arizona Board of Pharmacy. state Board of Pharmacy in Arizona. b. The technician’s supervisor. a. Do not need to be. c. The pharmacist-in-charge. b. Must be. d. The general manager. c. Sometimes need to be. d. Never need to be. 6. Pharmacies in Arizona must have a dispensing, compounding, and drug stocking area that is at least ______feet. a. 60. b. 500. c. 300. d. 100.

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Page 9 Pharmacy.EliteCME.com Chapter 2: Best Practices for Prescribing Opioids in Chronic Non-Cancer Pain 3 Contact Hours

By: Katie Blair, PharmD, RPh Author Disclosure: Katie Ingersoll and Elite do not have any actual or Questions regarding statements of credit and other customer service potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $12.00. Universal Activity Number (UAN): 0761-9999-18-003-H01-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: January 11, 2018 a provider of continuing pharmaceutical education. This Expiration Date: January 11, 2020 program is approved for 3 hours (0.3 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70% is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a statement of credit. Please submit your answers online at participants who have successfully completed the post-test. Participants Pharmacy.EliteCME.com must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives After reading this monograph, pharmacists should be able to: Explain the side effects associated with opiate treatment, including Describe how to assess patients for the appropriateness of treatment management of side effects. with opioid analgesics. Discuss switching between opiates and variables that may influence Explain how to start opiate therapy, change dosages, and opioid rotation. discontinue treatment with opioid analgesics. Describe the important points that must be conveyed to the patient Recognize the types of written agreements that can be used to during patient consultation. initiate and monitor therapy with opioid analgesics. Explain general and product-specific information related to the Describe how to monitor patients on opiate therapy, including high- prescribing of extended-release/long-acting opiates. risk patients and those showing signs of abuse. Introduction Opioid analgesics are widely used for the treatment of severe acute pain education related to extended-release (ER) and long-acting (LA) opioid and chronic pain related to active cancer or at the end of life [1]. The analgesics [9]. The previous year, the White House Office of National widespread use of opioids for other types of moderate-to-severe chronic Drug Control Policy, in collaboration with other branches of the pain, however, has been evolving in the past two decades and continues federal government, introduced the “Action Plan to Address National to generate controversy. Prior to the 1990s, clinicians often viewed Prescription Drug Abuse Epidemic” [10]. These initiatives, echoing opioid pain medications with skepticism and avoided prescribing them, statements in recent clinical guidelines, seek to balance a crack-down on even when risks were thought to be low [2]. This perspective gave way nonmedical use of opioids while simultaneously protecting the delivery to the recognition that many patients were being under-treated for their of effective pain management to legitimate patients [5]. pain, leading to increased interest in the clinical value of opioids and a This CME monograph on best practices for prescribing opioids for dramatic rise in rates of opioid prescribing for analgesia. Prescriptions for chronic non-cancer pain is in step with these important efforts, covering opioids have nearly quadrupled from 1999 to 2014, but there has not been the educational themes put in place by the FDA and the federal plan to a change in the amount of pain Americans report [3]. Opioids were the combat prescription drug misuse. It will emphasize the importance of most commonly prescribed class of drugs in the United States in 2016 [4]. appropriate prescribing of opiates, as well as using patient education Unfortunately, escalating opioid prescribing rates have been mirrored to promote the safe use of long-acting opiates. This program offers by similar escalations in drug diversion and nonmedical uses of pharmacists a solid foundation for responsible and vigilant opioid use. opioids. The opioid medications associated with these problems include Definitions immediate- and extended-release products, as well as methadone. Many The International Association for the Study of Pain defines chronic people directly affected by the crisis have been previously healthy and pain as ‘‘pain that persists beyond normal tissue healing time, which is have had no history of substance misuse [17]. The scope of the problem assumed to be three months’’ [11] Numerous diseases and syndromes can be seen in these statistics: can result in chronic pain. For the purposes of this monograph, all ●● In 2014, the latest year for which data are available, an estimated chronic pain disorders outside of cancer pain or pain at end of life are 15 million Americans were abusing prescription drugs—more than collectively labeled ‘‘chronic non-cancer pain’’ (CNCP). the number abusing cocaine, heroin, hallucinogens, and inhalants, combined [5]. Many treatment modalities exist for CNCP—opioid pain medications ●● Emergency-room visits related to non-medical use of opioids rose are only one of many tools in the pain management armamentarium. 117% between 2005 and 2011 [6]. Not all patients are appropriate candidates for opioid medications, ●● Approximately 4.3 million Americals used prescription pain killers either because of the nature of their condition, the existence of relevant for non-medical purposes in one month in 2014 [7]. comorbid conditions, or their assessed risk for opioid abuse. Opioid ●● Opioids killed over 33,000 people in 2015, more than any year on therapy may be a useful component of a pain management plan, but in record with the Centers for Disease Control and Prevention [8]. selecting patients for an opioid trial, clinicians must weigh the potential benefits of opioids against the risk of significant harm, including a wide This rising tide of abuse, addiction, overdose, and death has led to range of adverse effects and outcomes associated with abuse potential. calls for tighter regulation of opioid pain medications and for greater prudence in prescribing on the part of clinicians. In July 2012, the U.S. Food and Drug Administration (FDA) released its final Risk Evaluation and Mitigation Strategies (REMS) content guidelines for prescriber

Pharmacy.EliteCME.com Page 10 The challenge of pharmacovigilance In their daily practice, clinicians who treat patients with chronic non- pain and function are anticipated to outweigh potential risks. If cancer pain face must balance pain relief with the risks associated with opiates are used, they should be combined with nonpharmacologic opioid analgesics. The term “pharmacovigilance” refers to the range of and non-opioid therapies. procedures and processes used to achieve this balance. Such procedures ●● Before starting opioid therapy for chronic pain, establish realistic need not be burdensome and are not unlike the kinds of balancing acts goals for pain and function, and consider how opioid therapy will be required in the prescription of a great many other therapeutic agents. discontinued if benefits do not outweigh risks. What makes opioids of particular concern is that, not only are they ●● When starting opioid therapy for chronic pain, prescribe immediate- potentially dangerous for patients, they are also highly sought after by release opioids instead of extended-release/long-acting (ER/LA) recreational drug users and criminals. opioids. In their efforts to find the appropriate, effective middle ground between ●● When using opioids for acute pain, clinicians should prescribe the relieving pain and preventing diversion and misuse of prescription lowest effective dose of immediate-release opioids and prescribe no opioids, clinicians must bear in mind that the problem of unrelieved more than what is needed for the expected duration of pain severe pain remains as urgent as ever. In a 2011 study, chronic pain was enough to require opioids. estimated to affect approximately 100 million Americans and to cost ●● Clinicians should evaluate benefits and harms with patients within roughly $635 billion annually in treatment and lost productivity [12]. 1 to 4 weeks of starting opioid therapy for chronic pain or of dose In fact, the incidence of chronic pain in the United States is greater than escalation, and every 3 months or more frequently. If benefits do not that of diabetes, heart disease, and cancer combined [13] [14]. outweigh risks, optimize other therapies and taper opioids to lower dosages or discontinue opioids. At the same time, opioids are subject to abuse and also have a wide ●● Periodically request the patient’s report on the prescription drug range of potential adverse effects that can predispose a patient to monitoring program (PDMP) to determine whether the patient serious morbidity and mortality. Risk is increased among older adults; is receiving prescriptions from other prescribers or dangerous those with impaired renal or hepatic function; individuals with obesity, combinations that put them at high risk for overdose. cardiopulmonary disorders, sleep apnea, or mental illness; and in ●● When prescribing opioids for chronic pain, clinicians should use patients who combine opioids with other respiratory depressants such as urine drug testing before starting opioid therapy and consider urine alcohol, sedative-hypnotics, benzodiazepines, or barbiturates. drug testing at least annually to assess for prescribed medications as In 2016, the Centers for Disease Control and Prevention (CDC) issued well as other controlled prescription drugs and illicit drugs. recommendations aimed at helping clinicians find a balance between The rest of this monograph details how to implement these general responsible opioid prescribing and minimizing the risks of abuse, guidelines in ways that are consistent with the time and budgetary addiction, and drug diversion [1]. The recommendations include: constraints often found in modern practice settings. ●● Nonpharmacologic and non-opioid treatments are preferred for chronic pain. Use opioid medications only if expected benefits to Case study: Initial presentation Matt Davidson, 69, is a retired high school physical education teacher. A full evaluation of the patient’s pain leads to a dual diagnosis of He has come to his primary care physician for his annual physical. He osteoarthritis and peripheral neuropathy secondary to chemotherapy. has a history of hypertension, osteoarthritis, and prostate cancer, for As part of the evaluation, the patient is asked how his pain is affecting which he was treated 2 years ago with a combination of external beam his life and whether it is preventing him from engaging in any activities. radiation and chemotherapy. His prostate-specific antigen (PSA) level He reports disturbed sleep, which he says makes him more irritable is now near zero and he has no signs of disease, although he continues during the day. He also says he no longer plays tennis, walking has to be troubled by mild urinary incontinence and erectile dysfunction. On begun to hurt, and it is becoming difficult to use the computer keyboard. this visit, Mr. Davidson complains of joint pain, as well as a burning, This information is used to create a treatment plan with the functional tingling pain in his hands and feet and asks if anything can be done for goals of reducing nighttime awakenings to no more than one per night; it. He says he has been taking between 800 and 1200 mg ibuprofen daily walking daily at least 1 mile without pain; and using the computer for the pain, which he rates as 7 to 8 on a 10-point scale, but has also without pain. A return to tennis is a possible goal if less strenuous been having heartburn as a result. He mentions his friend with similar goals are achieved first. Gabapentin is prescribed, and a follow up pain takes oxycodone, and says it works wonderfully for him. appointment is made in two weeks. Assessing patients for opioid therapy Determining if an opioid medication is appropriate for a patient with psychosocial history; family history; physical examination; and chronic non-cancer pain involves assessing both the condition itself examination of imaging and other diagnostic studies or tests. As when and the patient’s potential for misuse or abuse of the medications. The assessing any patient, clinicians should take the time to look beyond FDA has recommended that providers contemplating prescribing an the specific complaint or body part/system and evaluate holistically the opioid pain medication complete a “comprehensive history and physical broader mental, cultural, and socioeconomic contexts within which the examination, including assessment of psychosocial factors and family chief complaint is embedded [17]. history of substance misuse, as well as special considerations for the History and physical exam elderly, women, children, and cultural/ethnic groups” [15] Regulators Physical exams conducted as part of an assessment of pain should expect to see at least a basic physical examination as part of the include an evaluation of the patient’s nervous system, with focus on evaluation that leads to treatment with controlled substances [16]. The sensory function. Clinicians should assess for allodynia (pain from exact components of the examination, however, are left to the medical stimulation that would not normally evoke pain, such as light touch), judgment of the clinician, who is expected to have performed an hyperalgesia (amplified pain response to stimulation that would examination proportionate to the diagnosis that justifies a treatment. normally evoke only mild pain), or pain insensitivity. A sensory Any basic pain assessment includes the familiar elements of: chief examination could include response to light touch, light pressure, complaint; history of present illness; past medical, surgical, and pinprick, cold, or vibration [17]. Figure 1: Numeric Pain Scale 0 1 2 3 4 5 6 7 8 9 10 No pain Moderate Pain Worst pain possible

Page 11 Pharmacy.EliteCME.com It is important for clinicians to avoid the mistake of assuming that if Evaluating patients for risk of opioid dependence or abuse an organic pathology cannot be found, the patient’s pain is “all in their Whenever a clinician considers treating pain with a controlled head.” As Goodwin and Bajwa (2004) note, “Pain is what the patient substance, risk of misuse or diversion is always a possibility, no matter says it is” [18]. Psychological factors may be important in a patient’s how remote, and must be assessed. To date, no convincing data exist experience of pain, and the importance of such factors should be taken to support the strategy of focusing on any one specific population or seriously and incorporated into the overall treatment plan [19]. setting—which means that prescribers must be vigilant with all patients A comprehensive evaluation of a patient in pain usually requires moving [17]. The concept of “universal precautions” has been applied to this beyond the typical list of questions asked during a general history. It may approach, which means that any patient in pain could have a drug be possible to gather this information before an in-person visit by using misuse problem—just as any patient requiring a blood draw for a simple paper or online questionnaires. In most cases where pain is the chief lab test could have HIV. Treating everyone with the same screens, complaint, it is appropriate to begin by asking about the pain, and then to diagnostic tests, and administrative procedures can help remove bias review the broader context and impact of that pain [17]. Here are some and level the playing field so everyone is treated equally and screened points that may be useful to cover in an initial evaluation [17] [18]: thoroughly. ●● Location of pain. Nonetheless, it is also true that some patient characteristics are ●● Character of pain (i.e., shooting or stinging, continuous or predictive of a potential for drug abuse, misuse, or other aberrant intermittent, worse at night or in the morning). behaviors. The most predictive factor is a personal or family history of ●● Lowest and highest pain on a 10-point scale in a typical day. alcohol or drug abuse [5]. Some studies have also shown that younger ●● Usual pain on a 10-point scale on a typical day (augmented by age and the presence of psychiatric conditions are also associated with verbal descriptors). aberrant drug-related behaviors [5]. ●● How and when pain started. In evaluating patients with chronic pain for risk of addiction or signs ●● Exacerbating and relieving factors (i.e., stress, alcohol, other that they may be abusing a controlled substance, it may be helpful to medical concerns). consider the sets of characteristics listed in Table 1. ●● Effect of pain on sleep. ●● Effect of pain on mood. Table 1: Characteristics of Chronic-Pain ●● Effect of pain on functioning at work. Patients vs. Addicted Patients ●● Effect of pain on quality of personal life, such as relationships, sex, Chronic-pain patient Addicted patient or recreation. ●● Is the patient involved in a legal or protracted insurance process Medication use is not out of Medication use is out of control. connected to his or her chronic pain, such as a motor vehicle control. accident or a disability case? Medication use improves quality Medication use impairs quality ●● What activities could the patient do before pain impacted his or her of life. of life. life that he or she cannot do now? ●● What does the patient expect from medications or other treatments Wants to decrease medication if Medication use continues or in terms of analgesia or recovered function? adverse effects develop. increases despite adverse effects. ●● Review of past experience/exposure to opioids. Is concerned about the physical Unaware of or in denial about any ●● Review of past medical/surgical history. problem being treated with the problems that develop as a result ●● Review of family medical history, especially family history of drug. of drug treatment. substance abuse or psychiatric disorders. ●● Assessment of patient history of drug, alcohol, and tobacco use. Follows the practitioner-patient Does not follow opioid ●● Psychosocial evaluation (including history of mental illness). agreement for use of the opioid. agreement. During an initial evaluation, clinicians should be alert for signs that a May have leftover medication. Does not have leftover patient is minimizing his or her pain. This may result from a variety of medication. psychological or emotional factors. For example, some patients may Loses prescriptions. worry that they will be labeled a complainer if they mention pain, or that their health care provider will suspect they are addicted if they ask Always has a story about why about opioid pain medications. Other patients may underreport pain more drug is needed. because they fear pain medications will dull their cognitive abilities, Adapted from: Webster LR, Dove B. Avoiding Opioid Abuse While lead to addiction, or produce undesirable side effects. Clinicians should Managing Pain. Sunrise River Press, North Branch, MN. 2007. be empathic, supportive and honest, neither promising too much nor Many tools have been developed for the formal assessment of a removing all hope, when evaluating a patient in chronic pain [18]. patient’s risk of having a substance misuse problem, some of which are Psychosocial evaluation appropriate for routine clinical use because they are relatively brief and Pain affects every aspect of a patient’s life. Therefore, it is vital to easily implemented. Table 2 lists some tools for patient risk assessment, evaluate how pain impacts, or may be affected by, psychosocial although to date, no single tool has been widely endorsed or thoroughly elements of a patient’s life [5]. Clinicians must be alert for signs validated [5]. of depression or anxiety, which are very common. They must also Regardless of the tool used, it is important for health care professionals be particularly alert for suicidal thoughts since the risk of suicide to thoroughly assess a patient’s risk of abuse of controlled substances. is roughly double for patients with chronic pain [ ]. Some freely Patients who are determined to be at a high risk of opiate abuse should accessible instruments for gathering a psychiatric history are available be referred to a pain management specialist to ensure thorough follow- [see, for example, the Depression Anxiety & Positive Outlook Scale up and monitoring of the patient’s pain status and opiate use. (www.dapos.org) or the Patient Health Questionnaire (PHQ Screeners [www.phqscreeners.com]). Referral to a mental-health professional is warranted if the clinician’s judgment suggests the patient has active psychological issues beyond the clinician’s expertise. Clinicians should also probe for ways in which pain may be affecting the patient’s family, work, or social activities. Pain can seriously erode these spheres of life and evaluating these challenges and addressing them during treatment (for instance by referral to a vocational counselor or social worker) is just as important as treating the more immediate medical issues that may be contributing to chronic pain.

Pharmacy.EliteCME.com Page 12 Table 2: Tools for Patient Risk Assessment Tool Use Who administers? Length Access Current Opioid Misuse Measure Monitor for misuse by patients Patient self-report. 17 items. www.inflexxion.com/COMM/ (COMM) currently on long-term opioid therapy. Diagnosis, Intractability, Risk, Screen for risk of opioid addiction. Clinician. 7 items. Belgrade MJ, et al. J Pain. Efficacy (DIRE) 2006;7:671-81. Opioid Risk Tool (ORT) Screen for risk of opioid addiction. Clinician or patient 5 yes/no www.opioidrisk.com/node/887 self-report. questions. Screener and Opioid Assessment Screen for risk of opioid addiction. Patient self-report. 24 items. www.inflexxion.com/SOAPP/ for Patients with Pain, Version 1 and Revised (SOAPP, and SOAPP-R) Written agreements Written documentation of all aspects of a patient’s care, including opioid therapy [5]. Recently, the U.S. Department of Veterans Affairs assessments, informed consent, treatment plans, and provider/patient and the U.S. Department of Defense chartered an expert panel to agreements, are a vital part of opioid prescription best practices. Such undertake a systematic review of existing medical literature on this documentation provides a transparent and enduring record of a clinician’s subject. In the clinical practice guidelines resulting from that work, rationale for a particular treatment and provides a basis for ongoing the panel concluded that opioid treatment agreements are a standard monitoring and, if needed, modifications of a treatment plan [17]. of care when prescribing long-term opioid therapy [22]. [Samples of Many computerized systems are now available for the acquisition, several commonly used agreements, including a low-literacy version, storage, integration, and presentation of medical information. Most are available at: arkham.bsd.uchicago.edu/GmedIntranet/documents/ offer advantages that will benefit both patients and prescribers, such Op911-OpioidRxAgreements.doc]. as maintaining up-to-date records, and providing instant availability of Provider/patient agreements have many potential advantages, including information relevant to prescribing or treatment. Although automation [17]: can help, clear documentation is not dependent on electronic record- ●● Allowing treatment to start on a note of mutual respect and keeping; it merely requires a commitment to creating clear and enduring partnership. communication in a systematic fashion. Good documentation can be ●● Enhancing transparency. achieved with the most elaborate electronic medical record systems, ●● Engaging patients in a collaborative education and decision-making with paper and pen, or with dictated notes. Clinicians must decide for process. themselves how thoroughly, and how frequently, their documentation of ●● Helping to set functional goals and clarify the clinician’s and a patient’s treatment should be. patient’s roles and responsibilities to attain these goals. Informed consent ●● Documenting acceptance of treatment risks and benefits. Informed consent is a fundamental part of planning for any treatment, ●● Documenting informed consent. but it is critically important in long-term opioid therapy, given the ●● Helping avoid misunderstandings that may occur over long potential risks of such therapy. At its best, consent also fortifies the treatment time periods. clinician/patient relationship. ●● Providing a foundation for subsequent decisions about changes in medications or termination of treatment. Prescribers must be able to answer with confidence four key questions when obtaining informed consent in the context of treatment with Clinicians should strive to craft agreements that serve their patients’ opioids [21]: best interests and avoid coercive or punitive language. Thus, agreements 1. Does the patient understand the various options for treatment? should avoid [17]: 2. Has the patient been reasonably informed of the potential benefits ●● Putting all burden on the patient rather than sharing it between and risks associated with each of those options? patient and clinician. 3. Is the patient free to choose among those options, free from ●● Framing the agreement in terms of punishments for possible future coercion by the health care professional, family, or others? crimes or difficulties. 4. Does the patient have the capacity to communicate his or her ●● Using language that is stigmatizing, dominating, or pejorative. preferences—verbally or in other ways (e.g., if the patient is deaf or ●● Using coercion in any way. mute)? ●● Imposing limitations for the clinician’s convenience without clear and substantial benefit for the patient. Documentation related to these key areas can be accomplished by ●● Insisting on behaviors unrelated to actual use of medications. creating a separate paper or electronic informed consent form or by ●● Using the term “fired” to describe termination of treatment. incorporating informed consent language into a larger treatment plan or ●● Threatening abandonment or suggesting that patients will not have patient/provider agreement. continued access to non-opioid pain relieving treatments if opioids Patient-provider agreements are terminated. A written agreement between a clinician and a patient about the To be effective, written agreements must be clearly understood by specifics of their pain treatment with opioids can help clarify the plan the patient. This may require the provision of agreements in multiple with the patient, the patient’s family, and other clinicians who may languages and translators may be needed for speakers of other languages become involved in the patient’s care [5]. Such agreements can also to ensure understanding and effective informed consent. All agreements reinforce expectations about the appropriate and safe use of opioids should be written at the sixth- to seventh-grade level or even lower [23] [5]. Caution must be exercised, however, to ensure that patient/provider [24]. A patient who does not fully understand the potential risks and agreements are not used in a coercive way to unethically place patients benefits of a treatment cannot be truly “informed” as required by the legal in the position of having to agree to its terms or else lose an important and ethical guidelines for medical practice. Time must be allowed for component of their treatment (or even lose all treatment) [22]. patients to ask questions, and for prescribers to ensure patients understand Although evidence is lacking about the most effective methods to what they are being told. Some, or all, of these tasks may be handled by convey the information included in most patient-provider agreements, trained personnel (or staff members) rather than clinicians. such agreements have been widely used and are recommended by Although the term “agreement” is generally perceived as being more regulators and many experts on treatment guidelines for long-term patient-friendly than the word “contract,” clinicians should understand

Page 13 Pharmacy.EliteCME.com that, from a legal standpoint, any written or oral agreement between the patient, and are acceptable, attainable, and consistent with high- a prescriber and a patient may be considered a binding contract [25]. quality practice [26]. Clinicians should ensure the terms in any agreement are understood by Creating function-based opioid treatment plans Once a patient has been assessed and accepted as a candidate for Increased social activities. Report by family member or treatment with an opioid pain medication, and after informed consent friend. has been obtained for such treatment, a written plan for implementing the treatment should be drafted. Such plans typically include a statement Resumed sexual relations. Report by partner. of the goals of therapy. These goals should be written carefully in light Returned to work. Pay stubs from employer or of the inherent subjectivity of pain. Since pain itself cannot be measured letter confirming the patient is objectively, framing treatment goals solely in terms of pain relief means off of disability leave. that such goals cannot be objectively confirmed. Daily exercise. Gym attendance records or report Although a patient’s subjective pain and suffering are obviously important from family member or friend. factors, only the functional impact of the pain can be measured and used to create objective treatment goals. This impact takes many forms, but *Involving other persons requires explicit permission from the typically, chronic pain erodes foundations of daily life, such as physical patient, and this permission should be documented, preferably in activity, concentration, emotional stability, interpersonal relationships, writing. and sleep. This can, in turn, degrade functioning at work or in the home, Source: Fishman SM. Responsible Opioid Prescribing: A Clinician’s which can lead to depression, anxiety, insomnia, and even suicide. Guide, 2nd ed. Waterford Life Sciences. 2012 (in press). Clinicians should know that even relatively modest reductions in pain can Table 3 illustrates some simple functional goals and ways they might be translate into significant functional improvements as pain rating declines verified. [ ]. A 20% reduction in a pain score (i.e., roughly two points on the standard 10-point pain scale) may be acceptable if it produces significant The responsibility for obtaining evidence of success in meeting a functional benefits for a patient. functional goal lies with the patient and should be made explicit in the prescribing agreement. If a patient is unable to document or achieve the Framing treatment goals in terms of improved patient functioning, rather progress outlined in a treatment plan, this may suggest a need for goal than merely pain relief, offers two primary advantages to clinicians: readjustment. ●● Prescribing decisions (or decisions to terminate treatment) are based on outcomes that can be objectively demonstrated to both clinician Components of an effective treatment plan and patient (and, possibly, to the patient’s family). The creation of an effective function-based treatment plan must be a ●● Individual differences in pain tolerance become secondary to collaboration between patient and clinician. A patient’s pain score will be the setting and monitoring of treatment goals, since subjectively just one of many variables to be considered in framing goals. These goals perceived levels of pain are not the primary focus in determining should be realistic, meaningful to the patient, and verifiable. The details functionality. of a function-based treatment plan are necessarily specific to the patient, but one way to initiate the process is to begin with the question: “What do Basing treatment plans on functional goals is especially valuable when you hope to do as a result of treatment that you cannot do now?” prescribing opioid pain medications because such goals may help differentiate a patient who is opioid-addicted from one who merely The treatment plan can include a discussion of, and the setting of seems to be addicted. This differentiation is possible because addiction expectations about, periodic reassessment of goals. Patients may often leads to decreased functioning, while effective pain relief typically stabilize at a certain level, and the clinician and patient together must improves functioning. decide if this is acceptable or whether changes are needed. Functional decline itself may result from a range of problems, including As is the case in drafting other types of patient/provider documents, inadequate pain relief, non-adherence to a regimen, function-limiting patients should be reminded of the benefits and risks of a chosen side effects, or untreated affective disorders. Sometimes impaired therapy. With opioids, these include the realities of tolerance and functioning is the result of addiction or misuse, and these objective physical dependence and the potential need to taper the medication results may shed valuable light on an otherwise confusing presentation slowly to avoid withdrawal. Patients must also be educated about the of a patient’s pain symptoms. possibility that opioids may be either ineffective or have intolerable adverse effects, and that there is also the possibility of psychological Functional treatment goals should be realistic. Progress in restoring dependence, which could lead to misuse or, less commonly, addiction. function is usually slow and gains are typically incremental. Chronic non-cancer pain is often marked by long-standing physical and Another critical component of any treatment plan is a description of psychological deconditioning, and recovery may require reconditioning how treatment with an opioid medication might be terminated. Stopping that may take weeks, months, or years. It is much better to set goals opioid therapy in cases of chronic non-cancer pain is often more difficult that are slightly too low than slightly too high. Raising goals after a than starting it, and doses should always be tapered slowly, not abruptly patient has “succeeded” in achieving them is far more motivational and discontinued. Being clear about the conditions under which opioid encouraging than lowering goals after a patient has “failed.” therapy will end is important because opioids are not curative, have no standard duration of treatment, and may be associated with substantial Table 3: Evidence for Functional Goals risks [17]. Functional goal Evidence Termination may be required for many reasons, including: ●● Healing or resolution of a specific pathology underlying the pain. Begin physical therapy. Letter from physical therapist. ●● The experience of intolerable side effects. Sleeping in bed as opposed to Report by family member or ●● Lack of adequate response to a medication in terms of either pain lounge chair. friend (either in person or in relief or functional improvement. writing).* ●● Evidence of non-medical or inappropriate use of the medication(s). Participation in pain-support Letter from group leader. If inappropriate use of a prescription medication is discovered, group. treatment must usually be suspended, although provisions should be Increased activities of daily Report by family member or in place for continuation of some kind of pain treatment or referral to living. friend. other professionals or members of a pain management team. Some clinicians may be willing and able to continue a regimen of opioid Walk around the block. Pedometer recordings or written therapy even after the discovery of aberrant behavior if done with log of activity. intensified monitoring, patient counseling, and careful documentation

Pharmacy.EliteCME.com Page 14 of all directives. This level of vigilance and risk management, however, such cases, referral to a provider with specialized skill or experience in may exceed the abilities and resources of the average prescriber. In dealing with high-risk patients may be prudent. Case study: Treatment hits a roadblock Mr. Davidson returns for a follow-up after 2 weeks. He reports that his Further studies are needed to confirm more consistent control of arthritis pain has not improved, but that the burning/tingling pain in pain and improved adherence to prescribed therapy with use of ER/ his hands and fee has improved somewhat. He has not achieved any of LA opioids [5]. Although low-dose, short-acting opioids may offer his functional goals. Upon questioning, he reveals that he has been in the greatest safety for initiating opioid therapy, clinicians must significant pain over the past two weeks and he is afraid to work on the recognize that short-acting opioids are not intrinsically safer than tasks needed to achieve his goals due to the potential for pain. After a other formulations, and stress to their patients the importance of strict long and thoughtful discussion, a short acting oxycodone is prescribed adherence to prescribed doses/administration [5]. for use prior to walking or exercising. Considerations in opioid selection Initiating treatment with opioids Opioids, as a class, comprise many specific agents available in a wide Prior to an initial prescription of an opioid pain medication, clinicians range of formulations. A given patient might be appropriate for ER/LA should be certain that: 1) all other potentially effective treatments that therapy only, short-acting only, or a combination of an ER/LA opioid offer a more optimal benefit-to-risk profile have been considered or tried, with a short-acting opioid for breakthrough pain. 2) a complete evaluation has been performed and fully documented, 3) the Short-acting, orally administered opioids typically have rapid onset patient’s level of opioid tolerance has been determined, and 4) informed of action (10 to 60 min) and relatively short duration of action (2 consent and agreement to treat have been obtained [17]. At the outset, to 4 hours) [30]. They are used for acute or intermittent pain, or both the clinician and the patient should view a new opioid prescription breakthrough pain that occurs against a background of a persistent level as a short-term trial of therapy [5]. The goal of the trial is to provide data of pain [31]. Transmucosal immediate-release fentanyl is a special class to guide decisions on the continued appropriateness of opioid medications of short-acting opioid that is only approved for breakthrough pain in and on the specific dose and formulation of medication used. Such a trial cancer, and there is a separate FDA REMS devoted to this topic [31]. might be as brief as a few days or as long as several months. Combination products join an opioid with a non-opioid analgesic, Opioid selection, initial dosing, and titration must be individualized to usually for use in patients with moderate pain. Using a combination the patient’s health status, previous exposure to opioids, and treatment product when dose escalation is required risks increasing adverse effects plan [5]. Although still not widely used, it is also becoming increasingly from the non-opioid co-analgesic, even if an increase of the opioid possible to use commercially available genetic screening tools to assess dose is appropriate [17]. In such cases, using a pure opioid may be for genetic variations in drug metabolism that could affect the way a preferable. patient responds to opioids [27]. Caution should be exercised when using opioids in patients with conditions that may be complicated by Single-agent formulations are available for several types of adverse effects from opioids, including chronic obstructive pulmonary opioids, such as codeine, morphine, oxycodone, oxymorphone, and disease (COPD), congestive heart failure, sleep apnea, current or past hydromorphone. The FDA released new rules in 2014 that limit the alcohol or substance misuse, mental illness, advanced age, or patients amount of acetaminophen allowed in opioid combination products to with a history of renal or hepatic dysfunction [28]. In addition, opioids 325 mg in an attempt to limit liver damage and other ill effects from the should not be combined with other respiratory depressants, such as use of these products with over-the-counter (OTC) analgesics. Therefore sedative-hypnotics (benzodiazepines or barbiturates) unless there is a all combination products have a maximum of 325mg of acetaminophen specific medical or psychiatric indication for such a combination [30]. in each tablet [32]. In such cases, much more intensive monitoring is required. ER/LA opioids usually have a relatively slow onset of action (typically A decision to continue opioid therapy after an appropriate trial should between 30 and 90 min) and a relatively long duration of action (4 to be based on careful review of the trial outcomes. Outcomes to consider 72 hrs) and are typically used for patients with constant background include [17]: pain [31]. These agents achieve their extended activity in various ways. ●● Progress toward meeting therapeutic goals. Methadone and levorphanol have intrinsic pharmacokinetic properties ●● Changes in functional status. that make their effects more enduring than many short-acting opioids ●● Presence and nature of opioid-related adverse effects. [33]. ER/LA agents such as controlled-release morphine, oxycodone, or ●● Changes in the underlying pain condition. transdermal fentanyl achieve their prolonged time course via a delivery ●● Changes in medical or psychiatric comorbidities. system that is modified to slow absorption or to slow the release of ●● Degree of opioid tolerance in the patient. the active ingredient [31]. Clinicians should warn patients that unless ●● Identification of altered or aberrant behaviors, misuse, or diversion. specifically instructed otherwise, oral ER/LA opioids should not be broken, chewed, or crushed, and patches should not be cut or torn prior Dose titration to use, since this may lead to rapid release of the opioid and could cause Patients who are opioid-naïve (i.e., not tolerant) or have modest overdose or death. previous opioid exposure should be started at a low dose of a short- acting opioid and titrated slowly upward to decrease the risk of opioid- Prescribers should educate themselves about the general characteristics, related adverse effects [5]. If it is unclear whether a patient has recently toxicities, and drug interactions for ER/LA opioid products. [For been using opioids (either prescribed or non-prescribed), the clinician detailed information on current ER/LA opioid analgesics, see the FDA should assume that the patient is opioid-naïve and proceed as described. Blueprint for Prescriber Education, available at: http://www.er-la- Short-acting opioids are usually safer for initial therapy since they have opioidrems.com]. Respiratory depression is the most serious adverse a shorter half-life and may be associated with a lower risk of overdose effect of opioids as it can be immediately life-threatening. The risk of from drug accumulation [5]. respiratory depression or respiratory arrest is higher in patients with an upper respiratory infection, asthma, or other respiratory problem—if Tolerance to the sedating and respiratory depressant effects of opiates these conditions arise, the opioid dose needs to be reduced. Constipation should be established before prescribing an ER/LA opioid due to the is the most common long-term side effect, but can often be managed. increased risks associated with longer-acting formulations [29]. The Drug-drug interaction profiles vary among the products. Knowledge of selection of a starting dose and manner of titration are clinical decisions particular opioid-drug interactions, and the underlying pharmacokinetic that must be made on a case-by-case basis because of the many and pharmacodynamic mechanisms, allows for the safer administration variables involved, but health care providers should carefully weigh of opioid analgesics. the benefits vs. the risks before starting ER/LA opioid treatment. These risks include overdose, misuse, abuse, and addiction by the patient Central nervous system depressants (sedatives, hypnotics, tranquilizers, or other members of the patient’s household and tolerance, physical tricyclic antidepressants and alcohol) can have a potentiating effect on dependence, drug interactions, and accidental use by other household the sedation and respiratory depression due to opioids [30]. Alcohol members, especially children. consumption should be avoided entirely with some oral products (e.g.,

Page 15 Pharmacy.EliteCME.com morphine, hydromorphone, oxymorphone) because ethanol increases capsule releases the antagonist and neutralizes the opioid effect [31]. the plasma concentration of the opioid [30]. The central opioid antagonist compartment is eliminated from the body Opioids may enhance the neuromuscular blocking action of skeletal unchanged if the capsule is consumed normally without tampering. relaxants and produce an increased degree of respiratory depression. Another strategy is to modify the physical structure of tablets or Using opioids with monoamine oxidase inhibitors (MAOIs) may result in incorporate compounds that make it difficult or impossible to liquefy, possible increase in confusion, anxiety, and respiratory depression [30]. concentrate, or otherwise transform the tablets [31]. Opioids can reduce the efficacy of some diuretics by inducing the release Transdermal opioid formulations have been thought to be less of antidiuretic hormone (ADH) [30]. In addition, some opioids interact vulnerable to misuse, but such formulations can be abused. For with various cytochrome P450 enzyme inhibitors and inducers and thus, example, a transdermal, 7-day duration formulation of buprenorphine may result in higher or lower than expected blood levels of the drug. has been reported to be an increasingly abused opioid, particularly in prison populations [34]. As a partial opioid agonist, buprenorphine was Methadone can be an effective opioid, but it must be prescribed thought to be a lower-risk agent than full agonist opioids; however, it is carefully and with full knowledge of its highly variable clear that this medication can also be susceptible to abuse. pharmacokinetics and pharmacodynamics. Abuse-deterrent opioid formulations, of course, do not prevent users Abuse-deterrent formulations from simply consuming too much of a medication. These formulations As concern has risen about opioid misuse and abuse, efforts have been may help reduce the public health burden of prescription opioid abuse, made to create abuse-deterrent and tamper-resistant opioid formulations. but the evidence to date is inadequate to project whether this potential One class of deterrent formulation incorporates an opioid antagonist will actually be achieved [31]. into a separate compartment deep within a single capsule; crushing the Case study: Progress At the next scheduled follow-up visit, Mr. Davidson reports reduced pain zero.” Although seemingly reasonable, it is explained to Mr. Davidson and improved functioning. He says his pain is now 3-4 on a 10-point that, in fact, “zero pain” is an unrealistic goal for anyone, and that scale. He can now walk his dog twice daily, and is using the computer increasing the dose to achieve that goal would likely incur a range of without pain. He says his sleep has improved as well. Mr. Davidson side effects that would erode his overall quality of life. asks for a higher dose of the opioid “to see if I can get the pain down to Periodic review and monitoring If a trial of an opioid medication is deemed successful and opioid Daily or weekly monitoring may be necessary for patients at very high therapy is continued, periodic review and monitoring of pain risk for adverse outcomes. management, as well as the patient’s underlying condition, should be Reviewing functional goals performed for the duration of treatment. The tests performed, questions A key part of periodic monitoring is a careful review of previously asked, and evaluations made should be tailored to the patient as agreed-upon functional goals. Patients should come to appointments guided by the physician’s clinical judgment. For example, a physical ready to provide the evidence upon which an evaluation of progress can examination may or may not be required at each follow-up visit. be made. This evidence should span as many domains of a person’s life Clinicians must evaluate progress against agreed-upon treatment goals as possible: personal and social relationships, employment, physical and assess for a wide range of potential adverse effects, ranging from activities, health, hobbies, and spiritual activities. Functional goals physical side effects such as constipation or sedation, to behavioral that are not attained require investigation, possible adjustment, and side effects such as mood changes, signs of drug craving or seeking, encouragement that future progress is possible. If the goals have been or impaired function in various domains of daily living [17]. As part attained, clinicians should be supportive and positive, while setting new of routine practice, clinicians who prescribe opioids should perform goals to motivate further progress. medication reconciliation at each patient visit [35]. The American Medical Association defines “medication reconciliation” as “…making Functional goals related to physical activity are sometimes not achieved sense of a patient’s medications and resolving conflicts between by patients because they report that the agreed-upon activity hurts too different sources of information to minimize harm and maximize much. [17]. Such cases should be carefully evaluated before a decision therapeutic effects” [36]. is made to increase the dose of an opioid medication. All patients—even those with end-stage disease—can engage in some kind of physical The intensity and frequency of monitoring is dependent on an activity at least some time during the day. The motions or activity assessment of the patient’s risk for abuse, diversion, or addiction. may be extremely modest, yet they may nonetheless serve as effective Tools and techniques similar or identical to those used during an initial functional goals. Patients with chronic pain often require such micro- assessment of a patient’s risk can be used to reassess or monitor risk on level goals and controlled, gradually increasing motion or activity over an on-going basis [2]. sustained periods of time. States vary in their requirements for intervals at which follow-up visits Managing breakthrough pain are required when controlled substances such as opioid medications Patients with chronic pain receiving a steady dose of an opioid are prescribed. Although federal law allows for a 90-day supply of medication may experience episodes of pain that break through the prescriptions for patients receiving schedule II drugs (who are otherwise analgesic effects of the steady-state drug (regardless of the route of deemed safe to have this amount), state law can vary from 30 days to administration) [5]. Close monitoring of breakthrough episodes is key 6 months [2]. In cases where state and federal law conflict, the most to helping patients reduce pain and facilitate functioning. Providing restrictive rule prevails [2]. patients either paper or electronic pain diaries can help them track Relatively infrequent monitoring may be appropriate for low- breakthrough episodes and spot correlations between the episodes risk patients on a stable dose of opioids. More frequent or intense and variables in his or her life. If specific triggers are identified, this monitoring is appropriate for patients during the initiation of therapy or may provide opportunities for changes that will reduce the prevalence if the dose, formulation, or opioid medication is changed. Patients who of breakthrough episodes without recourse to increased reliance on may need more frequent or intense monitoring include [17]: medication [17]. ●● Those with a prior history of an addictive disorder, past abuse, or Non-opioid methods of dealing with breakthrough pain (e.g., cold or other aberrant use. warmth, massage, yoga, acupuncture, meditation, electrical stimulation) ●● Those in an occupation demanding mental acuity. might be considered prior to any increases in opioid medication; ●● Older adults. although research evidence regarding many complementary and ●● Patients with an unstable or dysfunctional social environment. alternative medicine (CAM) approaches is inconclusive. If a short- ●● Those with comorbid psychiatric or medical conditions. acting opioid preparation is prescribed for breakthrough pain, clinicians should remind patients about the potential problems of diversion and

Pharmacy.EliteCME.com Page 16 misuse of these agents. As with the management of the underlying screening and confirmatory tests regularly to build familiarity with the chronic pain condition, clinicians should use an agreed-upon set of range of normal results [17]. functional goals as a way to monitor and, if necessary, adjust the use of Prescribers should be familiar with the metabolites associated with as-needed opioid medications for breakthrough pain. each opioid that may be detected in urine, since the appearance Monitoring adherence of a metabolite can be misleading [2]. A patient who is prescribed Drug testing should be approached in a consensual manner as part of an codeine, for example, may test positive for morphine because agreed-upon treatment plan and with the idea that such testing benefits morphine is a metabolite of codeine. Similar misunderstandings may both the patient and the provider [2]. The potential benefits of clinical occur for patients prescribed hydrocodone who appear positive for drug testing include [2]: hydromorphone or oxycodone and oxymorphone (see Table 4). ●● Serving as a deterrent to inappropriate use. ●● Providing objective evidence of abstinence from drugs of abuse. Table 4: Urinary Analytes of Common Opioid Pain Medications ●● Monitoring response to treatment. Drug Urinary Analytes ●● Assisting with a diagnosis. ●● Helping patients allay concerns by family members, employers, or Morphine Morphine. law enforcement. Hydromorphone. ●● Demonstrating to regulatory authorities a clinician’s dedication to Codeine. monitoring best practices. Codeine Codeine. In the context of family practice settings, unobserved urine collection is Morphine. usually an acceptable procedure for drug testing. Prescribers, however, Hydrocodone. should be aware of the many ways in which urine specimens can be Hydrocodone Hydrocodone. adulterated. Specimens should be shaken to determine if soap products Hydromorphone. have been added, for example. The urine color should be noted on any 6-Hydrocodol. documentation that accompanies the specimen for evaluation, since unusually colored urine could indicate adulteration. If possible, urine Oxycodone Oxycodone. temperature and pH should be measured immediately after collection [2]. Oxymorphone. Hydrocodone. One way to reduce the risk of urine test false-positives or false- negatives is to develop a relationship with a single laboratory, become Source: Webster LR, and Dove B. Avoiding Opioid Abuse While familiar with its testing tools and threshold values, and use the same Managing Pain. Lifesource. 2007. Case study: A caution light After 3 weeks, the physician is given a message that a young woman Using PDMPs has called requesting an early refill of Mr. Davidson’s opioid “because PDMPs can serve an important clinical monitoring role. PDMPs he’s suffering.” This raises the physician’s suspicions. He accesses use secure Internet sites to offer point-of-care access to records of his state PDMP to see if Mr. Davidson might be getting prescriptions controlled substances from other prescribers and dispensing pharmacies. from another provider. He is not, and nothing appears unusual. The From these, clinicians can quickly glean patterns of prescription drug physician calls Mr. Davidson directly and Mr. Davidson confirms use that can be helpful in confirming or refuting suspicions of aberrant that he did ask his granddaughter to call for the prescription because behaviors. Information from a PDMP may also be clinically relevant in he was having increased pain after playing tennis for an hour. Mr. that it may reveal that a patient is being prescribed medications whose Davidson is advised to temporarily use an OTC NSAID (not more than combinations are contraindicated. 600 mg) and is asked to return for an in-person visit within a week. At By checking PDMP data (particularly for high-risk patients), clinicians that visit, a range of non-pharmacological strategies are reviewed to can get a sense of the controlled substances the patient has been receiving provide additional pain relief (i.e., post-exercise cold/warm treatments; from other prescribers and other pharmacies [36]. Individuals may have exercises to improve flexibility; massage; and the use of an elbow brace perfectly acceptable reasons for multiple prescribing episodes, but the to be used for tennis). existence of such a pattern should always trigger inquiry. Common issues related to opioid pain medications Preventing and managing opioid-related side effects Opioids and pregnancy Many patients treated with an opioid will experience side effects, the most Some data suggest an association between the use of long-term opioid common of which is constipation. Other possible effects include [31]: therapy during pregnancy and adverse outcomes in newborns, including ●● Respiratory depression. low birth weight and premature birth, though co-related maternal factors ●● Sedation. may play a role in these associations and causality is not certain [5]. ●● Urinary hesitancy or retention. Higher doses of antenatal methadone in tolerant mothers do not seem ●● Dry mouth. to increase complication rates [5]. Importantly, opioid withdrawal can ●● Nausea/vomiting. be expected in up to half of newborns of opioid-dependent mothers [5]. ●● Itching. If a mother is receiving long-term opioid therapy at or near the time ●● Sweating. of delivery, a professional experienced in the management of neonatal ●● Hypogonadism. withdrawal should be available [5]. ●● Myoclonus. Nonetheless, given the potential risks of opioids during pregnancy, Some side effects, such as sedation, may lessen over time after clinicians should encourage minimal or no use of opioids during treatment initiation. Others, such as constipation, rarely become less pregnancy unless the potential benefits outweigh risks [5]. If opioid problematic. Constipation is so common, in fact, that when patients medications are prescribed, clinicians should thoroughly counsel pregnant use opioids and do not have constipation, clinicians should consider women about the potential risks and benefits, and clinicians should be possible reasons ranging from rapid bowel transit time to diversion. prepared to anticipate and manage risks to the patient and newborn. Constipation requires proactive treatment, with stimulating laxatives Driving and work safety prescribed at the time of initiating opioids, and frequent reevaluation. Driving while using opioid medications remains a controversial issue. With the exception of constipation, uncomfortable or unpleasant side Particularly at the initiation of therapy, opioid medications may cause effects may potentially be reduced by switching to another opioid or sleepiness, clouded thinking, decreased concentration, slower reflexes, route of administration (such side effects may also be alleviated with or incoordination, all of which may pose a danger to the patient and adjunctive medications). others when driving or operating machinery [5]. On the other hand, a

Page 17 Pharmacy.EliteCME.com number of epidemiologic studies failed to show an association between school bus drivers and pilots) may be subject to restrictions in the use of long-term opioid use and motor vehicle accidents, fatalities, or citations opioid medications [5]. Clinicians should check with their state medical for impaired driving [5]. Since at least some of the cognitive and motor- society or the Federation of State Medical Boards to obtain up-to-date impairing effects of opioids resolve with steady use and a consistent information in this regard. dose, some activities or driving may be allowable at the discretion of Screening for endocrine function the clinician and in the absence of signs of impairment. Both male and female patients on long-term opioid therapy are at risk All patients who are initially prescribed opioid medications, or those for hypogonadism, thus the endocrine function of all patients should be who have their dose increased, should be advised not to drive or assessed at the start of long-term opioid therapy and at least annually engage in potentially dangerous work or other activities [5]. There is thereafter. The symptoms of hypogonadism in both genders may no consensus on exactly how long they should abstain from driving. include fatigue, mood changes, decreased libido, loss of muscle mass, Patients should be educated about the increased risk of impairment and osteoporosis. Although there are insufficient data to recommend when starting opioid therapy, when increasing doses, and when taking routine endocrine screening of asymptomatic patients, current other drugs or substances (such as, alcohol, benzodiazepines, or guidelines do recommend such testing for patients exhibiting any of the even some cold remedies) that may exacerbate cognitive and motor aforementioned signs and symptoms [5]. impairment. Clinicians should be aware that certain professions (i.e., Opioid rotation “Opioid rotation” means switching from one opioid to another to better found across the various charts and online calculator tools, and may balance analgesia and side effects. Rotation may be needed because of a account for some overdoses and fatalities [37]. The optimal dose for a lack of efficacy (often related to tolerance), bothersome or unacceptable specific patient must be determined by careful titration and appropriate side effects, increased dosing that exceeds the recommended limits monitoring, and clinicians must be mindful that patients may exhibit of the current opioid (e.g., dose limitations of co-compounded incomplete cross-tolerance to different types of opioids because of acetaminophen), or inability to absorb the medication in its present differences in the receptors or receptor sub-types to which different form (i.e., if there is a change in the patient’s ability to swallow, switch opioids bind [31]. to a formulation that can be absorbed by a different route such as In some cases, because of the risk of potential harm during the time of transdermal) [31]. Because of the large number of variables involved rotating from one chronic opioid regimen to another, it may be wise to in how any given opioid will affect any given patient, opioid rotation initially use lower doses of an ER/LA opioid than might be suggested must be approached cautiously, particularly when converting from by equianalgesic charts, while temporarily liberalizing, as needed, the an immediate-release formulation to an ER/LA product [31]. An use of a short-acting opioid. This would then be followed by gradual equianalgesic chart should be used when changing from one opioid titration of the LA opioid to the point where the as-needed short-acting to another or from one route of administration to another. Such charts opioid is incrementally reduced, until no longer necessary. must be used carefully, however. A high degree of variation has been Managing non-adherent patients Patients who begin to exhibit aberrant drug-related behaviors or non- ●● Misunderstandings related to lack of fluency with English. adherence to a prescription should be monitored more strictly than ●● Attempts to stretch a medication to save money. compliant patients. Suspicion that a patient is non-adherent should ●● Cultural or familial pressure not to take a medication. prompt a thorough investigation of the situation, including an honest ●● Stigma about taking a pain medication. evaluation of the patient/provider relationship. The way clinicians ●● Overmedication and fears about addiction. interact with patients can affect the relationship (for better or worse) ●● Misunderstanding of a prescription by a caregiver who has taken and influence treatment outcomes [17]. A clinician’s negative reactions responsibility for daily apportioning of medications. to non-adherence might include anger at the patient, disappointment ●● Confusion between two medications that look very similar to each and sadness at the apparent betrayal of trust, or fear that the patient’s other. behavior could expose the provider to legal jeopardy [17]. The use of patient-provider agreements and/or informed consent Before accusing a patient of not adhering to a prescribed regimen, documents can help clinicians navigate the uncertainties that can arise clinicians should assess the situation fully and document objective in cases of real or apparent non-adherence, and may help make the evidence of non-adherence, as well as their concerns about the patient. process less confrontational. Consultation with an addiction medicine Possible reasons for non-adherence include: specialist or psychiatrist may be necessary if addiction is suspected or ●● Inadequate pain relief. if a patient’s behavior becomes so problematic that it jeopardizes the ●● Misunderstanding of the specifics of the prescription. clinician/patient relationship. Case study: Stable improvement After a slight dose adjustment of the gabapentin, Mr. Davidson reports general health is better as a result. He says he would like to try to continued functional progress and acceptable levels of pain. He has taper down his use of the opioid, and he is given clear and specific increased his level of physical activity and reports that his mood and instructions for how to do so. Treatment termination Reasons for discontinuation of an opioid analgesic can include the is deemed in the best interest of the patient. This requires, careful healing of or recovery from an injury, medical procedure, or condition; consideration and a well-documented risk management plan that intolerable side effects; lack of response; or discovery of misuse addresses the greater resources necessary for opioid continuation of medications. Regardless of the reason, termination should be following evidence of misuse. accomplished so as to minimize unpleasant or dangerous withdrawal If termination of the provider/patient relationship is deemed necessary, symptoms by tapering the opioid medication slowly, or by carefully clinicians must ensure that the patient is transferred to the care of changing to a new formulation. Approaches to weaning range from another provider and that the patient has adequate medications to avoid a slow 10% reduction per week to a more aggressive 25% to 50% unnecessary risk, such as from uncontrolled or potentially dangerous reduction every few days [5]. In general, a slower taper will produce withdrawal [17]. Practitioners can be held accountable for patient fewer unpleasant symptoms of withdrawal. abandonment if medical care is discontinued without justification or In general, opioid therapy must be discontinued or reevaluated adequate provision for subsequent care. whenever the risk of therapy is deemed to outweigh the benefits being provided. A clinician may choose to continue opioid treatment with intensified monitoring, counseling, and careful documentation if it

Pharmacy.EliteCME.com Page 18 Methadone Methadone has received growing attention and concern because it is even in opioid-tolerant patients, because methadone appears to be more frequently involved in unintentional overdose deaths [38]. These deaths potent in patients who have been using higher doses of the pre-switch have escalated as methadone has increasingly been used as an analgesic opioid. In older patients or those with renal or hepatic comorbidities, drug for chronic pain [39]. At one time, methadone had been used almost lower starting doses, less frequent dosing, and more cautious dose exclusively in opioid maintenance therapy programs to treat addiction. Its titration are recommended. Because of its long half-life and variable relatively long plasma elimination half-life compared with its relatively pharmacokinetics, methadone is not recommended to treat breakthrough short analgesic half-life makes it optimal for maintenance, allowing for pain or as an as-needed medication. once-daily dosing. But methadone only exerts potent analgesic effects in When rotating from another opioid to methadone, extreme caution the early phase of its elimination half-life, and this, along with the fact must be used when referring to equianalgesic conversion tables. The that it is among the least expensive opioids, has led to a dramatic increase consensus recommendations from an expert panel suggest a 75% to in its use for alleviating chronic non-cancer pain [5]. 90% decrement in the equianalgesic dose from conventional conversion Methadone has unique pharmacokinetic and pharmacodynamic tables when a switch is made from another opioid to methadone [40]. characteristics that add substantial risk to its use. Although its chemical Because the risk of overdose is particularly acute with methadone, structure is different from classic opioids such as morphine, methadone patients should be educated about these risks and counseled to use acts on the same set of opioid receptors, though with different affinities methadone exactly as prescribed. They should also be warned about for the various opioid receptor subtypes [34]. In addition, methadone the dangers of mixing unauthorized substances with their medication. has non-opioid receptor effects that may explain some of its potential Benzodiazepines, in particular, pose a threat. Death investigations special efficacy. These varied effects across opioid receptors, along with often find that benzodiazepines have been used in combination with its non-opioid properties, have garnered methadone the reputation of methadone and other opioids [40]. Other respiratory depressants, being a broad-spectrum opioid [34]. For a number of reasons, however, including alcohol, pose similar risks. Dosing should, therefore, be methadone must be titrated very carefully to avoid overdose. These conservative and cautious until patients demonstrate the ability to reasons include [34]: tolerate and use the drug safely. ●● An analgesic half-life much shorter than its elimination half-life (leading to accumulation). The FDA warns that methadone can cause serious cardiac conduction ●● Metabolism by a group of liver enzymes that differ from those disturbances, including QT interval prolongation and Torsades de associated with most other opioids, hence leading to unexpected pointes, a potentially fatal ventricular arrhythmia [41]. It appears drug-drug interactions. that methadone-related corrected QT (QTc) interval prolongation ●● Significant genetic variations in the liver enzymes that metabolize and cardiac arrhythmias can occur at any dose but are more likely methadone, which contribute to the unpredictability of methadone’s at higher doses or with concomitant use of drugs that interact with effects and side effects. methadone or that themselves prolong QTc. Although uncommon, the ●● Metabolism may be affected by smoking (which accelerates cardiac arrhythmias that can be induced by methadone can be lethal elimination) and alcohol (which can augment methadone toxicity if not detected. The cardiac health of patients who are candidates for acutely and accelerate metabolism with chronic use). methadone should be assessed, with particular attention paid to any history of heart disease or arrhythmias [42]. An initial ECG may be The Centers for Disease Control and Prevention recommend against advisable prior to starting methadone, particularly if a patient has a the use of methadone as a first line agent. If used, dosages should be specific cardiac disease or cardiac risk factors or is taking agents that started as low as possible, and titrated upward no more frequently than may interact with methadone [45]. once weekly [1]. The lowest possible dose titration should be followed, Required patient education Thorough patient education about the safe use, storage, and disposal ●● Do not take a pain medicine with alcohol or other prescription or of opioid medications is an essential part of best practices opioid illegal sedatives, as this can result in overdose or death. prescribing. This education can be partially integrated into standard ●● Do not take a pain medicine to promote sleep. patient/provider agreements or informed consent documents. As with ●● Never break, chew, or crush medicines, particularly ER/LA opioid other patient-directed materials, education must be provided in a medications. language and at a reading level (typically 6th to 7th grade) appropriate ●● For transdermal products, external heat, fever, and exertion can for a clinician’s patient population. Examples of effective patient increase absorption, leading to a potentially fatal overdose. education can be found online, such as http://www.er-la-opioidrems. ●● Transdermal products with metal foil backings are not safe for use com/IwgUI/rems/pdf/patient_counseling_document.pdf in MRI scanners. Safe use of opioid medications means that patients carefully follow ●● Do not use transdermal products if they are broken or torn. their prescribed instructions, including special directions about timing Patients should be thoroughly counseled on the potential adverse effects of doses and whether to administer the medication with or without of opiates—including signs, symptoms, and risk factors for overdose, food. Clinicians should be mindful of any physical limitations (i.e., respiratory depression, constipation, and potential allergic reactions. poor eyesight) that a patient might have that could interfere with Risk for falls, especially in the elderly, should also be discussed with accurate and timely administration of prescribed opioids. Adherence to patients and caregivers, as well as limitations to activities including the prescribed directions is critical to adequate pain management, and driving and operating machinery. Patients and caregivers should be patients should contact their prescriber if doses are missed or pain is not instructed to consult with their health care provider if side effects occur, properly controlled. Product-specific information should be discussed in order to properly manage adverse reactions and maximize pain with the patient, and reinforced by encouraging the patient to read the management therapy. Providers should report adverse events to the medication guide they receive from the pharmacy. FDA online at https://www.accessdata.fda.gov/scripts/medwatch/index. Here are some key ideas to convey to patients about proper use [43]: cfm?action=reporting.home [16]. ●● Read the prescription container label each time to check dosage. Safe storage ●● Read the medication guide dispensed by the pharmacy. Patients need to be reminded that even children or close relatives can be ●● Tell all prescribers about the use of pain medications to ensure tempted to use pain medications they have not been prescribed. Opioids proper treatment of all disease states. are often obtained by teens, for example, from unsecured medicine ●● Never use medicines after expiration date. cabinets of family and friends. ●● Never share medicines with others, as this is not only illegal, but If possible, opioid pain medications should be stored in a locked cabinet can cause serious harm or death to the user. or other secure storage unit to protect from theft. Storage areas should ●● Never abruptly stop pain medications without consultation with the be cool, dry, and out of direct sunlight. Remind patients not to store prescriber. medications in their car, to keep medications in the original containers, Page 19 Pharmacy.EliteCME.com and to avoid storing medications in the refrigerator or freezer unless ●● Receive prescriptions of more than 50 mg of morphine equivalent/ specifically directed to do so by a health care provider or pharmacist. day. Proper disposal ●● Are being rotated from one opioid to another when there may be The FDA currently recommends that unused opioid pain medications incomplete cross-tolerance. be flushed down a toilet, to protect vulnerable populations from ●● Are opioid naïve and who have been prescribed methadone or who contact with potent medications [44]. However, some states may are rotated from another opioid to methadone. have different or more stringent guidelines. California, for example, ●● Are released after emergency medical care involving opioid instructs consumers not to flush any medicines down the toilet or drain, intoxication or poisoning. to avoid introduction of medications into the water supply. If flushing ●● Have a suspected history of substance abuse, dependence, or medicines is not allowed in your state, instruct patients to follow the nonmedical opioid use. instructions of a pharmacist for disposal or to mix the medicines with ●● Have known or suspected concurrent heavy alcohol use. an undesirable substance, such as used coffee grounds, put the mixture ●● Have a respiratory infection or illness. into a disposable container with a lid or a sealable bag, and place it in ●● May have difficulty accessing emergency medical services [48]. the trash. Dealing with opioid overdose Before they are thrown out, personal information, including the Because respiratory depression is the most serious potential harm from prescription number, should be removed from empty medication opioids, it is incumbent on clinicians to fully inform patients of this and containers. Patients should also be encouraged to use any drug take- educate them (and their home caregivers, if possible) on recommended back programs available in the local community. [Note: the Drug steps to take in an emergency. Respiratory depression might occur Enforcement Administration maintains up-to-date information on because a patient takes more than the prescribed amount, either national take-back programs, as well as ways to find drug collection intentionally or unintentionally, or because the patient was mistakenly sites in any given locale. Information can be accessed at: http:www. given too much medication by a caregiver. Respiratory depression deadiversion.usdoj.gov/drug_disposal/takeback/index.html] typically takes time to develop, hence there will be early warning signs of overdose including: Take-home naloxone ●● Intoxicated behavior—confusion, slurred speech, stumbling. It may become more common to provide patients and their caregivers ●● Feeling dizzy or faint. with the intranasal preparation of the opioid antagonist medication ●● Acting very drowsy or groggy. naloxone as a way to reverse the complications associated with ●● Unusual snoring, gasping, or snorting during sleep. accidental overdose; some states currently have protocols allowing ●● Difficulty waking up from sleep or staying awake. pharmacists to prescribe naloxone to vulnerable patients. Naloxone was FDA-approved in 1971 and has been used for decades by emergency Patients and their caregivers should be counseled to immediately call medical services personnel. In 2015, intranasal administration of 911 or an emergency service if they observe any of these warning signs. naloxone was approved by the FDA for at-home use as an antidote for If naloxone has been provided for the patient, it should be administered opioid overdose. Numerous studies and community initiatives have immediately, which will reverse respiratory depression and should attested to the safety, convenience, and effectiveness of providing allow the patient to begin breathing more normally. If a person has intranasal naloxone to patients who may be at risk of overmedication or stopped breathing, artificial respiration/cardiopulmonary resuscitation overdose [45]. This includes patients who: (CPR, including rescue breathing) should be begun immediately until emergency help arrives. Conclusion This monograph has summarized best practices for the responsible and procedures described in this monograph provide a roadmap and prescribing of opioid pain medications for chronic non-cancer pain. structure by which clinicians can achieve these twin goals without More detailed information on many of these topics is available from incurring undue burdens of time or energy. Pharmacovigilance simply the resources listed. The treatment of pain is a dynamic and evolving means that prescribers apply basic principles of prudent medicine to field, and clinicians should periodically refresh their knowledge through the needs of patients in pain. And because the evidence base for current reading, attending seminars or other events, or by taking additional guidelines remains suboptimal, clinicians retain a great deal of latitude CME courses. in deciding how that vigilance is best deployed on a day-to-day basis. Clinicians face the competing demands of relieving pain while minimizing potential harm to both patients and society. The steps

Pharmacy.EliteCME.com Page 20 Page 21 Pharmacy.EliteCME.com Pharmacy.EliteCME.com Page 22 Page 23 Pharmacy.EliteCME.com Pharmacy.EliteCME.com Page 24 Page 25 Pharmacy.EliteCME.com Pharmacy.EliteCME.com Page 26 Page 27 Pharmacy.EliteCME.com Pharmacy.EliteCME.com Page 28 Resources ●● American Academy of Pain Medicine, www.painmed.org ●● The National Association of State Controlled Substances ●● American College of Physicians, www.doctorsforadults.com Authorities, www.nascsa.org ●● Drug Enforcement Administration Diversion Control Program, ●● National Association of Drug Diversion Investigators, www.naddi.org www.DEAdiversion.usdoj.gov ●● University of Wisconsin Pain & Policy Studies Group, www. ●● Federation of State Medical Boards, www.fsmb.org painpolicy.wisc.edu References 1. Centers for Disease Control (2016). CDC Guideline for Prescribing Opioids for Chronic Pain. 22. Payne R, Anderson E, Arnold R, et al. A Rose by any other name: pain contracts/agreements. 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United States: Results from the 2014 National Survey on Drug Use Health. Retrieved from https:// 28. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf on March Consortium 9CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) 11, 2017. genotype. Clin Pharmacol Ther. 2012;91(2):321-6. 7. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. (2015). 29. Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Non-cancer Emergency Department Visits Involving Narcotic Pain Relievers. Rockville, MD. Retrieved from Pain: An educational aid to improve care and safety with opioid therapy. 2010 Update. https://www.openminds.com/wp-content/uploads/indres/061810shcnerusenarcotic.pdf on March 11, 30. U.S. Food and Drug Administration (FDA). Blueprint for Prescriber Continuing Education Program. 2017. July 9, 2012. 8. Substance Abuse and Mental Health Services Administration. (2016). Opioids. Retrieved from https:// 31. Zacharoff KL, McCarberg BH, Reisner L, Venuti SW. Managing Chronic Pain with Opioids in www.samhsa.gov/atod/opioids on March 11, 2017. Primary Care, 2nd Ed. Inflexxion, nc. Newton MA. 2010. 9. Centers for Disease Control and Prevention (CDC). (2017). Injury Prevention & Control: Opioid 32. U.S. Food and Drug Administration press release. FDA approves shared system REMS for TIRF Overdose. Retrieved from https://www.cdc.gov/drugoverdose/ on March 11, 2017. products. December, 2011. 10. U.S. Food and Drug Administration (FDA) news release. FDA Introduces new safety measures for 33. Harris G. FDA Plans New Limits on Prescription Painkillers. New York Times. January 13, 2011. extended-release and long-acting opioid medications. July 9, 2012. 34. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications 11. Executive Office of the President of the United States. Epidemic: Responding toAmerica’s with related concerns. Pain Medicine. 2002;3(4):339-348. Prescription Drug Abuse Crisis. 2011. Retrieved from https://www.ncjrs.gov/App/Publications/ 35. Goodnough A, Zezima K. When Children’s Scribbles Hide a Prison Drug. New York Times. May 26, abstract.aspx?ID=256103 on March 11, 2017. 2011. 12. International Association for the Study of Pain. Classification of chronic pain: Descriptions of chronic 36. American Medical Association (AMA). The physician’s role in medication reconciliation: issues, pain syndromes and definitions of pain terms. Prepared by the InternationalAssociation for the Study strategies and safety principles. 2007. of Pain, Subcommittee on Taxonomy. Pain Suppl S1–S226, 1986. 37. The PMP Center of Excellence. Available at http://www.pdmpassist.org/. Accessed March 11, 2017. 13. Institute of Medicine. Relieving Pain in America: A blueprint for transforming prevention, care, 38. Webster LY, Fine PG. Overdose Deaths Demand a New Paradigm for Opioid Rotation. Pain Med. education, and research. Report Brief. June 2011. 2012;13(4):571-4. 14. NCHS. Health, United States, 2006 with Chartbook on Trends in the Health of Americans. Hyattsville, 39. Webster LR, et al. Select medical-legal reviews of unintentional overdose deaths. Presented at 26th MD: U.S. Department of Health and Human Services; 2006. Annual Meeting of AAPM; February 3-6, 2010: San Antonio, TX. 15. American Cancer Society (ACS). Cancer Facts and Figures 2012. Atlanta: ACS; 2012. 40. Centers for Disease Control and Prevention. Increases in Poisoning and Methadone-Related Deaths: 16. Food and Drug Administration, CDER Final Blueprint for Prescriber Continuing Education Program. United States, 1999-2005. NCHS Health & Stats. February, 2008. July 9, 2012. 41. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: The science and limitations of the equianalgesic 17. Fishman SM. Responsible Opioid Prescribing: A Clinician’s Guide, 2nd Ed. Waterford Life Sciences. dose table. J Pain Symp Mangmnt. 2009;38(3): 426-439. 2012. 42. Food and Drug Administration. Public Health Advisory: Methadone Use for Pain Control May Result 18. Goodwin J, Bajwa ZH. Evaluating the patient with chronic pain. In: Principles and Practice of in Death and Life-Threatening Changes in Breathing and Heart Beat. November 27, 2006. Pain Medicine 2nd Ed. Warfield CA, and Bajwa ZH., Eds. 2004. New York, NY, McGraw-Hill 43. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone Companies, Inc. treatment. Ann Intern Med. 2009;150:387-395. 19. Goodwin J, Bajwa ZH. Understanding the patient with chronic pain. In: Principles and Practice of 44. U.S. Food and Drug Administration (FDA). Blueprint for Prescriber Continuing Education Program. Pain Medicine 2nd Ed. Warfield CA, and Bajwa ZH., Eds. 2004. New York, NY, McGraw-Hill July 9, 2012. Companies, Inc. p.58 45. Food and Drug Administration. (2017). Disposal of unused medicines: what you should 20. Tang NK, Crane C. Suicidality in chronic pain: a review of the prevalence, risk factors, and know. Retrieved from https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ psychological links. Psychological Medicine 2006; 36:575-586. BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/SafeDisposalofMedicines/ucm186187.htm 21. Gourlay D, Heit H. Universal precautions: a matter of mutual trust and responsibility. Pain Medicine. on March 11, 2017. 2006; 7(2):210-211. 46. Leavitt SB. Intranasal Naloxone for At-Home Opioid Rescue. Prac Pain Mngmnt. October, 2010:42- 46. Page 29 Pharmacy.EliteCME.com BEST PRACTICES FOR PRESCRIBING OPIOIDS IN CHRONIC NON-CANCER PAIN Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com

1. Long-acting (LA) and extended-release (ER) formulations of 7. Which of the following metabolites does not commonly arise on a opioids should not be used to treat which of the following types of urinalysis of a patient taking codeine? pain? a. Codeine. a. Cancer pain. b. Oxycodone. b. Acute pain. c. Morphine. c. End-of-life pain. d. Hydrocodone. d. Chronic non-cancer pain. 8. Which of the following is not a common side effect of opioid 2. Which of the following is the appropriate use of “universal medications? precautions” as it applies to patients with chronic pain? a. Respiratory depression. a. Exploring patients’ HIV status. b. Urinary hesitancy or retention. b. Assuming certain patients will misuse pain medication more c. Itching. than others. d. Insomnia. c. Understanding that there is a possibility of misuse or abuse of pain medications with all patients. 9. Methadone must be prescribed with particular caution because: d. Monitoring young patients for pain medication abuse more than a. Methadone is only appropriate for opioid maintenance therapy older patients. programs. b. Methadone’s analgesic half-life is much shorter than its plasma 3. Which of the following disease states is not considered to be elimination half-life. commonly complicated by adverse effects of opioids? c. Methadone is very short-acting. a. Cancer. d. Methadone may cause hypertension. b. Chronic obstructive pulmonary disease (COPD). c. Sleep apnea. 10. Which of the following is not an early warning sign of opiate d. Mental illness. overdose that patients should be counseled about? a. Intoxicated behavior—confusion, slurred speech, stumbling. 4. It is unsafe to combine opioids with which of the following types of b. Unusual snoring, gasping, or snorting during sleep. medicines? c. Difficulty waking up from sleep or staying awake. a. Stimulant medications. d. Difficulty getting to sleep or staying asleep. b. SSRI antidepressants. c. Benzodiazepines or barbiturates. d. Anti-hypertensive medications. 5. Short-acting opioids are most commonly used for which of the following types of pain? a. Chronic cancer pain. b. Breakthrough pain. c. Psychosomatic pain. d. Neuropathic pain. 6. What is the limit for acetaminophen in opioid combination products? a. 500 mg. b. 300 mg. c. 325 mg. d. 750 mg.

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Pharmacy.EliteCME.com Page 30 Chapter 3: Complications of Chronic Kidney Disease 2 Contact Hours

By: Katie Blair, PharmD, RPh Questions regarding statements of credit and other customer service Author Disclosure: Katie Blair and Elite Professional Education, LLC issues should be directed to 1-888-666-9053. This lesson is $8.00. do not have any actual or potential conflicts of interest in relation to this Educational Review Systems is accredited by the lesson. Accreditation Council of Pharmacy Education (ACPE) as a Universal Activity Number UAN: 0761-9999-18-016-H01-P provider of continuing pharmaceutical education. This Activity Type: Knowledge-based program is approved for 2 hours (0.2 CEUs) of continuing Initial Release Date: January 11, 2018 pharmacy education credit. Proof of participation will be Expiration Date: January 22, 2020 posted to your NABP CPE profile within 4 to 6 weeks to Target Audience: Pharmacy Technicians in a community-based setting. participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course To Obtain Credit: A minimum test score of 70 percent is needed to evaluation to receive continuing pharmacy education credit. obtain a credit. Please submit your answers either by mail, fax, or online at Pharmacy.EliteCME.com Audience This course is for all pharmacists and pharmacy technicians with a need to better understand kidney function and how chronic kidney disease affects it. Learning objectives Upon completion of this course, the reader should be able to: Describe the complications associated with chronic kidney disease Discuss normal kidney function and the effects of chronic kidney and their management. disease on kidney function. Recognize the medications used to treat common complications of Explain the definition of chronic kidney disease and causes of this chronic kidney disease. disease state. Introduction Chronic kidney disease (CKD) is often used as a broad term to describe The kidneys, when functioning normally, regulate the concentration many levels of decreased kidney function, from mildly decreased of fluid in the body. They remove excess water if body fluids are too renal output to severe kidney failure. This worldwide public health dilute, and remove excess salts such as sodium and potassium when issue affects a significant number of Americans, with the prevalence of body fluids are too concentrated. In addition, the kidney plays a role in approximately 14% in the general population. The leading causes of acid-base balance, by excreting hydrogen ions when the blood is too chronic kidney disease are high blood pressure and diabetes; nearly half acidic and excreting bicarbonate ions when the blood is too alkaline. of all patients diagnosed with chronic kidney disease have diabetes and/ Lastly, they remove metabolic byproducts such as creatinine, urea, and or cardiovascular disease. People with chronic kidney disease are also phosphorus that the body no longer needs. at a higher risk for developing cardiovascular disease, which occurs in In terms of hormones, the kidneys are responsible for converting nearly 70% of CKD patients aged over 65 years (National Institute of vitamin D to its active metabolite, which facilitates calcium absorption Diabetes and Digestive and Kidney Diseases, 2016). in the intestine. The kidneys also manufacture erythropoietin, a Chronic kidney disease presents a significant cost burden. In 2013, hormone that stimulates red blood cell production in the bone marrow. Medicare spending for chronic kidney disease in patients aged 65 years Renin is also produced in the kidney, and plays a significant role in and older exceeded $50 billion, which encompassed 20% of all Medicare sodium and blood pressure control (Hawley, 2015). spending for this age group. More than 70% of this spending occurred in Abnormal kidney function CKD patients with comorbidities of diabetes, congestive heart failure, or As kidney function decreases, the kidneys are less able to maintain both (National Institute of Diabetes and Digestive and Kidney Diseases, appropriate fluid concentrations in the body. Salts and fluids become 2016). With such a cost burden associated with chronic kidney disease, it increasingly difficult to remove from the bloodstream, resulting in is important to ensure patients are treated appropriately in order to slow edema and hypertension. Edema, or fluid overload, can cause symptoms disease progression and prevent adverse effects. This course serves as such as swollen ankles and legs, as well as shortness of breath due to an a review of chronic kidney disease and the medications used to prevent accumulation of fluid in the lungs, known as pulmonary edema. adverse effects of CKD and slow disease progression. A decline in kidney function can also result in a decreased ability to Normal kidney function remove metabolic byproducts, such as phosphorus and creatinine. High The kidneys are two bean-shaped organs, each of which is approximately phosphorus levels can lead to decreased blood calcium levels, which the size of a human fist, are located on the back side of the body on each triggers the parathyroid glands to release more parathyroid hormone to side of the spine, just below the rib cage. The primary function of the stimulate the release of calcium from the bones into the bloodstream. kidneys is to remove water and waste products from the body. They also If this mechanism is not suppressed, it can lead to excessive release of produce essential hormones including erythropoietin, renin, and vitamin D. calcium from the bones, resulting in bone demineralization, weaker Each kidney contains approximately one million functioning units, called bones, and bone pain. Since the kidneys produce vitamin D, lower levels nephrons, which perform the functions of forming urine and removing can be seen in patients with kidney disease, exacerbating this problem. unwanted substances from the bloodstream. Each nephron is made up Blood creatinine levels predictably increase in patients with decreased of two major parts. The glomerulus filters the blood, removing waste kidney function. The increase in creatinine level is used to determine products while keeping large molecules like proteins and blood cells in the level of kidney dysfunction, as it is a component in the calculation the bloodstream. The tubules receive and process the fluid filtered by the of glomerular filtration rate. glomeruli, saving necessary minerals for return back to the bloodstream and removing waste products for removal through the urine.

Page 31 Pharmacy.EliteCME.com Decreased kidney function also can cause a decrease in erythropoietin Chronic kidney disease is classified into 5 stages, with stage 1 indicating production, typically seen in later stages of disease progression. This the most mild disease and stage 5 representing kidney failure (Kidney causes a decrease in red blood cell production, which leaves fewer red Disease: Improving Global Outcomes (KDIGO) Work Group, 2013): blood cells to carry oxygen through the bloodstream to the tissues. This ●● Stage 1: Markers of kidney damage found, but GFR is normal or form of anemia can cause patients to become tired more easily, as well increased (>90 mL/min/1.73 m2). as develop shortness of breath after minimal activity. Patients with ●● Stage 2: Mildly reduced GFR (60-89 mL/min/1.73 m2). severe anemia may require administration of synthetic erythropoietin ●● Stage 3a: Moderately reduced GFR (45-59 mL/min/1.73 m2). since the kidneys are unable to maintain production. ●● Stage 3b: Moderately reduced GFR (30-44 mL/min/1.73 m2). ●● Stage 4: Severely reduced GFR (15-29 mL/min/1.73 m2). As kidney function declines, patients may be required to make diet 2 modifications to prevent accumulation of unwanted substances. Renal diets ●● Stage 5: Kidney failure (GFR <15 mL/min/1.73 m or dialysis). typically involve decreasing potassium, sodium, and phosphorus intake to In stage 1 and 2, the GFR alone should not be used alone to diagnose prevent over accumulation of these substances. Fluid restriction may also CKD, because GFR greater than 60 mL/min/1.73 m2 may be considered be required depending on the level of kidney disease. Medications to bind borderline normal. In these cases, one or more markers of kidney phosphates and supplement vitamin D levels may be required. damage should be used to determine the diagnosis (Kidney Disease: Symptoms may emerge when waste products begin to accumulate, Improving Global Outcomes (KDIGO) Work Group, 2013): causing a syndrome called uremia. Patients can experience headaches, ●● Albuminuria (albumin excretion >30 mg/24 hr or albumin:creatinine fatigue, nausea, vomiting, decreased appetite, decreased ability to ratio >30 mg/g). concentrate, and in increased tendency to bleed. High phosphorus levels ●● Urine sediment abnormalities. may also cause itching (Hawley, 2015). ●● Electrolyte and other abnormalities related to tubular disorders. ●● Histology abnormalities. Calculating kidney function ●● Structural abnormalities, often detected using imaging studies. Overall kidney function is estimated by calculating the glomerular ●● History of kidney transplantation. filtration rate (GFR). This rate describes the flow rate of fluid filtered by all glomeruli, presented as milliliters per minute, and can be calculated Epidemiology in several different ways. The National Kidney Foundation recommends According to the National Institute of Diabetes and Digestive and using the CKD-EPI Creatinine Equation to estimate GFR (National Kidney Diseases (NIDDK), some level of chronic kidney disease can Kidney Foundation, 2017). This equation takes age, sex, race, and be seen in one out of every ten adult Americans, and chronic kidney serum creatinine level into account to calculate an estimated glomerular disease is noted to be the ninth leading cause of death in the US. filtration rate. The calculation is as follows (National Institute of Chronic kidney disease prevalence increases significantly with age, Diabetes and Digestive and Kidney Diseases, 2017): occurring in approximately 4% of adults aged 29-39, and approximately 47% of adults over the age of 70; the most rapid growth is seen in GFR = 141 × min (S /κ, 1)α × max(S /κ, 1)-1.209 × 0.993Age × 1.018 cr cr patients over the age of 60. End-stage renal disease (ESRD) incidence [if female] × 1.159 [if black] rates appear to be stable, with roughly 350 cases occurring per 1 million ○○ S = serum creatinine in mg/dL. cr people (United States Renal Data System, 2015). ○○ κ = 0.7 for females and 0.9 for males. ○○ α = -0.329 for females and -0.411 for males. Chronic kidney disease occurrence can vary significantly with race. Incidence rates of end-stage renal disease in the United States for black ○○ Min indicates the minimum of Scr /κ or 1. patients are nearly four times higher than incidence rates for white ○○ Max indicates the maximum of Scr /κ or 1. patients. It is also noted that specific causes of chronic kidney disease There are many online calculators available to estimate GFR using this can occur at different frequencies for different races. For example, the equation, such as the one provided by the National Kidney Foundation, risk of nephropathy associated with diabetes or hypertension is higher in found at https://www.kidney.org/professionals/kdoqi/gfr_calculator Hispanic and black races (United States Renal Data System, 2015). In the past, many healthcare professionals were trained to calculate Causes of chronic kidney disease creatinine clearance using the Cockcroft-Gault equation to estimate There are a wide variety of causes of chronic kidney disease. Diabetes kidney function. Creatinine clearance calculations using this equation and high blood pressure are among the most common, but other less tend to exceed true GFR by between 10 and 20% or more, depending on common causes include (Arora, 2017): the proportion of urinary creatinine derived from tubular secretion. In the ●● Vascular disease, such as renal artery stenosis or renal vein past, this error was balanced by a nearly equivalent error in measuring thrombosis. serum creatinine, but national standardization of blood creatinine assays ●● Cystic kidney disease. has essentially removed this error. Therefore, creatinine clearance ●● Glomerular disease, such as focal and segmental glomerulosclerosis measurements using the Cockcroft-Gault equation typically reflect a (FSGS). GFR that is falsely inflated, which should be considered when calculating ○○ Glomerular disease can also be secondarily caused by a variety medication dosages for patients with kidney disease (Inker, 2017). of conditions including lupus, rheumatoid arthritis, scleroderma, Defining chronic kidney disease endocarditis, HIV, parasitic infections, and heroin use. The Kidney Disease: Improving Global Outcomes (KDIGO) Work ●● Tubulointerstitial disease, which can be caused by infections, Group defines chronic kidney disease as abnormalities of kidney certain medications such as sulfonamides and allopurinol, chronic structure or function, present for greater than three months, with hypercalcemia or hypokalemia, heavy metal poisoning, and implications for health. This can be measured by either a glomerular radiation. filtration rate (GFR) of less than 60mL/min/1.73m2, or can be defined ●● Urinary tract dysfunction or obstruction, which can be caused by by one or more markers of kidney damage (Kidney Disease: Improving kidney stones, benign prostatic hypertrophy, tumors, neurogenic Global Outcomes (KDIGO) Work Group, 2013). bladder, and urethral stricture. ●● Congenital defects of the kidney or urinary system. ●● Acute kidney injury that does not resolve. Complications of chronic kidney disease Volume overload a higher GFR, if ingested quantities of water and salts exceed the body’s In chronic kidney disease, salt and water processing is impaired, decreased ability for removal. Volume overload can lead to edema, decreasing sodium and free water excretion. Failure to remove adequate worsening congestive heart failure, and hypertension (Arora, 2017). fluids and salts can cause volume overload. Since the body develops Chronic kidney disease patients in volume overload often respond to alternative methods for dealing with this reduction in fluid and salt a combination of diuretic medications and dietary sodium restriction. removal, clinical manifestation of this impairment is often seen when the 2 Loop diuretics, such as furosemide, are often used for diuresis in GFR falls to less than 10-15mL/min/1.73m , after alternative systems symptomatic patients. The KDIGO workgroup recommends restricting have been exhausted. Volume overload can also be seen in patients with Pharmacy.EliteCME.com Page 32 dietary sodium to less than 2 grams per day in all adult CKD patients ●● Cardiovascular disease development, leading to increased unless contraindicated (Rosenberg, 2017, KDIGO Workgroup, 2012). cardiovascular mortality. Hypertension ●● Development or worsening of heart failure. High blood pressure affects over 80% of chronic kidney disease ●● Decreased quality of life. patients. Hypertension is often a result of volume overload and salt The KDIGO workgroup suggests checking hemoglobin levels when retention, due to the reduced ability of the kidneys to remove excess clinically indicated, and at least annually in CKD Stage 3 patients, at fluid and salts. In addition, the renin-angiotensin-aldosterone system, least biannually in CKD stage 4 and 5 patients, and at least quarterly which plays a significant role in regulating blood pressure, is located in patients on dialysis in patients not already diagnosed with anemia. in the kidneys and is over activated in chronic kidney disease. Since For those patients diagnosed with anemia, hemoglobin levels should be hypertension can cause chronic kidney disease, adequate control of checked when clinically indicated, at least quarterly in CKD stage 3 to 5 blood pressure and suppression of the renin-angiotensin-aldosterone patients, and monthly in patients on hemodialysis (KDIGO Workgroup, system is critical to preventing disease progression and reducing 2012; Rosenberg 2017). cardiovascular complications (Rosenberg, 2017). Bone and mineral disease Hyperkalemia Bone and mineral disorders are a frequent complication of chronic Hyperkalemia can develop in patients with chronic kidney disease due kidney disease, due to the altered balance of mineral levels in the body, to a reduced ability to excrete potassium through the kidney, particularly and can be collectively referred to as chronic kidney disease bone and in patients with GFR less than 20-25mL/min/1.73m2. High potassium mineral disease (CKD-BMD). levels can also be seen in earlier stages of chronic kidney disease as In healthy individuals, phosphate and calcium levels are carefully well, particularly in patients who eat a potassium-rich diet or those with balanced in the body, and have opposing effects on each other; increases low aldosterone levels. When kidney function declines, the hormone in calcium levels cause decreases in phosphate levels, and vice versa. aldosterone increases excretion of potassium in the gastrointestinal tract, Dietary calcium and phosphate are absorbed through the small intestine, but this mechanism is often insufficient to maintain normal potassium and are filtered and reabsorbed through the kidney. Phosphate binds with levels in patients with severe or end-stage kidney disease (Arora, 2017). calcium for storage in the bone, which serves as a reservoir to provide Preventative measures can be applied to patients with CKD to avoid additional phosphate and calcium when levels are low. To maintain hyperkalemia. Initiation of a low potassium diet, with restriction calcium and phosphate in balance, parathyroid hormone (PTH) aids in between 1500-2700 mg/day, can reduce potassium available for lowering blood phosphate levels and increasing blood calcium levels. absorption. Avoiding medications that increase potassium levels can Activated vitamin D, known as calcitriol, helps to raise blood phosphate also be beneficial. Potassium levels should be closely monitored in and calcium levels. CKD patients at risk of hyperkalemia (Rosenberg, 2017). Patients with chronic kidney disease experience increased secretion Dyslipidemia of parathyroid hormone early in the course of chronic kidney disease, Abnormal lipid levels are common in chronic kidney disease patients, around the time the GFR drops below 60mL/min/1.73m2. This increase particularly hypertriglyceridemia. Since high lipid levels can increase in PTH helps to maintain normal blood calcium and phosphate levels. cardiovascular risk and cause atherosclerosis, treatment may be However, when the GFR falls to below 20-25 mL/min/1.73m2, the required depending on the level of severity and the patient’s underlying kidneys can no longer keep up with excretion of excess phosphate, cardiovascular risk (Rosenberg, 2017). which results in hyperphosphatemia. High phosphate levels then trigger Metabolic acidosis more release of parathyroid hormone, contributing to high parathyroid Metabolic acidosis can occur in late-stage chronic kidney disease, as levels, or hyperparathyroidism. evidenced by muscle weakness and a loss of lean body mass. Chronic Vitamin D levels are reduced in CKD patients due to reduced activation kidney disease can cause a decreased production of ammonia in of Vitamin D in the kidneys. This results in a reduction in calcium the proximal tubules, which aids in the excretion of acids produced absorption from the small intestine, contributing to lower blood calcium by the body by forming ammonium. Lower levels of ammonia levels, as well as a decrease in bone uptake of calcium. When phosphate production lead to increased acid levels. Additionally, accumulation levels are high, calcium can precipitate with phosphate, contributing of phosphates, sulfates, and organic anions can also contribute to to lower blood calcium levels and additional release of parathyroid increased acid levels. High blood acid levels, or metabolic acidosis, hormone (Rosenberg, 2017). can cause a negative impact on protein balance, leading to reduced Overall, these mineral abnormalities contribute to specific types of protein creation and processing, and causing protein-energy bone structure abnormalities common in CKD patients, such as osteitis malnutrition, muscle weakness, and a loss of lean body mass. Since fibrosa, osteomalacia, and adynamic bone disease. bone can act as a buffer when blood acid levels are high, metabolic acidosis can also lead to bone mineral loss (Arora, 2017). Sexual dysfunction Patients with advanced kidney disease frequently experience Anemia abnormalities in reproductive and sexual function. More than 50% Anemia often begins early on in chronic kidney disease, and progresses of men with uremia experience symptoms including decreased libido in occurrence and severity as renal impairment progresses, affecting and erectile dysfunction. Women with CKD commonly experience about 8% of CKD stage 1 patients and nearly 53% of CKD stage 5 menstruation disturbances, which often progress to amenorrhea by the patients. Decreased renal production of erythropoietin in CKD patients time end-stage renal disease develops (Rosenberg, 2017). reduces stimulation of the bone marrow to produce red blood cells, leading to reduced oxygen-carrying capacity of the blood and reduced Other effects of chronic kidney disease red blood cell survival. Uremia, or buildup of waste products in the Other clinical syndromes associated with end-stage renal disease, blood, can also cause platelet dysfunction which increases the risk of particularly in those patients who are not receiving adequate dialysis, bleeding (Arora, 2017). include (Arora, 2017): ●● Gastrointestinal effects such as nausea, vomiting, diarrhea, or Anemia is diagnosed in CKD patients when the hemoglobin level is anorexia. less than 12 g/dL in females and 13 g/dL in males, and other causes of ●● Malnutrition and failure to thrive. anemia are excluded, such as iron, folate, or vitamin B12 deficiency. ●● Neurological effects, including restless leg syndrome, peripheral Anemia is often associated with the following clinical observations neuropathy, and encephalopathy. (Arora, 2017): ●● Dermatological effects such as pruritus, dry skin, and ecchymosis. ●● Decreased exercise capacity. ●● Pericarditis. ●● Fatigue. ●● Platelet dysfunction leading to an increased risk of bleeding. ●● Reduced immune and cognitive function.

Page 33 Pharmacy.EliteCME.com Management of chronic kidney disease The focus of chronic kidney disease management should be on as these medications have been shown to decrease the risk of long determining the underlying cause of kidney disease and implementing term dialysis and mortality. Patients must be closely monitored for secondary prevention measures to slow or potentially stop disease kidney disease progression and hyperkalemia, a known side effect of progression. Treatment of the underlying condition, as well as treatment these two classes of medication. A small increase in serum creatinine and prevention of adverse effects of chronic kidney disease should be levels is common with ACE inhibitors and ARBs, but if an increase of implemented soon after diagnosis. Patients should see a nephrologist more than 30% occurs, these medications should be stopped. Patients soon after disease detection and maintain follow up to ensure the best with advanced renal failure or renal artery stenosis should avoid these possible outcomes (Arora, 2017). medications (Arora, 2017). Clinical practice guidelines have been published by the National Since hypertension in CKD is often related to volume expansion, Kidney Foundation’s Kidney Disease Outcomes Quality Initiative diuretics are recommended to remove excess fluids and reduce the (KDOQI) to guide management of all CKD stages, as well as associated patients’ weight to their “dry weight,” or their normal weight without complications. Recommendations to delay or cease CKD progression edema. Loop diuretics such as furosemide are recommended for this include (Arora, 2017, KDIGO Workgroup, 2012): purpose. Thiazide diuretics are not typically used to treat hypertension ●● Treating the underlying condition causing chronic kidney disease. and edema in CKD patients because their effectiveness decreases when ●● Treating high lipid levels to bring levels to targets established by the estimated GFR falls below 20 mL/min/1.73m2. current guidelines. Avoiding nephrotoxic medications ●● Aggressive treatment of high blood pressure to bring levels to A frequent cause of worsening kidney function is the administration of targets established by current guidelines. medications that adversely affect renal function. Medications to avoid in ●● Aggressive treatment of high blood sugar in diabetic patients patients with chronic kidney disease include (Rosenberg, 2017): to bring levels to targets established by the American Diabetes ●● Aminoglycoside antibiotics, such as gentamycin. Association, such as hemoglobin A1c levels of less than 7%. ●● Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen ●● Avoiding nephrotoxic medications such as IV contrast dyes, and meloxicam. aminoglycosides, and non-steroidal anti-inflammatory drugs. ●● IV contrast dye used in certain MRI and CT scans. ●● Using medications that block the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) or Many other medications may be considered potentially nephrotoxic, angiotensin receptor blockers (ARBs) in patients with proteinuria. but may not require strict avoidance in chronic kidney disease ●● Reducing protein intake to 0.8 g/kg/day in patients with GFR less patients. Oftentimes, when dosed appropriately and closely monitored, than 30 mL/min/1.73m2, and avoiding high protein diets in CKD potentially nephrotoxic medications can be used safely in early-stage patients at risk of progression. CKD patients. References should be consulted prior to initiating new medications in CKD patients to ensure appropriate medications are used Cardiovascular risk management at appropriate dosages to prevent nephrotoxicity and adverse effects. The KDIGO workgroup guidelines recommend wide use of statins to reduce cardiovascular risk in patients with chronic kidney disease. Their Protein restriction recommendations include (Arora, 2017, KDIGO Workgroup, 2012): Since excess dietary protein intake can lead to the accumulation of waste ●● Treatment with a statin or statin plus ezetimibe for adults 50 and products in the body, the KDIGO workgroup recommends reducing older with an estimated GFR of less than 60 mL/min/1.73m2 who protein intake to 0.8 g/kg/day in patients with GFR less than 30 mL/ 2 are not on long term dialysis. min/1.73m , and avoiding high-protein diets that include more than 1.3 ●● Adults 50 an older with CKD and an estimated GFR of greater than g/kg/day in early-stage CKD patients at risk of progression. Restricting 60mL/min/1.73m2 should also receive a statin. dietary protein must be done cautiously, because insufficient protein ●● Adults 18-49 with an estimated GFR of less than 60mL/min/1.73m2 intake can decrease lean body mass and lead to malnutrition. Advanced who are not on long term dialysis should receive a statin if they chronic kidney disease is associated with protein wasting syndrome, have coronary disease, prior stroke, diabetes, or an estimated 10 which causes increased morbidity and mortality, so protein restriction year risk of coronary death or non-fatal myocardial infarction may be inappropriate in late-stage patients. Dietary changes should be greater than 10%. patient-specific and target individual goals (KDIGO Workgroup, 2012). ●● Statins should not be started in patients on dialysis, though those Renal diet already on a statin when dialysis begins should continue. Patients with chronic kidney disease may need to make changes to their ●● Kidney transplant patients should receive a statin, as these patients diet to prevent disease progression. A reduction in salt intake can aid in are at a higher risk of coronary events. slowing the progression of chronic kidney disease, in part by helping to ●● LDL alone is an insufficient test to identify cardiovascular risk in lower blood pressure, a significant risk factor for disease progression. CKD patients; a complete lipid profile should be assessed. Other dietary restrictions may be indicated depending on the patient, Blood pressure control including water restriction to avoid fluid overload, protein restriction to Aggressive control of blood pressure can help slow the decline in reduce proteinuria, phosphate restriction in patients with high phosphate kidney function in CKD patients. The KDOQI Workgroup suggests a levels, and potassium restriction in hyperkalemic patients (Arora, 2017). target blood pressure of 130/80 mmHg in CKD patients. Systolic blood Renal replacement therapy (dialysis) pressure is considered the priority, though it is the more difficult value Patients with a GFR of less than 15mL/min/1.73m2 should be closely to control in elderly CKD patients. A 2012 study by Peralta et al noted monitored for clinical indications that dialysis may be necessary. The that high systolic blood pressure (SBP) accounted for the majority of Canadian Society of Nephrology recommends in its 2014 guidelines that the risk of progression to end-stage kidney disease. Risk began at a SBP dialysis should be delayed in asymptomatic patients until their estimated of 140 mmHg, and was found to be highest among patients with SBP of GFR falls to 6mL/min/1.73m2 or until the first onset of clinical symptoms at least 150 mmHg (Arora, 2017, Peralta, 2012). of ESRD, including fluid overload, refractory hyperkalemia, metabolic The use of angiotensin-converting enzyme (ACE) inhibitors or acidosis, or uremia. Other factors may influence the choice to initiate angiotensin-receptor blockers (ARBs) is recommended as tolerated, dialysis, including the rate of renal function decline, severity of existing uremia symptoms, and patient education (Arora, 2017; Nesrallah, 2014). Treatment of chronic kidney disease complications Medication usage estimated GFR, while others are contraindicated in moderate or A reduction in kidney function can affect the body’s ability to remove severe renal impairment due to accumulation of the medication or its medications from the bloodstream. This reduced function can cause metabolites. Any time a new medication is added in a patient with differing effects depending on the medication in question. Some chronic kidney disease, appropriate references should be consulted medications may require dosage adjustments based on the patient’s to determine if any dosage adjustments are necessary. Dosages may

Pharmacy.EliteCME.com Page 34 need to be lowered, or administered at extended intervals, to prevent to sevelamer in reducing phosphate levels, with comparable rates accumulation and adverse effects. of adverse effects. Sucroferric oxyhydroxide appears to have more Treatment of Hyperphosphatemia frequent side effect rates and more frequent drug discontinuation rates The KDIGO workgroup guidelines recommend maintaining normal due to side effects. Adverse reactions are similar to those experienced serum phosphate levels within normal range is recommended in patients with administration of iron, and include diarrhea, nausea, constipation, with stage 3-5 CKD, and reducing levels toward normal in patients vomiting, and changes in taste. A typical starting dose of Sucroferric with end-stage CKD. Phosphate levels can be reduced through dietary oxyhydroxide is 2.5g three times daily with meals (Berkoben, 2017). phosphate restriction as well as the use of phosphate binders (Arora, Ferric citrate, sold under the brand name Auryxia, is another iron-based 2017). Dietary phosphate can be restricted to approximately 900 mg/ phosphate binder used to treat hyperphosphatemia. While effective in day. Processed foods such as cola should be restricted over high reducing serum phosphorus levels, citrate in any form has been proven biologic value foods such as meat and eggs (Berkoben, 2017). to increase intestinal absorption of aluminum, increasing aluminum Patients with high phosphate levels despite dietary phosphate restriction toxicity risk. Since this can be a potentially severe reaction in patients may require the use of phosphate binders. Phosphate binders work by with chronic kidney disease, some references recommend avoiding binding with dietary phosphate in the gastrointestinal tract to reduce the all citrate products in chronic kidney disease patients. Ferric citrate amount of phosphate available for absorption. Phosphate binders can be can also increase iron levels, and potentially cause iron overload, so divided into several categories: calcium containing phosphate binders, ferritin and iron saturation levels should be monitored at baseline and non-calcium-containing phosphate binders, iron-based phosphate periodically thereafter. Other adverse reactions are related to the iron binders, and aluminum based phosphate binders (Berkoben, 2017). content and include nausea, vomiting, diarrhea, constipation, and dark stools (Berkoben, 2017). Calcium-containing phosphate binders Calcium-containing phosphate binders include calcium acetate and Aluminum-based phosphate binders calcium carbonate; calcium acetate may be a more efficient phosphate Aluminum hydroxide is an effective phosphate binder, but due binder than calcium carbonate. Their calcium content can potentially to the risk of aluminum toxicity in patients with chronic kidney lead to hypercalcemia, and when combined with high phosphate levels, disease, it is only recommended for short-term treatment of severe can lead to extraskeletal calcium-phosphate deposits. Calcium levels hyperphosphatemia for less than 4 weeks. Its use is infrequent in should be monitored in patients on calcium-containing phosphate chronic kidney disease patients due to the aluminum toxicity risk, binders, and these medications should be reduced or discontinued if which can cause anemia, muscle and bone pain, dementia, and vitamin hypercalcemia develops (Berkoben, 2017). D-resistant osteomalacia (Berkoben, 2017). Calcium acetate (PhosLo) is the most commonly used calcium- Hyperparathyroidism: Vitamin D analogs containing phosphate binder. It is typically started at a dosage of Since reduced levels of activated vitamin D in chronic kidney disease 1334mg three times daily with each meal, and can be increased every patients can contribute to the development of hyperparathyroidism, 2 to 3 weeks until phosphate levels are in target range. Side effects treatment with calcitriol or vitamin D analogs may be necessary to associated with calcium acetate include hypercalcemia, nausea, maintain normal parathyroid hormone levels. More selective vitamin D vomiting, and constipation. analogs such as paricalcitol or doxercalciferol were developed to reduce the risk of hypercalcemia and hyperphosphatemia associated with Non-calcium-containing phosphate binders calcitriol, but the selectivity of these agents has not been consistently Non-calcium-containing phosphate binders include sevelamer and proven in chronic kidney disease patients. Studies show all vitamin D lanthanum. It appears both products are equally effective in lowering analogs demonstrate the potential to increase calcium and phosphate phosphate levels, though more long-term safety data is available for levels, particularly at high doses, leading to increased mortality; adding sevelamer. a phosphate binder may be necessary to maintain normal phosphate Sevelamer is available in two forms: sevelamer hydrochloride, sold levels (Quarles, 2017). under the name Renagel, and sevelamer carbonate, sold under the All three agents appear to have comparable efficacy in reducing name Renvela. Sevelamer works by binding phosphate through ion parathyroid hormone levels, and studies have not shown a preference exchange. It is typically administered three times daily, at a dose of 800 for one agent over others. Price and insurance coverage may be the mg TID for phosphate levels between 5.6-7.4 mg/dL, or 1600 mg TID deciding factor, with many insurance companies preferring calcitriol for phosphate levels greater than 7.5 mg/dL. The cost of sevelamer is due to its lower cost. significantly more than calcium containing phosphate binders, and may need to be considered when choosing a phosphate management regimen Calcitriol, paricalcitol, and doxercalciferol should not be administered for chronic kidney disease patients. until blood phosphorus and calcium levels have been controlled. This is due to the risk of increasing calcium levels in the presence of high Lanthanum is a rare earth element that has effectiveness in reducing phosphorus levels which can lead to precipitation, increasing the risk of phosphate levels in chronic kidney disease patients, sold under vascular calcification. the brand name Fosrenol. It appears to cause reduced rates of hypercalcemia and parathyroid hormone oversuppression when Treatment regimens that limit the dose of calcitriol or vitamin D compared with calcium carbonate. Lanthanum tablets are chewable analogs may be beneficial due to the ability of these agents to induce rather than swallowed whole, which may be a benefit over sevelamer hypercalcemia and hyperphosphatemia. Despite this risk, a number of to some patients. It is typically initiated at a dose of 500 mg three times benefits have been noted with administration of calcitriol and vitamin D daily, and increased by 750 mg per day every 2 to 3 weeks until target analogs, including reduced all-cause death and cardiovascular mortality in phosphate levels are achieved (Berkoben, 2017). hemodialysis patients with adequate vitamin D levels (Quarles, 2017). Short-term safety studies of up to two years have not uncovered any Calcitriol severe adverse effects with lanthanum treatment. Gastrointestinal effects Calcitriol is the activated form of vitamin D. It is available in an oral were the principal adverse effects that developed, and no evidence preparation, associated with the brand name Rocaltrol, and an IV of hepatic toxicity was found. Long-term effects on bone and other preparation, associated with the brand name Calcijex. Oral preparations organs remain unclear; since lanthanum accumulated in several organs are typically used in chronic kidney disease patients; IV administration in animal studies, such as the liver, further research may be needed to is generally reserved for dialysis patients with significant hypocalcemia. evaluate this possibility. Short-term use appears to be unlikely to cause Oral administration can be started at a dose of 0.25 mcg QD, and lanthanum toxicity (Berkoben, 2017). adjusted after 4 to 8 weeks based on calcium and parathyroid hormone levels. Calcitriol should be discontinued if hypercalcemia develops Iron based phosphate binders (Quarles, 2017). Sucroferric oxyhydroxide is an iron-based chewable phosphate binder, sold under the name Velphoro. It is FDA-approved for Paricalcitol treating hyperphosphatemia in patients with a GFR of less than 15 Paricalcitol is a vitamin D analog approved for the treatment of mL/min/1.73m2. Sucroferric oxyhydroxide has comparable efficacy hyperparathyroidism, sold under the brand name Zemplar. It is typically

Page 35 Pharmacy.EliteCME.com started at a dose of 1 mcg daily, and adjusted based on parathyroid due to its inexpensive cost and easy availability, while intravenous is hormone, calcium and phosphate levels every 2 to 4 weeks. preferred for patients who require rapid iron repletion, have a history of Paricalcitol appears to have comparable effectiveness to calcitriol in not responding to iron in the past, or have severe anemia. reducing parathyroid hormone levels. However, a long-term study Several oral iron preparations are available, with the preferred agent has found significantly lower mortality rates with paricalcitol when being ferrous sulfate. Tablets containing 325 mg of ferrous sulfate compared with calcitriol in dialysis patients, beginning after 12 months contain 65 mg of elemental iron, and dosing is based on anemia of treatment. Paricalcitol was also associated with less elevation in severity, ranging from once to three times daily. Side effects of oral iron serum phosphate and calcium levels. Unfortunately, this study was are typically gastrointestinal in nature, and include nausea, vomiting, not randomized and had significant differences in patient baseline constipation, dyspepsia, and dark stools. characteristics, so this trial alone is not considered a reason to prefer Ferrous gluconate typically contains less elemental iron, with 240 mg of paricalcitol over other agents (Quarles, 2017). ferrous gluconate containing 27 mg of elemental iron. This often results Doxercalciferol in a lower incidence of gastrointestinal side effects, though the lower Doxercalciferol is another vitamin D analog approved for the treatment iron content is less ideal when trying to replete iron stores. of hyperparathyroidism, sold under the brand name Hectorol. It is There are also several intravenous iron products available, which appear available in both oral and IV forms, though the IV form is typically to have equal efficacy in treating iron deficiency anemia: reserved for severe cases of hyperparathyroidism in dialysis patients. In ●● Iron sucrose (Venofer) 200 mg doses given five times over two non-dialysis patients, it is started at a dose of 1 mcg daily, and adjusted weeks. based on parathyroid hormone, calcium and phosphate levels every 2 ●● Sodium ferric gluconate complex (Ferrlecit, Nulecit) 125-250 mg weeks up to a maximum dose of 3.5 mcg/day (Quarles, 2017). weekly for 3 to 8 weeks. Hyperparathyroidism: Calcimimetics ●● Ferumoxytol (Feraheme) 510 mg administered once, followed by a Calcimimetics work by increasing the increasing sensitivity of the second 510 mg dose given 3 to 8 days after the first dose. calcium receptor in the parathyroid gland to calcium, which regulates ●● Ferric carboxymaltose (Injectafer) 15 mg/kg, up to 750 mg per parathyroid hormone secretion. This allows for a reduction in serum dose, given in two doses at least 7 days apart. parathyroid hormone levels, as well as a decrease in calcium and ●● Iron dextran – not preferred for treating iron deficiency anemia phosphate levels. Unlike vitamin D analogs, calcimimetics can be in CKD patients due to a higher incidence of severe side effects administered in patients with hyperphosphatemia. There are two including anaphylaxis. calcimimetics available in the US: cinacalcet, an oral medication sold Side effects associated with intravenous iron can be severe, and include under the name Sensipar, and etelcalcetide, an IV product sold under the anaphylaxis, hypotension, and gastrointestinal effects such as nausea, name Parsabiv (Quarles, 2017). vomiting, and abdominal discomfort (Berns, 2017). Cinacalcet is effective in reducing parathyroid hormone levels, as well After ruling out iron deficiency, anemia treatment with erythropoiesis- as helping patients achieve goal calcium and phosphate levels, which stimulating agents may be necessary in patients with hemoglobin levels can be difficult to control as CKD progresses. It has been shown to less than 10 g/dL. The KDIGO workgroup recommends considering be effective in patients unable to take adequate vitamin D doses due the potential benefits of reducing anemia-related symptoms and to high calcium and phosphate levels, though it appears to be more avoiding blood transfusions versus the risks of potential harm of effective in targeting parathyroid hormone levels when administered erythropoiesis-stimulating agents, such as hypertension, stroke, and in combination with vitamin D products. Cinacalcet was not shown to vascular access loss in CKD patients with anemia. If the choice to start reduce mortality in hemodialysis patients under 65 years of age, but an erythropoiesis-stimulating agent is made, using the lowest effective may provide some benefit in older patients with a higher cardiovascular dose is recommended as higher doses are associated with increased risk (Quarles, 2017). cardiovascular events and mortality. Cinacalcet is typically started at a dose of 30 mg once daily, and can be Two erythropoiesis stimulating agents are available for use in CKD increased every 2 to 4 weeks by 30 mg per dose, up to 180 mg per day. patients with anemia. Epoetin, sold under the names Procrit and It should not be started in patients with hypocalcemia. Adverse reactions Epogen, is administered subcutaneously at an initial starting dose of associated with cinacalcet include hypocalcemia and gastrointestinal approximately 50-100 units/kg/week. Lower doses may be appropriate, symptoms; GI symptoms may be reduced when the product is particularly in patients with hemoglobin levels near 10 g/dL. In practice, administered with food and typically resolve with chronic use. Serum many patients are dosed at an even number of units, since vials are calcium and parathyroid hormone levels should be frequently monitored available in 2000, 3000, 4000, 10000, 20000, and 40000 units per to assess for effectiveness and prevent hypocalcemia (Quarles, 2017). mL vials. Therefore, many patients are started at 4000 to 10000 units Etelcalcetide, newly approved by the FDA in February 2017, is weekly or 10000 to 20000 units every other week. Outcomes appear to approved for use in hemodialysis patients with hyperparathyroidism. be similar with weekly and every other week dosing. It is administered after dialysis three times weekly. Short- term studies Darbepoetin, sold under the name Aranesp, is also administered showed it produced a more robust reduction in parathyroid hormone subcutaneously, with initial starting doses between 60 and 200 mcg levels over cinacalcet, though it also caused more hypocalcemia. Side every two to four weeks. effects with etelcalcetide include nausea, vomiting, and prolongation of the QT interval. Serum calcium and parathyroid hormone levels should Target hemoglobin levels are not well defined, though many sources be frequently monitored (Quarles, 2017). recommend goals between 10 and 11.5 g/dL using the lowest effective dose of erythropoiesis-stimulating agents. Therapy should be Anemia individualized based on patient-specific factors. Goal hemoglobin levels Chronic kidney disease patients with anemia should first be assessed over 13 g/dL are not recommended as this may increase the risk of for iron deficiency. Iron administration in deficient patients is typically mortality and cardiovascular events. based on lab values, such as ferritin and transferrin saturation. Most CKD patients require iron supplementation when transferrin saturation Adverse effects associated with erythropoiesis-stimulating agents values are less than 20%, and/or serum ferritin less than 100 ng/ include hypertension, hypertensive encephalopathy, seizures, mL. Depending on the severity of anemia, iron can be administered cardiovascular events, increased mortality, and malignancy (Berns intravenously or orally. The oral form is administered to most patients, 2017). References Arora, P. (2017). Chronic Kidney Disease. Retrieved from https://emedicine.medscape.com/ kidney-disease?source=search_result&search=anemia%20of%20chronic%20kidney%20 article/238798-overview#showall disease&selectedTitle=1~150 Berkoben, M & Quarles, D. (2017). Treatment of hyperphosphatemia in chronic kidney disease. Berns, J. (2017). Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients. Retrieved from https://www.uptodate.com/contents/treatment-of-hyperphosphatemia-in-chronic- Retrieved from https://www.uptodate.com/contents/treatment-of-iron-deficiency-in-nondialysis- kidney-disease?source=see_link§ionName=TREATMENT&anchor=H6#H6 chronic-kidney-disease-ckd-patients?source=related_link Berns, J. (2017). Treatment of Anemia in Nondialysis Chronic Kidney Disease. Retrieved Hawley, M. A. (2015). The Kidney Transplant/Dialysis Association Patient Handbook. Retrieved from from https://www.uptodate.com/contents/treatment-of-anemia-in-nondialysis-chronic- http://msl1.mit.edu/ESD10/kidneys/HndbkHTML/ch1.htm

Pharmacy.EliteCME.com Page 36 Inker, L., & Perrone, R. (2017). Calculation of the creatinine clearance. Retrieved from https://www. timing the initiation of chronic dialysis. CMAJ, 186(2):112-7. Retrieved from http://www.cmaj.ca/ uptodate.com/contents/calculation-of-the-creatinine-clearance content/186/2/112.long Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. (2013). KDIGO 2012 Peralta, C.A., Norris, K.C., Li, S., Chang, T.I., Tamura, M.K., Jolly, S.E., … KEEP Investigators. Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney (2012). Blood Pressure Components and End-Stage Renal Disease in Persons with Chronic Kidney Int Suppl, 3:1-150. Retrieved from http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/ Disease: The Kidney Early Evaluation Program (KEEP). Arch Intern Med, 172(1):41-47. Retrieved KDIGO_2012_CKD_GL.pdf from https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1108640 National Institute of Diabetes and Digestive and Kidney Diseases. (2017). Estimating Glomerular Quarles, L.D. & Berkoben, M. (2017). Management of secondary hyperparathyroidism and mineral Filtration Rate. Retrieved from https://www.niddk.nih.gov/health-information/communication- metabolism abnormalities in dialysis patients. Retrieved from https://www.uptodate.com/contents/ programs/nkdep/laboratory-evaluation/glomerular-filtration-rate/estimating management-of-secondary-hyperparathyroidism-and-mineral-metabolism-abnormalities-in-dialysis- National Institute of Diabetes and Digestive and Kidney Diseases. (2016). Kidney Disease Statistics patients?source=see_link§ionName=Calcimimetics&anchor=H25#H25 for the United States. Retrieved from https://www.niddk.nih.gov/health-information/health-statistics/ Rosenberg, M. (2017). Overview of the management of chronic kidney disease in adults. Retrieved kidney-disease from https://www.uptodate.com/contents/overview-of-the-management-of-chronic-kidney-disease-in- National Kidney Foundation. (2017). GFR Calculator. Retrieved from https://www.kidney.org/ adults?source=search_result&search=chronic%20kidney%20disease&selectedTitle=1~150#H6 professionals/kdoqi/gfr_calculator United States Renal Data System. (2015). USRDS annual data report: Epidemiology of Kidney Nesrallah, G.E., Mustafa, R.A., Clark, W.F., Bass, A., Barnieh, L., Hemmelgarn, B.R., . . . Canadian Disease in the United States. Retrieved from https://www.usrds.org/2015/view/v1_01.aspx Society of Nephrology. (2014). Canadian Society of Nephrology 2014 clinical practice guideline for

COMPLICATIONS OF CHRONIC KIDNEY DISEASE Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com

1. The National Kidney Foundation recommends using ______to 7. ______is a rare-earth element that has effectiveness in estimate GFR. reducing phosphate levels in chronic kidney disease patients. a. CKD-EPI Creatinine Equation. a. Lanthanum. b. Cockroft Gault Equation. b. Calcium carbonate. c. 24 hour urine collection. c. Doxercalciferol. d. Jelliffe equation. d. Cinacalcet. 2. The Kidney Disease: Improving Global Outcomes (KDIGO) 8. ______is an iron-based chewable phosphate binder, sold Work Group defines chronic kidney disease as abnormalities of under the name Velphoro. kidney structure or function, present for greater than_____, with a. Sevelamer. implications for health. b. Sucroferric oxyhydroxide. a. Three days. c. Lanthanum. b. Three months. d. Calcium acetate. c. Two weeks. 9. ______is the activated form of vitamin D. d. Thirty days. a. Calcitriol. 3. Which of the following accurately describes Stage 4 CKD? b. Doxercalciferol. a. Markers of kidney damage found, but GFR is normal or c. Paricalcitol. increased (>90 mL/min/1.73 m2). d. Calcium acetate. b. Mildly reduced GFR (60-89 mL/min/1.73 m2). 10. Unlike vitamin D analogs, calcimimetics can be administered in c. Severely reduced GFR (15-29 mL/min/1.73 m2). d. Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis). patients with: a. Hyperphosphatemia. 4. The KDIGO workgroup recommends restricting dietary sodium to b. Hypoparathyroidism. ______per day in all adult CKD patients unless contraindicated. c. Hypertension. a. Less than 4 grams. d. Hyperlipidemia. b. Less than 2 grams. c. Greater than 2 grams. d. Less than 1 gram. 5. The KDOQI Workgroup suggests a target blood pressure of ______in CKD patients. a. 120/80mmHg. b. 130/80mmHg. c. 135/85mmHg. d. 140/90mmHg. 6. ______diuretics are not typically used to treat hypertension and edema in CKD patients because their effectiveness decreases when the estimated GFR falls below 20 mL/min/1.73m2. a. Thiazide b. Loop. c. Potassium-sparing. d. Sodium-sparing.

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Page 37 Pharmacy.EliteCME.com Chapter 4: Diabetic Medications and Insulin Pump Therapies 6 Contact Hours

By: Katie Blair, PharmD, RPh Questions regarding statements of credit and other customer service Author Disclosure: Katie Blair and Elite Professional Education do issues should be directed to 1-888-666-9053. This lesson is $24.00. not have any actual or potential conflicts of interest in relation to this Educational Review Systems is accredited by the lesson. Accreditation Council of Pharmacy Education (ACPE) as a Universal Activity Number UAN: 0761-9999-17-259-H01-P provider of continuing pharmaceutical education. This Activity Type: Knowledge-based program is approved for 6 hours (0.6 CEUs) of continuing Initial Release Date: August 21, 2017 pharmacy education credit. Proof of participation will be Expiration Date: August 21, 2019 posted to your NABP CPE profile within 4 to 6 weeks to Target Audience: Pharmacists in a community-based setting. participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course To Obtain Credit: A minimum test score of 70% is needed to evaluation to receive continuing pharmacy education credit. obtain a statement of credit. Please submit your answers online at Pharmacy.EliteCME.com Audience This medication-rich course is for all pharmacists responsible for managing patients with diabetes. Overview Diabetes and glycemic medications are in the news every day. Staying This course provides the latest in diabetic medications and treatment ahead of current research and treatment options is an uphill challenge. options, including insulin pump therapies. Learning objectives Describe the normal processing of blood glucose in a healthy Discuss the characteristics of glucagon-like peptide-1 (GLP-1) person. receptor agonists, including effects on blood glucose control, Discuss the altered processing of blood glucose in diabetic patients. cardiovascular effects, adverse reactions, and the use of short-acting Recognize the effects of sulfonylureas on blood glucose control, vs. long-acting agents. cardiovascular effects of sulfonylureas, their adverse reactions, and Explain the characteristics of dipeptidyl peptidase-4 (DPP- the currently available sulfonylureas. 4) inhibitors, including effects on blood glucose control, Describe the characteristics of meglitinides, including effects on cardiovascular effects, adverse reactions, and the currently available blood glucose control, cardiovascular effects, adverse reactions, and DPP-4 inhibitors. the medications available in this class. Identify the characteristics of sodium-glucose cotransporter 2 Discuss metformin’s effects on blood glucose control, (SGLT-2) inhibitors, including effects on blood glucose control, cardiovascular effects, and its potential adverse reactions. common adverse reactions, and the currently available SGLT-2 Recognize the characteristics of thiazolidinediones, including inhibitors. effects on blood glucose control, impact on cardiovascular health, Discuss the available insulin products, including the difference and contraindications to the use of this class of medication. between basal and prandial insulin, the insulin products currently Explain the effects of amylin analogs on blood glucose control, available, common types of insulin regimens, and the use of insulin cardiovascular effects, adverse reactions, and their dosing. pumps. Describe the characteristics of alpha glucosidase inhibitors, including effects on blood glucose control, cardiovascular effects, and the dosing and availability of these agents. Introduction Diabetes is a metabolic disorder characterized by high blood glucose 73,000 lower limb amputations were performed on diabetic patients in levels and insufficient or ineffective insulin. It is a highly prevalent 2010. These complications make up a significant portion of the total disease that has created a significant public health issue in the United cost of diabetes (Centers for Disease Control, 2016). States. The Centers for Disease Control and Prevention reported that With such a high disease burden, appropriate treatment of diabetes is 9.3% of the US population had diabetes in 2014. Over 8 million people increasingly important to prevent the development of severe diabetic who meet the criteria for a diabetes diagnosis remained undiagnosed and complications. Early initiation of pharmacologic therapy is associated untreated, increasing their risk for complications associated with diabetes. with improved glycemic control and reduced long-term complications The high prevalence of diabetes resulted in a staggering estimated total in diabetic patients (Centers for Disease Control, 2016). With a cost of over $245 billion in 2012 (Centers for Disease Control, 2016). wide variety of medications available for the treatment of diabetes, Controlling blood glucose levels is critical to the prevention of severe pharmacists must familiarize themselves with the tools available to diabetic complications. Complications associated with improperly treat this growing public health problem. This course serves to review controlled diabetes include retinopathy, neuropathy, kidney disease, the medications available for the treatment of diabetes, as well as the slow wound healing and can lead to limb amputation. Over 4 million current recommendations for choosing pharmacologic treatment. diabetic patients had diabetic retinopathy between 2005 and 2008, and Normal processing of blood glucose (University of California San Francisco, 2016) In order to understand the use of medications to treat diabetes, it is person. The following section will focus on reviewing key terms used in important to review the normal control of blood glucose in a healthy to describe the body’s normal processing of glucose.

Pharmacy.EliteCME.com Page 38 Insulin transit of food through the stomach, and stimulates the brain to make a Insulin is a hormone released by the beta cells in the pancreas. When person feel full after eating. insulin levels are high, sugar is driven into liver cells to store it for Stress hormones future use. In turn, glucose is converted to glycogen for storage in the Other hormones involved in the control of blood sugar levels include liver. Insulin also facilitates the movement of glucose into muscle and cortisol, growth hormone, and epinephrine. Cortisol, a steroid hormone, fat cells for storage. In a healthy person, insulin levels are relatively low is released from the adrenal gland, and increases the resistance of and constant between meals and overnight; these low insulin levels are the fat and muscle cells to the effects of insulin. It also increases known as basal insulin levels. After eating, insulin is released in higher the liver’s production of glucose. Under normal conditions, cortisol levels from the pancreas. The bolus of insulin released after food intake counterbalances the action of insulin. Stress (or the use of synthetic helps remove excess glucose from the bloodstream and store it for cortisol medications such as prednisone) increases cortisol levels, future use. resulting in resistance to insulin and in the requirement of more insulin Glucagon to maintain normal blood sugar levels. Glucagon is a hormone made by the islet cells of the pancreas, which Growth hormone is released by the pituitary gland in the brain, and acts controls the production of glucose and ketones by the liver. It stimulates to counterbalance the effects of insulin on fat and muscle cells. When the liver to convert glycogen into glucose, which is released between growth hormone levels are high, insulin resistance develops, similar meals and overnight to maintain blood sugar levels. After meals, when to the effect observed when cortisol levels are high. Epinephrine is the liver does not need to release glucose, glucagon levels are low. released from the adrenal gland and nerve endings, and has direct action Glucagon also promotes fat breakdown in fat cells, which creates on the liver to increase glucose production through glycogenolysis. It supplies needed to make ketones. also promotes the release of fat nutrients that can be converted by the The liver liver into glucose and ketones. In terms of blood glucose control, the liver serves as a reservoir to store Along with glucagon, cortisol, growth hormone, and epinephrine are excess glucose in response to insulin when blood glucose levels are high, referred to as stress hormones, or “gluco-counter-regulatory” hormones. and releases it in response to glucagon when blood glucose levels are When the body is under stress, it tries to increase blood sugar levels to low. Immediately after meals, when insulin levels are high and glucagon produce fuel in stressful situations. To accomplish this, insulin levels are levels are low, glucose is stored in the liver as glycogen. When blood decreased, and epinephrine and glucagon levels are increased to release glucose levels are low between meals or overnight, the liver converts more glucose from the liver. Growth hormone and cortisol levels also glycogen into glucose through a process called glycogenolysis. The liver rise, causing muscle and fat tissues to increase resistance to insulin in is also capable of manufacturing glucose from certain amino acids, fat order to minimize the uptake of glucose by muscle and fat. Overall, this byproducts such as glycerol, and waste products such as pyruvate and increases the levels of glucose in the bloodstream, so the body has fuel lactate, through a process called gluconeogenesis. to work under stress. When glycogen storage levels are low, the body conserves glucose supplies for organs that can only function with glucose as energy, such Diabetes consideration: While the stress response is a natural as red blood cells, the brain, and parts of the kidney. In this situation, response to a significant threat, such as being chased by a tiger, in the liver uses fats to create alternative fuel, called ketones, through a modern society, stress comes in many forms. Family and work stress process called ketogenesis. Ketones are then used by muscle and other can develop the same physiological response over time. organs as fuel, reserving glucose for the organs that need it most. Ketones Incretins In healthy people, the production of ketones is the body’s adaptation Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic to starvation. Ketones are alternative fuels the liver makes by breaking polypeptide (GIP) are incretin hormones that are released by the down fats when glucose supplies are limited. They are most commonly gastrointestinal tract when stimulated by ingestion of food. Incretins made overnight, and during periods of fasting. Insulin levels are low signal beta cells to increase their secretion of insulin, and decrease the during these periods, but epinephrine and glucagon levels remain release of glucagon from alpha calls in response to a meal. GLP-1 also relatively normal. This combination of hormone levels stimulates the acts to slow the transit of food from the stomach, and triggers the brain release of fat from fat cells, which travel to the liver for processing into to produce a sensation of fullness and satiety. GLP-1 is broken down ketones, which are then used by muscle and other tissues to fuel the by an enzyme called dipeptidyl peptidase 4, which is a target of a class body. of antidiabetic medications. GLP-1 is also a pharmacologic target, with Practice question #1 products available to stimulate GLP-1 receptors to mimic the effects of Which of the following is NOT a hormone involved in the regulation of GLP-1. blood glucose levels? Amylin a. Cortisol. Amylin is a hormone released from the beta cells of the pancreas along b. Glucagon-like peptide-1. with insulin, and has a similar effect to GLP-1. It lowers glucagon c. Ketones. levels after a meal to decrease the liver’s glucose production, slows the d. Amylin. Diabetic processing of blood sugar (University of California San Francisco, 2016; Aronoff et al, 2004) Diabetes can have a significant impact on the function of various insulin, requiring more insulin to uptake the same amount of glucose hormones in the body. Here, we will review the effects of diabetes on from the blood. These actions result in increased blood sugar levels. the hormones that regulate the processing of blood sugar. Glucagon Insulin In contrast to the mechanism in healthy people, diabetic patients Type I diabetes occurs due to the autoimmune-mediated destruction of experience a rise in glucagon levels after a meal, stimulating the liver beta cells in the pancreas. Depending on when the disease process is to continue producing glucose from glycogen and causing blood sugar detected, some or most beta cells are affected, resulting in an inability to levels to rise inappropriately after the meal. provide enough insulin for normal glucose processing. This results in an Incretins increase in serum blood sugar levels, since the pancreas cannot provide Diabetic patients have malfunctioning or non-functioning beta cells, enough insulin to stimulate the uptake of adequate amounts of glucose resulting in abnormally low or absent insulin and amylin levels. Since by the liver for storage. incretins signal beta cells to increase their secretion of insulin, this In type II diabetic patients, beta cells malfunction, resulting in decreased mechanism is less effective in diabetic patients, resulting in an increase insulin production after a meal and, therefore, higher blood sugar in blood sugar levels. levels after meals. Liver, fat and muscle cells also develop resistance to GLP-1 levels are also lower in diabetic patients. Since GLP-1 stimulates amylin to slow the transit of food from the stomach, trigger the brain

Page 39 Pharmacy.EliteCME.com to make a person feel full and satiated, and suppress glucagon, lower growth hormone and cortisol. The rapid release of epinephrine increases GLP-1 levels can contribute to increased appetite in diabetic patients, the liver’s production of glucose and promotes the release of fat ultimately leading to increased blood sugar after a meal through these byproducts for use by the liver to make glucose and ketones, to increase mechanisms. blood sugar levels. The slower release of growth hormone and cortisol Amylin results in increased fat and muscle cell resistance to insulin to minimize When pancreatic beta cells are destroyed in people with type I diabetes, the use of available blood glucose, and increases the liver’s production levels of the hormone amylin are also lowered, since amylin is also of glucose to increase blood sugar levels. This response can last for 6 secreted by the beta cells. Patients with type II diabetes have decreased to 8 hours, and blood sugar control can be difficult in this period.The beta cell function, which can also lead to decreased amylin levels. The occurrence of low blood sugar followed by high blood sugar is known decreased amylin levels in diabetic patients result in higher glucagon as a “Somogyi” or rebound reaction. It often occurs after an episode levels after meals, which prompts the liver to continue glucose of untreated nighttime hypoglycemia, resulting in high blood glucose production after a meal despite there being no need for additional levels in the morning. glucose at this time. Since amylin also slows the transit of food through Ketones the stomach and stimulates the brain to make a person feel full after In people with type 1 diabetes, an excess of ketones can be very eating, these mechanisms are less functional in diabetic patients, dangerous, and life threatening. Fat cells continue releasing fats to contributing to an increase in blood sugar levels. continue ketone production in the liver due to the lack of insulin, Stress hormones resulting in an excess of ketones. The high levels of ketones decrease When people with diabetes have low blood sugar, the stress response is the blood pH, causing diabetic ketoacidosis, an emergency situation triggered, releasing epinephrine rapidly, followed by slower release of requiring immediate care. Medications to treat diabetes Insulin secretagogues: Sulfonylureas (Hollander, 2008; McCulloch, of sulfonylureas on K-ATP channels may be seen in cardiac cells 2016) in addition to pancreatic beta cells, preventing adequate coronary Sulfonylureas have been available in the US since 1954, and were one vasodilation during a myocardial infarction and increasing the area of of the first widely used classes of oral antidiabetic agents. They work by myocardial damage. Other hypotheses suggest that sulfonylureas may stimulating the release of insulin from the pancreas by directly acting interfere with ischemic preconditioning or cause arrhythmias. Newer on the potassium sensitive adenosine triphosphate (K-ATP) channel sulfonylureas, such as glimepiride, appear to be more selective for of pancreatic beta cells; this channel regulates the release of insulin pancreatic beta cells over cardiac cells, and have not been shown to from the beta cells. Sulfonylureas may also have effects outside of the increase cardiovascular mortality when compared with metformin or pancreas, such as increasing tissue sensitivity to insulin, but it appears other agents, though studies have not been conducted on this yet. that the clinical effects of this action are minimal. They are effective Adverse reactions in patients who still have some beta cell function, making them Sulfonylureas are generally fairly well tolerated. The most common side particularly useful in type II diabetes, and less useful in type I diabetes. effect is hypoglycemia, which can limit the use of these medications Sulfonylureas can be divided into two subclasses: first generation in elderly patients and those patients for whom hypoglycemia can agents, such as chlorpropamide, and second generation agents, such as be associated with more severe side effects, such as falls. A 2014 glyburide, glimepiride, and glipizide. systematic review found that when compared with DPP-4 inhibitors and Effects on blood glucose control GLP-1 agonists, medications that typically do not cause hypoglycemia, Sulfonylureas have been shown to decrease A1c by 1 to 2%. A 2013 sulfonylureas were associated with severe hypoglycemia in 0.8% of meta-analysis of 31 studies found that monotherapy with a sulfonylurea patients, and glucose levels less than 56mg/dL in 10.1% of patients decreases A1c levels by 1.5% more than placebo, and that adding (Schopman et al., 2014). sulfonylureas to another oral agent such as metformin decreased A1c Hypoglycemia occurs more commonly with longer acting sulfonylureas 1.62% more than placebo (Hirst et al., 2013). such as glyburide and chlorpropamide. Patients should be counseled on Cardiovascular effects situations when hypoglycemia is more common, such as after missing The cardiovascular effects of sulfonylureas are uncertain, despite a a meal or exercising, those who are undernourished, those who abuse number of studies performed to explore this topic. A 2013 meta-analysis alcohol, those with impaired cardiac or renal function, those with assessed the cardiovascular safety of sulfonylureas compared with gastrointestinal disease, when taking sulfonylureas in combination active comparators in type II diabetic patients treated for at least six with sulfonamides, gemfibrozil, warfarin, or salicylates, after being months; it found no difference in the incidence of major cardiovascular hospitalized, and when sulfonylurea dosages are too high. events, but overall mortality was increased (Monami et al., 2013). Diabetes consideration: Hypoglycemia is a significant side effect Subsequent meta-analysis of trials lasting at least one year did not find of sulfonylureas. Patients at a high risk of significant adverse effects sulfonylureas to be associated with increased risk of cardiovascular when hypoglycemic, such as elderly patients at risk of significant mortality, overall mortality, myocardial infarction, or stroke. injury from falling, should not be started on sulfonylureas. When compared with metformin, randomized trials, as well as retrospective studies, have suggested sulfonylureas may be associated Sulfonylureas are excreted by the kidney, creating a higher risk of with higher rates of cardiac events than metformin. However, it is hypoglycemia in patients with chronic kidney disease. Short-acting unclear if these increased cardiac event rates are related to sulfonylurea sulfonylureas with inactive metabolites, such as glimepiride or glipizide, toxicities or to the protective effects of metformin. are preferred in these patients to minimize the risk of hypoglycemia. Studies have also suggested that sulfonylureas may also be linked Patients who are allergic to sulfonamides may experience an allergy to poor outcomes in patients who have a myocardial infarction, to sulfonylureas. While this association appears to be unfounded, though the evidence appears to be conflicting. The University Group caution is advised in patients with severe sulfonamide allergies, such as Diabetes Study noted in 1976 that tolbutamide is linked with increased anaphylaxis. cardiovascular disease mortality. These findings were not replicated in Other adverse reactions associated with sulfonylureas include skin the 2004 United Kingdom Prospective Diabetes Study (UKPDS), which reactions such as rash and photosensitivity, abnormal liver function found no increase in death in patients taking sulfonylureas at the time of tests, and nausea. Sulfonylureas are also associated with weight gain, a myocardial infarction (UK Prospective Diabetes Study Group, 1998). making them a less attractive option in obese patients. However, other studies have replicated the link between sulfonylureas First generation sulfonylureas and poor myocardial infarction outcomes. First generation agents are not commonly used anymore, due to their Several hypotheses have discussed this possible link between longer duration of action leading to increased risks of hypoglycemia, sulfonylureas and poor outcomes. One hypothesis is that the action as well as to other adverse reactions, including hyponatremia and

Pharmacy.EliteCME.com Page 40 Antabuse-like effects of alcohol-induced nausea and vomiting. First Glipizide generation sulfonylureas are not typically initiated in patients with Glipizide is a preferred agent in patients with chronic kidney disease diabetes anymore, but treatment may continue in patients started on who are not on dialysis because it is metabolized by the liver and its these agents a long time ago if glucose levels remain in control. inactive metabolites are excreted through the urine. Chlorpropamide Glipizide is typically initiated at a dose of 2.5mg once daily, and can be Chlorpropamide has been associated with a relatively high incidence of increased slowly in 2.5mg increments every 2 to 4 weeks if needed. The hypoglycemia, particularly in older patients. It is also associated with maximum dosage of glipizide is 40mg once daily, but doses greater than unique adverse effects. It can lead to flushing after alcohol ingestion 10mg per day typically do not improve blood glucose control, so higher due to inhibiting the metabolism of acetaldehyde, and can cause doses should be avoided. Doses over 30mg per day are typically divided hyponatremia through increased action of vasopressin. into twice-daily dosing. Initial doses are in the range of 100 to 250mg once daily. Glipizide is available in a short-acting and long-acting form, under Chlorpropamide is available as a generic medication, associated with the brand names Glucotrol and Glucotrol XL. It is also available in the brand name Diabinese. combination with metformin under the name Metaglip. Tolazamide Glimepiride Initial dosing of tolazamide is typically 250mg once daily. Tolazamide Glimepiride is a preferred agent in patients with chronic kidney disease is available as a generic medication, associated with the brand name who are not on dialysis because it is metabolized by the liver and Tolinase. its inactive metabolites are excreted through the urine. Glimepiride Tolbutamide is preferred in patients with cardiovascular disease, due to its Tolbutamide has been linked with an increased risk of cardiovascular selective action in the pancreas over cardiac cells and therefore lower disease mortality and is, therefore, rarely used. Initial doses are typically cardiovascular risk. 1 gram once daily. Tolbutamide is available as a generic medication, Glimepiride is often started at a dose of 1 to 2mg once daily with associated with the brand name Orinase. breakfast; 1mg is the preferred initial dose in patients at an increased Second generation sulfonylureas risk of hypoglycemia, such as elderly patients and those with kidney Second generation agents are thought to be more potent, associated with disease. It can be increased in 1 or 2mg increments every 2 to 4 weeks fewer side effects, and cause more weight gain as compared with first if necessary. Typical daily dose of glimepiride is 2 to 4mg once daily, generation agents. In comparison with first generation agents, second though the maximum dosage is 8mg per day. generation sulfonylureas are preferred for their shorter duration of Glimepiride is available as a generic medication, associated with action and their comparatively lower incidence of hypoglycemia. the brand name Amaryl. It is also available in combination with Glyburide pioglitazone under the name Duetact, and in combination with Glyburide has been associated with a relatively high incidence of rosiglitazone under the name Avandaryl. hypoglycemia, particularly in older patients. Therefore, its use is limited Practice question #2 in patients over the age of 65 and those at high risk of hypoglycemia. Which of the following sulfonylureas should NOT be used in patients Glyburide is typically initiated at a dose of 2.5mg once daily, given with over the age of 65? the first meal of the day, and can be increased in 2.5 to 5mg increments a. Glimepiride. every 2 to 4 weeks as needed. b. Glyburide. c. Glipizide. Glyburide is available as a generic medication, associated with the d. Metformin. brand names Diabeta and Micronase. It is also available in combination with metformin, associated with the brand name Glucovance. Rapid acting secretagogues: Meglitinides (Hollander, 2008; McCulloch, 2016) Similar to sulfonylureas, meglitinides act on the pancreatic beta cells Cardiovascular effects to increase the secretion of insulin. This is accomplished by closing No long-term studies have been conducted to assess the cardiovascular the K-ATP channels of beta cells, which results in opening calcium effects of meglitinides in patients with type II diabetes. Since their channels to increase insulin secretion. The chemical structure of mechanism of action is similar to sulfonylureas, which have been meglitinides is different than that of sulfonylureas and therefore, associated with an increased risk of cardiovascular mortality, there are meglitinides can be used in patients with a sulfonylurea or sulfa allergy. concerns that meglitinides may have similar effects. A retrospective Meglitinides have a rapid onset of action and a relatively short half- study of type II diabetic patients taking glyburide or repaglinide found life, which results in a more targeted decrease of post-prandial blood no difference in the risk of adverse cardiovascular outcomes between sugars. They are administered with meals, so that their effect will target these medications after 30 days. postprandial hyperglycemia. Since their action is short, they carry a Repaglinide lower risk of hypoglycemia. This also results in a need for multiple Repaglinide is primarily metabolized in the liver, and less than 10% daily doses, as the effects of meglitinides wear off quickly. is excreted through the kidneys. This allows for safe administration in Effects on blood glucose control patients with chronic kidney disease. Dose adjustments are not required Meglitinides, when used as monotherapy, have a similar efficacy for patients with a creatinine clearance greater than 40mL/min. Patients to sulfonylureas, causing an average reduction in A1c of 1 to 2%. with creatinine clearance between 20 and 40mL/min should start with However, they are not frequently used as monotherapy due to the 0.5mg before the largest meal of the day and can be titrated up to 0.5mg requirement of frequent dosing. before each meal. Repaglinide use has not been studied in patients with a creatinine clearance of less than 20mL/min. Repaglinide is typically started in patients without prior diabetes Evidence-based practice alert! A 2007 meta-analysis analyzed medication treatment at a dose of 0.5mg before meals; patients who meglitinide efficacy in comparison with metformin, insulin, or have previously taken oral hypoglycemic medications and have an A1c placebo. According to the results of the study, both repaglinide greater than 8% can be started at 1 or 2mg prior to meals. Dosages are and nateglinide appear effective in reducing A1c levels, but adjusted based on fasting glucose levels measured at least a week after a repaglinide is more effective at reducing A1c than nateglinide. dose adjustment. The maximum dose of repaglinide is 4mg before each Repaglinide efficacy appeared to be similar to metformin in terms meal. If a meal is skipped, repaglinide should not be taken. Repaglinide of A1c reduction (Black et al., 2007). should not be administered in patients taking gemfibrozil, as gemfibrozil can prolong the plasma concentrations of repaglinide.

Page 41 Pharmacy.EliteCME.com Repaglinide is available as a generic medication, associated with the Adverse reactions brand name Prandin. Meglitinides are generally well tolerated. They carry a similar risk of Nateglinide weight gain to that of sulfonylureas. They do carry a risk of causing Nateglinide is metabolized in the liver, and its active metabolites are hypoglycemia, with approximately 16% of patients experiencing excreted through the kidney. Therefore, it should be avoided in patients hypoglycemia (Hollander, 2008; McCulloch, 2016). Hypoglycemia with chronic kidney or liver disease. risk with meglitinides appears to be less than with sulfonylureas, but this risk should be considered when considering meglitinides in The recommendation for nateglinide dosing is 120mg before each meal. patients with a high risk of severe hypoglycemia or complications of Nateglinide is available as a generic medication, associated with the hypoglycemia, such as geriatric patients who are at a high risk of falls. brand name Starlix. Other rare but significant side effects with meglitinides include upper respiratory infection, rhinitis, sinusitis, elevated hepatic enzymes, thrombocytopenia, leukopenia, and anaphylaxis. Insulin sensitizers: Biguanides (Hollander, 2008; McCulloch, 2016b) Biguanides, a class of antidiabetic medications that are a common first Dosing line agent in the treatment of type II diabetes, consist of only one drug: Metformin is typically initiated at a dose of 500mg once daily with metformin. Metformin works by decreasing glucose production by the food. It is then commonly titrated up by 500mg every one to two weeks liver by inhibiting gluconeogenesis. It also increases the use of glucose as tolerated, to a typical goal dosage of 1000mg twice a day. Titration by peripheral tissues such as muscle, especially after meals, allowing of the dose can minimize the risk of adverse gastrointestinal effects, and for a reduction in fasting hyperglycemia. Metformin also has effects on taking it with food can help improve tolerability as well. The maximum lowering free fatty acid concentrations in the bloodstream by reducing recommended dose of metformin is 2550mg per day, though this dose is the availability of fatty acids for gluconeogenesis. It has also been often associated with more gastrointestinal adverse effects. shown to reduce food intake and decrease weight. Diabetes consideration: Gastrointestinal side effects are often a Effects on blood glucose control limiting factor when initiating metformin. Patients should be titrated Similar to sulfonylureas, metformin typically reduces A1c by 1 to 2% to the highest dose they can tolerate, and if additional blood glucose when used as monotherapy. The 1995 Multicenter Metformin Study lowering is necessary, additional antidiabetic agents can be added. Group found that after 29 weeks, type II diabetic patients inadequately controlled with diet who were randomly assigned to receive metformin Metformin is available in 500mg, 850mg, and 1000mg tablets. had an average A1c of 7.9% vs 8.6% compared to patients randomly Extended release forms are also available; these can be taken once assigned to receive a placebo (DeFronzo and Goodman, 1995). daily to reduce pill burden but do not provide any additional benefits. Cardiovascular effects It is available in combination with alogliptin, linagliptin, saxagliptin, A number of studies have assessed the cardiovascular effects of sitagliptin, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, metformin, and in general, it appears that metformin does not repaglinide, and canagliflozin. cause adverse cardiovascular events and can decrease the risk of Adverse effects cardiovascular events in certain populations. The large United Kingdom The most common side effects associated with metformin are Prospective Diabetes Study (UKPDS) found that obese patients gastrointestinal in nature, including nausea, abdominal discomfort, who received metformin had a decreased risk of macrovascular and diarrhea, mild anorexia, and a metallic taste. These effects are generally microvascular complications, as well as a decreased risk of all-cause mild and transient, and are reversible upon discontinuation. Clinical mortality, as compared with placebo over an average of 10.7 years. trials have shown a 5% discontinuation rate due to gastrointestinal side These risk reductions were maintained after the study in the post- effects (Hollander, 2008; McCulloch, 2016b). interventional observation period as well (UK Prospective Diabetes Up to 30% of patients taking metformin experience reduced intestinal Study Group, 1998). absorption of vitamin B12. This results in only 5 to 10% of patients These effects on cardiovascular mortality were replicated in a 2016 experiencing lowered serum B12 concentrations, and rarely leads to meta-analysis of 179 trials and 25 observational studies. The studies megaloblastic anemia (Hollander, 2008; McCulloch, 2016b). However, assessed the comparative effectiveness and safety of monotherapy with some patients may experience peripheral neuropathy, which can be metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, difficult to differentiate from diabetic neuropathy that is common as a glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones, result of the diabetic disease state. Higher doses and longer durations and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and selected are correlated with higher risks of B12 deficiency (Hollander, 2008; metformin-based combinations in type II diabetic adults. Effects on McCulloch, 2016b). Supplementation with oral or injectable vitamin cardiovascular mortality, A1c, lipid profiles, body weight and adverse B12 can help to correct this issue if it occurs. effects were assessed. Metformin was found to be associated with Lactic acidosis is a significant side effect of metformin, and while it reduced cardiovascular mortality when compared with sulfonylureas. has a relatively low incidence of approximately one case per 33,000 Metformin, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors patient-years, it can be fatal. It is more likely to occur in patients with were also associated with reduced or maintained body weight (Maruthur insufficient renal function, as metformin can accumulate in these et al., 2016). patients. Symptoms of lactic acidosis are generally nonspecific, and Cardiovascular benefits of metformin may be associated with its can include nausea, vomiting, anorexia, abdominal pain, lethargy, lipid lowering activity, as metformin has been shown to lower serum hypotension, and hyperventilation. Metformin is also contraindicated triglycerides, free fatty acid concentrations, and have minimal effects in in conditions associated with acidosis, such as metabolic acidosis or lowering LDL and increasing HDL concentrations. ketoacidosis, due to the risk of additive blood acidification. Other risk factors for developing lactic acidosis due to metformin include patients with renal failure (acute or chronic), heart failure (acute or chronic), Evidence-based practice alert! Metformin monotherapy is sepsis, dehydration, acute pulmonary decompensation, maternally not typically associated with significant weight gain, unlike inherited diabetes and deafness, and overdoses of metformin. sulfonylureas and insulin. When compared with glyburide in Practice question #3 a large 2006 study, metformin was shown to reduce weight Which of the following side effects is common when treating patients by an average of 2.9kg, as opposed to glyburide, which was with metformin? correlated with an average weight gain of 1.6kg over a period a. Diarrhea. of 5 years (Kahn et al., 2006). b. Lactic acidosis. c. Injection site reactions. d. Rhinitis.

Pharmacy.EliteCME.com Page 42 Contraindications and precautions Since metformin is excreted through the urine, it should not be initiated Due to the risk of lactic acidosis, metformin is contraindicated in in patients with a glomerular filtration rate between 30 and 45mL/min patients with the following comorbidities: due to the risk of accumulation, which can increase the risk of lactic ●● Active alcohol abuse. acidosis. Patients who are taking metformin and experience a decrease ●● Acute heart failure patients at risk of hypoxemia and hypoperfusion. in their glomerular filtration rate to below 45mL/min should have their ●● Patients who have a history of lactic acidosis while taking risks and benefits of continued treatment with metformin reassessed. If metformin. their glomerular filtration rate falls below 30mL/min, metformin should ●● Patients with hemodynamic instability or decreased tissue perfusion. be discontinued. ●● Active or progressive hepatic disease. Patients receiving iodinated contrast dye for procedures should ●● Impaired renal function with a glomerular filtration rate of less than have metformin held until their renal function is determined to be 30mL/min. stable, as contrast dyes have the potential to induce renal failure, a contraindication to the use of metformin. Thiazolidinediones (TZDs) (Hollander, 2008; McCulloch, 2016c) Thiazolidinediones have a complex mechanism of action that may with a more favorable lipid profile. Pioglitazone was associated with not be thoroughly understood. It is thought that thiazolidinediones consistent LDL levels when used as monotherapy or in combination increase insulin sensitivity by increasing the utilization of glucose and with other agents, while rosiglitazone was associated with an 8 to 16% decreasing the production of glucose. More specifically, they work increase in LDL levels. Both thiazolidinediones were associated with an by binding to the nuclear regulatory protein peroxisome proliferator- average increase in HDL of 10%, but pioglitazone was associated with activated receptor (PPAR) gamma and/or alpha, which is involved in decreased triglyceride levels more commonly than rosiglitazone. transcription of genes that regulate fat and glucose metabolism. PPAR- Meta analyses have shown that rosiglitazone may be associated with alpha is found in the heart, skeletal muscle, liver, and vascular walls, an increased risk of myocardial infarction. While some individual while PPAR-gamma is found in pancreatic beta cells, adipose tissue, studies have not found an increased risk of myocardial infarction with macrophages, the central nervous system, and vascular endothelium. rosiglitazone, a meta-analysis of 42 trials that compared rosiglitazone PPAR-gamma concentrations in skeletal muscle are increased in with insulin, sulfonylureas, metformin, or placebo found rosiglitazone diabetic and obese patients, and are correlated with lower serum insulin to be associated with more frequent myocardial infarctions. This concentrations. By acting on PPAR to facilitate glucose transport into analysis found 86 myocardial infarctions in the rosiglitazone group, as muscle cells, thiazolidinediones increase the rate of glucose utilization compared with 72 in the control group, and while it was not originally by muscle cells, lowering blood glucose concentrations. intended to assess cardiovascular risk, these results are significant PPAR-gamma activation in the central nervous system by (Nissen and Wolski, 2007). thiazolidinediones may contribute to weight gain by increasing food The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of intake. Central nervous system effects of thiazolidinediones may also Glycaemia in Diabetes (RECORD) study was specifically designed to lead to improving hepatic insulin sensitivity. evaluate rosiglitazone’s effects on cardiovascular events and mortality. There are two thiazolidinediones available in the US, rosiglitazone and Over 4000 patients in Europe and Australasia who failed treatment with pioglitazone, which appear to have differing effects on PPAR-alpha and sulfonylurea or metformin monotherapy and had an A1c greater than PPAR-gamma. Pioglitazone appears to affect both PPAR-gamma and 7% were randomly assigned to receive metformin, sulfonylurea, or PPAR-alpha, while rosiglitazone appears to only affect PPAR-gamma. rosiglitazone, with patients not receiving the same medication they had This difference in the mechanism of action of these two drugs may previously failed. After 5.5 years, similar numbers of patients experienced account for differences in their side effect profiles. the primary endpoint, cardiovascular hospitalization or death. However, Activation of PPAR-gamma in the pancreatic beta cells may be there was a persistent increased risk of fatal and non-fatal heart failure associated with preserved beta cell function, though this effect was in the rosiglitazone group, shown in 61 rosiglitazone patients and 29 primarily demonstrated with a thiazolidinedione that is no longer on the patients in the control group. The effects of rosiglitazone on myocardial market in the U.S. infarctions were inconclusive, though this may have been affected by higher statin use in the rosiglitazone group (Home et al., 2009). Effects on glucose control Although their frequency of use is decreasing due to the risk of Practice question #4 adverse effects, and they are not typically used as a monotherapy, Rosiglitazone has been shown to increase the risk of all the following thiazolidinediones appear to have a similar efficacy to metformin when cardiovascular conditions, EXCEPT: used as monotherapy. A 26-week randomized controlled trial comparing a. Myocardial infarction. rosiglitazone with placebo in type II diabetic patients found that 4mg of b. Fatal heart failure. rosiglitazone lowered average A1c values by 1.2%, and 8mg lowered c. Non-fatal heart failure. A1c by 1.5%. However, this study found rosiglitazone to be associated d. Hypertension. with weight gain of 4.2kg over 26 weeks, as well as with increased The effects of pioglitazone on cardiovascular risk do not appear to serum HDL and LDL levels when compared with placebo (Lebovitz be the same as rosiglitazone. A meta-analysis of 19 trials comparing et al., 2001). Similar effects have been shown with pioglitazone pioglitazone with rosiglitazone, metformin, sulfonylurea, or placebo monotherapy (Hollander, 2008; McCulloch, 2016c). found 1.5% of pioglitazone patients experienced a myocardial Thiazolidinediones have been shown to be effective in combination infarction, while 2% of patients in the control group experienced with other antidiabetic agents, such as metformin, sulfonylureas, myocardial infarction. The primary endpoint, a composite endpoint of and insulin. They appear to exhibit higher efficacy when used in nonfatal myocardial infarction, nonfatal stroke, and death, occurred in combination with agents that have differing mechanisms of action, to 4.4% of pioglitazone patients, and in 5.7% of control patients. Similar target hyperglycemia from multiple angles. to the rosiglitazone meta- analysis, this meta-analysis was not originally intended to assess cardiovascular risk, but these results are significant The typical onset of action of TZDs is relatively slow; effects may begin nonetheless (Lincoff et al., 2007). within 2 weeks of treatment initiation, but maximum benefits are not seen for approximately 3 months, though these effects may occur more The Prospective Pioglitazone Clinical Trial In Macrovascular Events rapidly when combined with insulin or sulfonylureas. (PROactive) study found a 16% reduction in all-cause mortality, non-fatal myocardial infarction, or stroke. However, this study did Cardiovascular effects find a higher incidence of heart failure in patients taking pioglitazone, Since rosiglitazone and pioglitazone appear to have differing specificity though it does not appear to increase the risk of all-cause mortality. for PPAR activation, some differences can be seen in their effects on the Since pioglitazone carries an increased risk of heart failure and edema cardiovascular system. For example, their effects on serum lipid levels compared with placebo, the overall benefits on macrovascular events is appear to be different. It seems that pioglitazone treatment is correlated minimal (Yki-Järvinen, 2005).

Page 43 Pharmacy.EliteCME.com Overall, the cardiovascular effects of thiazolidinediones remain unclear; Diabetes consideration: Women with osteoporosis, low bone therefore, they should be used with caution, particularly in patients who density, or risk factors for fracture may benefit from avoiding the have or are at risk for heart failure. Typically, alternative therapies are use of thiazolidinediones. considered before the use of thiazolidinediones, and patients taking rosiglitazone who are not meeting glycemic goals may require changing There are concerns that pioglitazone may increase the risk of bladder to an alternative agent. cancer. The PROactive trial found a higher incidence of bladder cancer in the pioglitazone group as compared with placebo with 14 cases in Adverse effects pioglitazone patients, and 5 cases in placebo patients. This risk appears Since thiazolidinediones lower blood glucose by improving insulin to be higher in patients taking pioglitazone in higher doses and for sensitivity, monotherapy is not typically associated with hypoglycemia. longer durations. Therefore, pioglitazone should be avoided in patients It appears that both thiazolidinediones are associated with weight with active bladder cancer and in patients with a history of bladder gain. Higher doses and longer durations of treatment are associated cancer (Yki-Järvinen, 2005). with more weight gain, caused in part by fluid retention, which may Rare cases of hepatotoxicity have been reported in patients taking both be a contributing factor in the development of heart failure. Fluid rosiglitazone and pioglitazone. Since an older thiazolidinedione was taken retention appears to be more common in patients taking insulin in off the market due to increased reports of severe hepatic injury, it may combination with thiazolidinediones. Between 4 to 6% of patients be a class effect. Increased transaminase levels may be seen in patients taking thiazolidinediones experience peripheral edema, which occurs taking thiazolidinediones. Thiazolidinediones should be used with more commonly in patients with a history of heart failure. Since fluid caution in patients with hepatic disease, and liver function tests should be retention can precipitate or worsen heart failure, patients with pre- assessed prior to treatment initiation, and periodically during therapy. existing heart failure should not be prescribed thiazolidinediones. Availability Weight gain may also be associated with increased feeding and higher Rosiglitazone is typically initiated at a dose of 4mg once daily, and can adipose tissue mass in patients taking thiazolidinediones, which may be increased to 8mg once daily as appropriate. It is available under the be caused by its actions on PPAR in the central nervous system and brand name Avandia, in both 4 and 8mg tablets, and is also available in adipose tissue. combination with metformin and glimepiride. Other studies have shown that thiazolidinediones are associated with Pioglitazone is typically started at a dose of 15mg once daily, and can be decreased bone density and an increased risk of fractures, especially increased in 15mg increments up to 45mg once daily as appropriate to in women. This may be due to suppression of osteoblast formation control blood glucose levels. It is available under the brand name Actos, and differentiation associated with the activation of PPAR-gamma. in 15mg, 30mg, and 45mg tablets. It is also available in combination Effects on bone density have been observed with both rosiglitazone and with metformin, glimepiride, and alogliptin. pioglitazone. Amylin analogs (Dungan, 2016) Amylin, a peptide secreted with insulin from pancreatic beta cells, Adverse effects affects the control of glucose by slowing gastric emptying and reducing The most common side effect reported with pramlintide is nausea, food intake, as well as affecting the regulation of postprandial glucagon. which can be minimized with a slow titration of the dose upon Its effects are similar to glucagon-like peptide-1 (GLP-1), with the initiation. It appears that nausea is more common in patients with type I exception that amylin does not affect insulin secretion. Amylin levels diabetes (Hollander et al., 2003). are typically low in patients with type II diabetes, and deficient in those A slow dose titration can also reduce the risk of hypoglycemia, with type I diabetes. particularly in type I diabetic patients. Higher rates of severe The only available amylin analog, pramlintide, produces similar actions hypoglycemia were seen in type I diabetic patients who were started to amylin and can be used in type I and type II diabetic patients using on a full dose of pramlintide without lowering the insulin dose, so dose insulin. The long-term outcomes associated with pramlintide are not changes of insulin are often necessary when starting pramlintide. Severe clear, and with the numerous other antidiabetic agents available, its hypoglycemia rates were not found to be higher in patients who were clinical use is not common at this time. started on pramlintide with a concurrent 25% reduction in their insulin Pramlintide works by slowing gastric emptying after a meal, allowing dose (Hollander et al., 2003). the patient to feel satiated after a meal to slow the intake of glucose. It Diabetes consideration: The higher rates of hypoglycemia in also suppresses the abnormal rise of glucagon after a meal in patients type I diabetic patients may be correlated with poor timing of with diabetes, helping to lower post-prandial glucose levels. These prandial insulin doses. Since pramlintide delays gastric emptying, actions do not typically lead to the development of hypoglycemia, the post meal peak glucose is also delayed, so rapid acting insulin unless combined with other agents that can cause hypoglycemia. administered before the meal may peak before the post meal glucose Effects on glucose control level peaks, causing an early post meal hypoglycemia and delayed Pramlintide has demonstrated efficacy in both type I and type II diabetic hyperglycemia. patients. A randomized controlled trial of type I diabetic patients receiving 30 or 60mcg of subcutaneous pramlintide given with meals Precautions or placebo showed modest decreases in A1c levels of less than 1% in Pramlintide should be avoided in patients who are not aware of the the pramlintide groups over the course of 52 weeks. More than twice as symptoms of severe hypoglycemia due to the potential for significant many patients taking pramlintide achieved their goal A1c of less than adverse effects. It may be beneficial for patients to administer their 7%, without increasing insulin dosing or inducing severe hypoglycemia. prandial insulin after meals until they are familiar with the effects of The pramlintide group was also associated with mild reductions in body pramlintide on satiety and with the decreases in their carbohydrate weight of an average of 0.5kg, as compared with weight gain in the intake that it can cause. group treated with only insulin (Whitehouse et al., 2002). Since pramlintide can delay gastric emptying, patients with Similar findings were seen in type II diabetic patients using pramlintide. gastroparesis should avoid using pramlintide. If the patient is A placebo controlled trial that added pramlintide to existing insulin concurrently taking oral medication that requires rapid absorption from therapy in type II diabetic patients with or without metformin or a the gastrointestinal tract, the medication should be administered an hour sulfonylurea found an average 0.6% reduction in A1c over the course of before or two hours after pramlintide use, in order to prevent slowed a year with the 120mcg dose given twice daily. This dose also produced absorption of these medications. an average weight loss of 1.4kg. These effects appeared to be greatest in Dosing patients with a higher initial body weight (Hollander et al., 2003). Pramlintide is approved for use in type I and II diabetic patients taking prandial insulin. It should be administered three times daily immediately before meals, and pre-meal prandial insulin doses should be reduced

Pharmacy.EliteCME.com Page 44 by up to 50% upon pramlintide initiation to prevent hypoglycemia. Type II diabetic patients should receive an initial dose of 60mcg with Prandial insulin can then be titrated back up to achieve blood glucose each meal, titrated slowly upward toward a goal dose of 120mcg with goals once the target dose of pramlintide is reached. each meal. The initial dose of pramlintide in type I diabetic patients is 15mcg Pramlintide cannot be mixed with insulin or injected in the same local before meals of at least 250 calories or 30 grams of carbohydrates. It area, due to the absorption properties of pramlintide. can then be titrated up in 15mcg increments every three to seven days Availability as appropriate. The goal dose in type I diabetic patients is 60mcg before Pramlintide is available under the brand name Symlin. It is a each meal. Patients should be counseled not to skip meals once a dose subcutaneously injected product that must be stored under refrigeration, of pramlintide has been administered. If persistent nausea develops, the between 36 °F to 46 °F. dose should be titrated back until it resolves. Alpha glucosidase inhibitors (McCulloch, 2016d) Alpha glucosidase inhibitors work by inhibiting alpha glucosidase, or placebo for an average of 3.3 years. Surprisingly, acarbose reduced a gastrointestinal enzyme responsible for breaking down complex the risk of cardiovascular events by 49% when compared with placebo, carbohydrates for absorption. This allows for slower absorption of with the highest reductions seen in the incidence of myocardial glucose, resulting in a slower increase in postprandial blood glucose infarction. Additionally, acarbose decreased the risk of developing high levels. These effects can be beneficial in both type I and type II diabetic blood pressure by 34% (Chiasson et al., 2003). patients. There are two alpha glucosidase inhibitors available in the US, Adverse effects acarbose and miglitol. Acarbose may also increase insulin sensitivity in The most common side effect associated with alpha glucosidase older type II diabetic patients (McCulloch, 2016d). inhibitors is flatulence, affecting over 70% of patients. While Effects on blood sugar control symptoms are typically mild, they may have some effect on decreasing Acarbose has demonstrated efficacy in type II diabetic patients.A 1994 compliance. Slowly titrating the drug upon initiation can minimize trial of approximately 350 patients treated with diet alone, or diet plus these symptoms. Other gastrointestinal side effects, such as diarrhea and metformin, a sulfonylurea, or insulin, had acarbose or placebo added abdominal pain, are common as well. and were followed for a year. Adding acarbose resulted in an average Diabetes consideration: Since their primary action is in the postprandial glucose level reduction of 63mg/dL across all groups, intestines, alpha glucosidase inhibitors are not associated with lowering A1c levels by 0.4% to 0.9%. Adding acarbose resulted in hypoglycemia. They are also not significantly absorbed, so their higher effects in reducing A1c as compared with fasting glucose, systemic side effects are minimal. due to its effects on lowering postprandial glucose levels (Chiasson et al., 1994). Similar effects were noted with miglitol when given in Dosing and availability combination with insulin, a sulfonylurea, or alone, in comparison with Acarbose is available as a generic medication, associated with the brand placebo. No head-to-head trials comparing miglitol with acarbose are name Precose, in 50mg and 100mg tablets. The initial dose is 50mg available, but their effects appear to be comparable. three times daily, administered with the first bite of each meal. It can then be titrated up to 100mg three times daily, if the gastrointestinal Cardiovascular effects side effects are tolerated. Since the side effects are dose related, if they Cardiovascular effects of acarbose were studied in the Study to Prevent become intolerable, decreasing the dose will often resolve the issue. Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM). In this trial of nearly 1500 patients with impaired glucose tolerance, patients Miglitol is available as a generic medication, associated with the brand were randomly assigned to receive acarbose 100mg three times daily name Glyset. It is typically started at a dose of 25mg three times daily, administered at the onset of each meal. Incretin based therapies: Glucagon-like peptide-1 (GLP-1) receptor agonists (Hollander, 2008; Dungan & DeSantis, 2016) GLP-1 is produced in the enteroendocrine L-cells of the small intestine, blood glucose goals with reduced insulin doses, as well as by causing and the presence of nutrients stimulates its secretion. Once secreted, less hypoglycemia and weight gain. This combination can lead to GLP-1 binds to a GLP-1 specific receptor, which can be found in many increased gastrointestinal side effects. tissues, including the gastric mucosa, pancreatic beta cells, kidney, Effects on glycemic control heart, lungs, hypothalamus, and skin. GLP-1 is rapidly degraded by GLP-1 agonists have been proven effective in improving glycemic dipeptidyl peptidase 4 (DPP-4); GLP-1 based therapies must exhibit control. A 2011 meta-analysis evaluated 17 studies comparing GLP-1 resistance to DPP-4 to achieve any meaningful therapeutic effect. agonists to placebo or an active comparator in patients with suboptimal Stimulation of GLP-1 receptors leads to improvements in glucose control of their type II diabetes on metformin and/or sulfonylureas. control through several mechanisms. These include slowing gastric When compared to placebo, all GLP-1 agonists showed a reduction in emptying to slow the intake of food, stimulation of glucose-dependent A1c levels by an average of 1% over 8 to 30 weeks of trial duration insulin release from pancreatic beta cells, and reducing postprandial (Shyangdan et al., 2011). glucagon levels to minimize glucose production by the liver after meals. Cardiovascular effects Since the role of GLP-1 in the treatment of type I diabetes is not clear Patients with type II diabetes and cardiovascular disease may at this time, GLP-1 agonists are typically reserved for type II diabetic experience some benefit with the use of GLP-1 agonists. When patients. GLP-1 agonists are not FDA approved for use in type I diabetic liraglutide was given to type II diabetic patients with at least one patients. cardiovascular condition or risk factor, it was shown to significantly Use of GLP-1 agonists reduce A1c, weight, and systolic blood pressure over the course of 36 While GLP-1 receptor agonists are approved for use as initial months when compared to placebo. Liraglutide treatment also resulted monotherapy, they are typically not added on to a patient’s medication in fewer patients reaching the primary endpoint of the trial, a composite regimen initially, in part due to the injectable nature of these drug endpoint of cardiovascular death, nonfatal myocardial infarction, or products as well as their relatively high cost. More commonly, they nonfatal stroke, when compared with placebo over an average of 3.8 are added on as combination therapy after treatment failures with oral years. Lastly, the liraglutide group experienced a lower number of medications. GLP-1 agonists are not typically combined with DPP- add-on medications for lipid lowering, diuresis, and additional diabetes 4 inhibitors, as the combination does not appear to provide additive medications when compared to placebo (Marso et al., 2016). effects on lowering blood glucose levels. Lixisenatide was not proven to reduce the risk of cardiovascular There do appear to be additive benefits when combining GLP-1 agonists disease progression when compared with placebo. In a study of 6028 with basal insulin; the combination appears to help patients achieve patients with type II diabetes and a history of myocardial infarction

Page 45 Pharmacy.EliteCME.com or hospitalization for unstable angina within 180 days, patients were insulin, providing additional A1c lowering when added to an existing randomized to receive lixisenatide or placebo in addition to other regimen. diabetes medication treatments. After 25 months, no statistically Due to its elimination through the kidney, lixisenatide is not significant difference was found in the number of patients who reached recommended for use in patients with chronic kidney disease, who have the study’s endpoint, a composite of cardiovascular death, nonfatal a creatinine clearance of less than 30mL/min. It should also be avoided myocardial infarction or stroke, or hospitalization for unstable angina in patients with severe gastrointestinal disease, such as gastroparesis, (Pfeffer et al., 2015). due to additive gastrointestinal side effects. While the data available has not proven a class effect of GLP-1 agonists Lixisenatide is available under the brand name Adlyxin, in a prefilled in reducing the risk of cardiovascular disease, the relatively short study subcutaneous injection pen containing 10 or 20mcg of lixisenatide. It is durations warrant additional long-term study in this area. typically started at the 10mcg dose, administered within an hour prior to Side effects the same meal daily, and increased after two weeks to 20mcg. Since GLP-1 exhibits effects on slowing gastric emptying and action Practice question #5 on appetite centers in the brain, treatment with GLP-1 agonists are Which of the following patients should avoid using lixisenatide? associated with weight loss. GLP-1 agonists also frequently cause side a. A patient with a creatinine clearance of 15mL/min. effects of nausea and vomiting, which can thereby lead to weight loss, b. A patient with an A1c of 9.5%. but studies have shown that patients who did not experience nausea and c. A patient with a creatinine clearance of 60mL/min. vomiting with GLP-1 agonists also experienced weight loss (Pfeffer et d. A patient who is on basal insulin. al., 2015). Long-acting GLP-1 agonists Long-acting GLP-1 agonists with longer half-lives have been developed Evidence-based practice alert! The 2011 meta-analysis with more resistance to DPP-4. This allows for continuous activation comparing GLP-1 agonists to placebo or an active comparator of the GLP-1 receptor, and allows for less frequent subcutaneous showed patients taking GLP-1 agonists experienced weight loss injections. When compared to short-acting GLP-1 agonists, longer of 1.5 to 2.5kg over the course of 30 weeks. Additional research acting agents typically have a more prominent effect on lowering fasting has continued to support this result (Shyangdan et al., 2011). glucose levels, and a less prominent effect on postprandial glucose levels and gastric emptying. Long-acting GLP-1 agonists must be stored in the refrigerator. Choosing an agent Liraglutide Both long-acting and short-acting GLP-1 agonists are currently Liraglutide was developed with the ability to bind to serum albumin in available. Longer acting agents such as extended release exenatide, order to lengthen its half- life and allow for once daily injections. It is liraglutide, and dulaglutide were shown to have a significantly greater effective when combined with oral antidiabetic agents as well as with reduction in A1c when compared to twice-daily exenatide. In addition, basal insulin. Liraglutide should be used with caution in patients with long- acting agents may be preferable due to patient convenience renal impairment. factors, though payer coverage often plays a significant role in choosing an agent due to the costly nature of these injectable drug products. Liraglutide is available under the brand name Victoza, a prefilled pen Patients at a higher risk of myocardial infarction or stroke may for subcutaneous injection. The dose is typically titrated to minimize experience more benefit with liraglutide if payer coverage is reasonable. the risk of gastrointestinal side effects, starting at 0.6mg once daily for seven days, followed by 1.2mg once daily for seven days, and finally to Short-acting GLP-1 agonists the maintenance dose of 1.8mg once daily if blood sugar targets have The short-acting GLP-1 agonists, exenatide twice daily and lixisenatide, not been met. activate the GLP-1 receptor for a short period of time. They typically lead to a more prominent effect on gastric emptying and postprandial Exenatide extended release hyperglycemia, and lead to a less pronounced effect on fasting glucose Exenatide extended release is approved for use as a once weekly when compared with longer acting agents. They must all be stored in subcutaneous injection. It can be used as monotherapy, but is more the refrigerator. typically used in combination with oral antidiabetic agents or basal insulin. Exenatide twice daily Exenatide is an injectable, synthetic form of exendin 4, a substance When compared with twice-daily exenatide, the extended release form found in the saliva of the Gila monster that is similar to human GLP-1. of exenatide was shown to be more effective in reducing A1c levels, It displays many of the same biological effects of natural GLP-1, but with the extended release version displaying an average A1c reduction it is more resistant to breakdown by DPP-4, resulting in a significantly of 1.5% compared with 0.9% for twice-daily exenatide (Pfeffer et al., longer half-life than native GLP-1. 2015). Exenatide is effective in combination with oral agents and basal insulin, Similar to short-acting exenatide, extended release exenatide should providing additive A1c lowering. It is administered in doses of 5 or not be used in patients with severe renal impairment with a creatinine 10mcg twice daily, given subcutaneously immediately before or within clearance of less than 30mL/min. It should also be avoided in patients one hour before morning and evening meals. Exenatide is eliminated with severe gastrointestinal disease, such as gastroparesis, due to through the kidney, and its clearance is impaired in renal impairment. additive gastrointestinal side effects. Exenatide should not be used in patients with severe renal impairment Extended release exenatide is available in the US under the brand with a creatinine clearance of less than 30mL/min. name Bydureon, available in injection kits with vials for reconstitution, The most common side effect associated with exenatide is nausea. or single dose pens. Both versions must be reconstituted prior to Exenatide should be avoided in patients with severe gastrointestinal administration, and once reconstituted, it must be administered disease, such as gastroparesis, due to additive gastrointestinal side immediately. It is administered in a dose of 2mg once weekly, given effects. Use of exenatide in combination with sulfonylureas is subcutaneously in the abdomen, thigh, or upper arm. It can be given at associated with an increase in the risk of hypoglycemia. any time of day without regard to meals. Exenatide administered twice daily is available in prefilled pens of 5 or Albiglutide 10mcg under the brand name Byetta. Similar to liraglutide, albiglutide was formed by fusing a DPP-4 resistant GLP-1 analog to human albumin in order to extend the Lixisenatide half-life of the medication. This product’s half-life is between five to Lixisenatide, a short-acting GLP-1 agonist, shares structural similarities seven days, allowing the product to be administered once weekly. It is with exendin 4, the substance found in Glia monster saliva. It is effective in combination with oral antidiabetic agents, as well as with effective in combination with oral antidiabetic agents as well as basal basal insulin. Albiglutide should be used with caution in patients with renal impairment.

Pharmacy.EliteCME.com Page 46 Albiglutide is available under the brand name Tanzeum, in prefilled long-acting GLP-1 agonists should be avoided in patients with a pens with a powder and diluent that must be reconstituted prior to personal or family history of multiple endocrine neoplasia or medullary administration. It is typically started in a dose of 30mg once weekly, thyroid cancer, due to the theoretical risk and data available from animal and can be increased to 50mg weekly after six to eight weeks if blood studies showing these agents could contribute to the cause of these sugar levels remain above goal. disease states. Dulaglutide Adverse effects Dulaglutide was given its long-acting properties with structural The most common side effects reported with GLP-1 agonists are modifications that prevent its breakdown by DPP-4, allowing for gastrointestinal in nature, including nausea, vomiting, and diarrhea. a longer half-life of approximately five days. This allows for the These side effects have been reported in 10 to 50% of patients. Nausea medication to be administered once weekly. It has been shown to be can wane as therapy continues, and titrating the dose upon treatment effective in combination with oral antidiabetic medications, as well as initiation can minimize the risk of nausea. Since GLP-1 inhibitors are with prandial insulin. When compared to glargine insulin, dulaglutide associated with slowed gastric emptying, they should be used with caused three to eight times more nausea, vomiting, and diarrhea, so caution in patients with gastroparesis. patient tolerability is something to keep in mind with this medication. Acute pancreatitis has been reported to be associated with GLP- Dulaglutide should be used with caution in patients with renal 1 agonists. While the relationship between GLP-1 inhibitors and impairment. pancreatitis has not been fully established, pancreatitis should be Dulaglutide is available in the US under the brand name Trulicity. It considered in patients with severe, persistent abdominal pain, and the comes in a premixed pen or prefilled syringe that does not need to be GLP-1 agonist should be discontinued. If pancreatitis is confirmed, reconstituted before subcutaneous injection into the thigh, abdomen, treatment with GLP-1 agonists should not be restarted. GLP-1 agonists or upper arm. It is typically started at a dose of 0.75mg once weekly, should not be started in patients with a history of pancreatitis. and titrated up to 1.5mg once weekly after six to eight weeks if blood Since all GLP-1 agonists are injectable medications, local injection glucose levels are not at goal. This medication should be refrigerated site reactions are a possible adverse effect. Injection site reactions with before use, but each prefilled syringe or single dose pen can be kept at GLP-1 agonists appear to be more common than with insulin. room temperature for up to 14 days. It is possible for antibodies to GLP-1 agonists to develop, though the Diabetes consideration: All GLP-1 agonists are injectable products majority of patients experience a decrease in antibody levels over time, that must be kept under refrigeration before use, at a temperature and in many cases, antibody levels do not appear to affect glycemic between 36 °F to 46 °F. control, though there have been some reports of patients with high Precautions antibody titers that attenuate glycemic control (Pfeffer et al., 2015). Patients with a history of pancreatitis should not use GLP-1 receptor The risk of hypoglycemia is low with GLP-1 agonists, though agonists, due to reports of GLP-1 agonists causing pancreatitis. All hypoglycemia can occur more commonly when administered with agents known to cause hypoglycemia, such as sulfonylureas or insulin. Incretin based therapies: Dipeptidyl peptidase-4 (DPP-4) inhibitors (Dungan and DeSantis, 2016b) DPP-4 inhibitors work by preventing the breakdown of GLP-1 in patients with cardiovascular disease (CVD) or multiple risk factors for order to maximize the beneficial effects of GLP-1 on glucose control. CVD who were taking DPP-4 inhibitors when compared with placebo. GLP-1 is normally broken down rapidly by the enzyme DPP-4; DPP-4 It also analyzed 38 studies that provided low quality evidence of no inhibitors aim to inhibit this enzyme in order to increase the lifespan of increase in the risk of heart failure (Li et al., 2016). GLP-1. This allows for enhancement of the beneficial effects of GLP- While the data is conflicting at this point, and long-term studies need to 1, including slowing gastric emptying to slow food intake, reducing be conducted to assess the long-term effects of these medications, the postprandial glucagon levels, and enhancing glucose-dependent insulin FDA recommends discontinuing saxagliptin or alogliptin in patients secretion from the pancreatic beta cells. who develop heart failure and monitoring their glycemic control Available agents in this class include sitagliptin (Januvia), saxagliptin to assess if alternative therapies are necessary (US Food and Drug (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Although Administration, 2016). approved for use as monotherapy, the cost of these agents is high, so Side effects they are not typically used as an initial monotherapy. They are more DPP-4 inhibitors are not associated with any effects on body weight, commonly used in combination with metformin and other antidiabetic and do not carry a risk of hypoglycemia on their own. Common agents. side effects include headache, upper respiratory tract infection, and Since the role of GLP-1 in the treatment of type I diabetes is not clear nasopharyngitis. Rare reports of acute pancreatitis have been reported in at this time, DPP-4 inhibitors are typically reserved for type II diabetic patients taking DPP-4 inhibitors. patients. Diabetes consideration: While acute pancreatitis appears to be Effects on glycemic control rare, patients who develop pancreatitis should stop taking DPP-4 The available DPP-4 inhibitors appear to have similar effects in terms inhibitors, and DPP-4 inhibitors should not be initiated in patients of lowering blood glucose levels. When saxagliptin and sitagliptin were with a history of pancreatitis. compared in a head-to-head trial in patients who were not adequately controlled with metformin, they both experienced similar reductions Post-marketing reports have associated DPP-4 inhibitors with in A1c over an 18-week period: sitagliptin reduced A1c by 0.62% vs. hypersensitivity reactions including angioedema, skin conditions such saxagliptin’s reduction of 0.52% (Scheen et al., 2010). as Stevens Johnson syndrome, and anaphylaxis. If the use of a DPP-4 inhibitor has caused a serious hypersensitivity reaction, the use of DPP- DPP-4 inhibitors generally do not cause hypoglycemia, unless 4 inhibitors is contraindicated. combined with other medications that can lead to hypoglycemia. Musculoskeletal side effects, such as severe joint pain, myalgia, muscle Cardiovascular effects weakness, and muscle spasms, have been reported with some DPP-4 A number of studies have been performed to evaluate the cardiovascular inhibitors. The majority of these symptoms resolved within 30 days of effects of DPP-4 inhibitors in order to satisfy FDA safety requirements. discontinuing the medication. If severe joint pain occurs while taking Overall, these studies do not appear to indicate an increase in the risk a DPP-4 inhibitor, the medication should be stopped and the patient of coronary heart disease with short-term use of DPP-4 inhibitors, should be monitored for symptom resolution. DPP-4 inhibitors should but some data has shown that there may be an increased risk of heart then be avoided in these patients. failure with certain agents. While the data available is limited to short- term studies, a meta-analysis of the available data found 5 studies Sitagliptin with moderate quality evidence of an increased risk of heart failure in The typical dose used in the treatment of type II diabetes is 100mg once daily. Dosages need to be adjusted in patients with chronic kidney Page 47 Pharmacy.EliteCME.com disease based on the patient’s creatinine clearance (CrCl): 50mg for Linagliptin is available as a single agent under the brand name patients with creatinine clearance of 30 to 50 mL/min, and 35mg for Tradjenta. It is also available in combination with metformin under patients with creatinine clearance less than 30mL/min. the name Jentadueto, and in combination with empagliflozin under the Sitagliptin is available as a single agent, known as Januvia. It is also brand name Glyxambi. available in a tablet combined with metformin, known as Janumet, that Alogliptin is taken twice daily. A combination of sitagliptin with extended release Alogliptin is typically given in a dose of 25mg once daily. Dosage metformin, is also available, known as Janumet XR, which can be taken reductions are required in patients with chronic kidney disease; those once daily. with a creatinine clearance of 30 to 60 mL/min should receive 12.5mg Saxagliptin once daily, and those with a creatinine clearance of less than 30mL/min The typical dose of saxagliptin is 2.5 to 5mg once daily. Patients with or those on dialysis should receive 6.25mg once daily. chronic kidney disease who have a creatinine clearance less than 50mL/ Rare reports of hepatic dysfunction have occurred in patients taking min should receive 2.5mg once daily to reduce accumulation. Those alogliptin, resulting in increases in liver enzymes and hepatitis. Liver taking medications that are strong inhibitors of the enzyme CYP 3A4, function tests should be evaluated before initiating treatment with such as ketoconazole, should also receive the lower dose of 2.5mg once alogliptin and reassessed every three months during the first year of daily. therapy. If the liver enzymes aspartate aminotransferase (AST) or Saxagliptin is available as a single agent under the brand name Onglyza. alanine aminotransferase (ALT) are increased more than three times the It is also available in combination with extended release metformin, upper limit of normal, alogliptin should be discontinued. under the brand name Kombiglyze XR. Alogliptin is available as a single agent under the brand name Nesina. It Linagliptin is also available in combination with metformin under the brand name Linagliptin is typically given in a dose of 5mg once daily. Since it is Kazano, as well as in combination with pioglitazone under the brand eliminated through the hepatic route, no dosage adjustments are needed name Oseni. in patients with chronic kidney disease, making linagliptin a good Practice question #6 choice for patients with chronic kidney disease. Which of the following DPP-4 inhibitors does NOT require dosage Patients taking medications that are strong inducers of CYP3A4, such as adjustments in patients with chronic kidney disease? rifampin, should receive alternative agents due to the decreased efficacy a. Sitagliptin. of linagliptin. b. Saxagliptin. c. Linagliptin. d. Alogliptin. Glucose excretion therapies: Sodium-glucose co-transporter 2 (SGLT2) inhibitors (DeSantis, 2016) Sodium-glucose co-transporter 2 inhibitors, or SGLT2 inhibitors, are related blindness, vitreous hemorrhage, new or worsening nephropathy, a relatively new class of antidiabetic agents that work to reduce blood or initiation of retinal photocoagulation, as seen in 14% of empagliflozin sugar levels by increasing the urinary excretion of glucose. Specifically, groups compared with 20.5% in the placebo group. It appears new they inhibit the action of SGLT2, a protein bound to cell membranes or worsening nephropathy was a significant player in driving these found in the proximal tubule of the nephron. SGLT2 is responsible reductions, as new or worsening nephropathy was seen in 12.7% of for reabsorbing glucose that has been filtered for secretion through empagliflozin patient and 18.8% of placebo patients. The mechanism the urine, bringing it back into the body before it can be excreted. behind the reduction in risk of nephropathy is thought to be related to the Inhibiting SGLT2 blocks the glucose reabsorption process, resulting in direct effects of empagliflozin in the kidney (Zinman et al., 2015). an increased amount of glucose being excreted via urine. Reductions in blood pressure have also been noted in systematic Since the glucose lowering effect of SGLT2 inhibitors is not dependent reviews of canagliflozin and dapagliflozin trials, showing systolic blood on insulin, they typically do not cause hypoglycemia. They have been pressure reductions of 1.3 to 7.3mmHg. found to have effects of decreasing blood pressure and weight. Weight loss has also been noted in patients taking SGLT2 inhibitors. Effects on glycemic control Short-term (12 week) trials of empagliflozin, canagliflozin, and Compared with alternative antidiabetic agents, SGLT2 inhibitors result dapagliflozin have reported weight loss of between 2 and 3kg with in relatively low reductions in blood glucose levels. Reductions in SGLT2 inhibitors, which appears to be sustained over time. Meta analyses A1c, when compared with placebo, are typically in the range of 0.4 to of longer- term trials comparing SGLT2 inhibitors to placebo confirmed 1.1%, with higher reductions seen in patients with higher baseline blood significant weight loss with SGLT2 inhibitors (DeSantis, 2016). glucose levels. Meta-analysis of studies comparing SGLT2 inhibitors Use of SGLT2 inhibitors with active comparators or placebo showed that adding SGLT2 While approved for monotherapy, SGLT2 inhibitors are typically not inhibitors resulted in A1c reduction of 0.5 to 0.7%. used until the patient has been tried on alternative agents first due Cardiovascular effects to their cost and modest improvement in blood glucose levels. They To evaluate the risk of cardiovascular morbidity and mortality in type II may be particularly beneficial in patients needing a second or third diabetic patients with cardiovascular disease, a 2015 study evaluated over medication to control glucose and those for whom weight loss would be 7000 patients who were randomized to receive once daily empagliflozin beneficial. 10mg, empagliflozin 25mg, or placebo. After 3 years of study, both Contraindications and precautions empagliflozin groups experienced a significant reduction in risk of SGLT2 inhibitors are not indicated in patients with type I diabetes. cardiovascular death when compared with placebo, as fewer patients in the empagliflozin groups experienced the primary outcome composite of Since SGLT2 inhibitors exhibit their primary action in the kidney, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. caution must be used in patients with chronic kidney disease. Each Other notable benefits seen in the empagliflozin group when compared medication has a specific creatinine clearance under which their use with placebo included a lower rate of hospitalization for heart failure, should be avoided; this information can be found under the details for lower A1c levels, reductions in waist circumference, weight, both systolic each agent. and diastolic blood pressure, and uric acid. This study only assessed very SGLT2 inhibitors should be used cautiously with other medications high-risk patients with cardiovascular disease, so whether the same effect that can predispose a person to acute kidney injuries, such as diuretics, is seen in patients without significant cardiovascular disease remains to angiotensin converting enzyme (ACE) inhibitors, angiotensin II be seen. It is also unclear at this time if these effects are class effects, or receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs specific to empagliflozin (DeSantis, 2016). (NSAIDs). Prior to initiating treatment, renal function and volume On a microvascular level, fewer patients in the empagliflozin groups status should be assessed, and dehydration should be corrected before reached the composite secondary microvascular endpoint of diabetes- treatment initiation.

Pharmacy.EliteCME.com Page 48 Since SGLT2 inhibitors increase the amount of glucose in the urine, It is not known at this time if these effects are class effects or related they can increase the risk of urinary tract infections and genitourinary only to canagliflozin. yeast infections. Patients who experience recurrent urinary tract Monitoring parameters infections or genitourinary yeast infections may want to avoid using In addition to monitoring blood glucose control through fasting blood SGLT2 inhibitors, or be counseled on their risks. sugar levels and routine A1c, renal function should also be monitored. Since reports of bone fractures have occurred more frequently in Dapagliflozin patients taking canagliflozin, SGLT2 inhibitors should be used Dapagliflozin is typically taken in a dose of 20mg once daily, at any cautiously in patients at a high risk for falls or fractures, as well as those time of day, without regard to food. Patients with pre-existing chronic with low bone mineral density. kidney disease and a creatinine clearance of less than 60mL/min should Adverse effects avoid using dapagliflozin. Dapagliflozin should be avoided in patients Due to the action of SGLT2 inhibitors increasing urine glucose levels, with active bladder cancer, due to slightly higher rates of bladder cancer studies have found a significant increase in the risk of vulvovaginal in dapagliflozin trials. candidiasis, which was reported in 10 to 15 % of women. Increases in Dapagliflozin is available under the brand name Farxiga. the rates of urinary tract infections have also been noted, as well as rare urosepsis and pyelonephritis. Rare reports of bladder cancer have also Canagliflozin been made in patients taking dapagliflozin( DeSantis, 2016). Canagliflozin is typically initiated in a dose of 100mg once daily, and can be titrated up to 300mg once daily as necessary to achieve glycemic Diabetes consideration: Urinary tract infections and vaginal goals. It is taken orally before the first meal of the day. candidiasis are significant adverse effects of SGLT2 inhibitors. Patients with pre-existing chronic kidney disease and a creatinine Patients at a high risk of complications from urinary tract infections, clearance of 40 to 59mL/min should not receive doses in excess of such as geriatric patients who may not display standard symptoms of 100mg daily. Patients with a creatinine clearance of less than 45mL/min urinary tract infections, should avoid the use of SGLT2 inhibitors. should avoid using canagliflozin. SGLT2 inhibitors have been shown to cause osmotic diuresis, which can Canagliflozin is available under the brand name Invokana, and in lead to hypotension, particularly when combined with diuretics, ACE combination with metformin under the brand name Invokamet. inhibitors, and ARBs. This osmotic diuresis also increases urine output Empagliflozin and can contribute to dehydration if not monitored appropriately. Empagliflozin is typically initiated in a dose of 10mg once daily, and Acute kidney injury has been reported in patients taking dapagliflozin can be titrated up to 25mg once daily as necessary to achieve glycemic and canagliflozin. Some patients required hospitalization and/or goals. Patients with a prior medical history of stroke or myocardial dialysis. For this reason, renal function should be assessed before infarction may benefit from using empagliflozin over other SGLT2 starting an SGLT2 inhibitor in patients predisposed to acute renal injury inhibitors due to the benefits noted in the cardiovascular outcomes study due to comorbidities or use of other medications that can predispose a of empagliflozin (DeSantis, 2016). patient to acute kidney injury. Patients with pre-existing chronic kidney disease and a creatinine Diabetic ketoacidosis has been reported in type II diabetic patients clearance of less than 45mL/min should avoid using empagliflozin. taking SGLT2 inhibitors whose blood glucose levels were below Empagliflozin is available as a single agent under the brand name 250mg/dL. Since the lower blood sugar levels can prevent the Jardiance, as well as in combination with linagliptin under the brand recognition of diabetic ketoacidosis, serum ketone levels should be name Glyxambi, and in combination with metformin under the brand obtained in patients taking SGLT2 inhibitors who are experiencing name Synjardy. nausea, vomiting, or malaise, and the SGLT2 inhibitor should be discontinued if acidosis is present. Practice question #7 In which of the following conditions should the use of all SGLT-2 Bone fractures have been reported more frequently in patients taking inhibitors be avoided? canagliflozin, and have been reported as soon as 12 weeks after starting a. Waist circumference of 54 inches. treatment. Bone density has also been shown to be adversely affected by b. Chronic kidney disease with a creatinine clearance of 20mL/min. canagliflozin. Fractures may also be related to orthostatic hypotension c. History of myocardial infarction. causing dizziness and falls, particularly in older adults (DeSantis, 2016). d. Hypertension. ALTERNATIVE ANTI-DIABETIC AGENTS Colesevelam (Handlesman, 2009) Colesevelam is a bile acid sequestrant that has demonstrated effects glucose control. Since colesevelam is not absorbed from the intestinal in lowering blood glucose levels. It works by binding to bile acids in tract, the majority of side effects are gastrointestinal in nature, and the intestines in order to prevent their reabsorption. Since colesevelam include flatulence, constipation, diarrhea, abdominal pain, nausea, prevents bile acid reabsorption, the liver is forced to utilize cholesterol vomiting, and dyspepsia. Other possible side effects include headache, from liver cells to create more bile acids, lowering cholesterol levels. and rarely, myalgia and increases in liver transaminase levels. The mechanism for its effects in lowering blood glucose levels is not Colesevelam is available under the brand name Welchol. For the clear, but since the medication is not absorbed from the digestive tract, adjunctive treatment of type II diabetes, it is typically taken in a dose of it is thought to have local effects on glucose absorption in the intestines. 1.875 grams twice daily, or 3.75 grams once daily. Using a twice-daily Since many patients with type II diabetes have altered lipid profiles, the dosing schedule can help to decrease the risk of gastrointestinal side addition of colesevelam to an existing antidiabetic medication regimen effects. can help with both lowering lipid levels, as well as with contributing to Bromocriptine (DeFronzo, 2011) Bromocriptine is a dopamine agonist that has been available for quite the liver. Since it does not increase insulin release or improve insulin some time, for the treatment of Parkinson’s disease and pituitary sensitivity in peripheral tissues, it is not associated with hypoglycemia. tumors. In 2009, it was approved by the FDA for the treatment of type Adding bromocriptine to a type II diabetic medication regimen has II diabetes. It is thought that administration of bromocriptine within been shown to reduce A1c levels by 0.5 to 0.7%. Initial trials have two hours of awakening can supplement low dopamine levels in the shown bromocriptine to reduce cardiovascular events by as much hypothalamus, which can lead to a reduction in post meal plasma as 40%. It has also been shown to be effective in reducing free fatty glucose levels due to improved suppression of glucose production in acid and triglyceride levels, which may be related to the decrease in cardiovascular events.

Page 49 Pharmacy.EliteCME.com Adverse effects associated with bromocriptine include nausea, concentrations within 60 minutes; therefore, generic longer acting dizziness, fatigue, headache, vomiting, diarrhea, and constipation. bromocriptine products should not be substituted. Bromocriptine for the While there are traditional generic bromocriptine products available, treatment of type II diabetes is available under the brand name Cycloset, bromocriptine for the treatment of type II diabetes is formulated in in 0.8mg tablets. It is typically initiated at a dose of 0.8mg once daily, a way that allows it to dissolve quickly, and reach maximum plasma and can be titrated to a maximum dose of 4.6mg once daily. It should be administered within 2 hours of awakening in the morning. Insulin (McCulloch, 2016e; McCulloch, 2016f) Insulin was one of the first products created for the treatment of Rapid acting insulin products are colorless. They are only administered diabetes. Developed in the 1920s, insulin was originally derived from subcutaneously, either through individual injections or subcutaneous the pancreas of dogs and cattle, and was considered a miracle in the infusions, and can be mixed in the same syringe with NPH insulin if treatment of high blood sugar levels when it first became available. necessary, so long as the rapid acting insulin is drawn up first. Rapid Prior to insulin, doctors did not have many tools available to treat acting insulins can be used in insulin pumps. They are available in diabetes; diets low in carbohydrates and calories were prescribed, with vials, prefilled pens, and cartridges for reusable pens in concentrations poor outcomes expected, as well as a short life expectancy for diabetic of 100 units/mL. All rapid acting insulin products are only available by patients. Nowadays, a variety of insulin products are available, with prescription. varying concentrations, durations of action, and injection mechanisms Short-acting insulin available (American Diabetes Association, 2012). Short-acting insulin products, known as regular insulin, have a slower Diabetes consideration: Insulins derived from animal sources are no onset of action when compared with rapid-acting products. They longer available in the United States. typically onset within 30 to 60 minutes, and their peak effects are seen within 2 to 4 hours. Their effects last around 5 to 7 hours. Since their All types of diabetic patients can be treated with insulin. Each patient’s onset of action is slower, short-acting insulins must be administered 30 insulin needs are different, and depend on a variety of factors including to 60 minutes before meals in order for their peak action to correlate the type of diabetes they are diagnosed with, their current ability to with peak blood glucose levels after a meal. In order to assess the secrete insulin, and their body’s level of insulin resistance. In general, effects of a dose of regular insulin, blood sugar levels can be assessed type I diabetic patients require lifelong treatment with insulin, since either two hours after a meal, or right before the next meal. their pancreatic beta cells are virtually incapable of producing insulin, There are two commonly available regular insulin products in the while type II diabetic patients often require insulin later in their disease United States: course as beta cell function declines over time. ●● Humulin R. Ideally, type II diabetic patients are treated with diet, weight reduction, ●● Novolin R. and oral agents first, but certain situations warrant the initiation of Regular insulin is the only type of insulin that can be administered insulin more quickly. These include a rapidly progressing disease state through alternative routes. It can be administered subcutaneously, with severe symptoms, those with an initial A1c over 9.5%, fasting either through individual injections or subcutaneous infusions, as well glucose over 250mg/dL, random glucose levels consistently greater as intramuscularly and intravenously. The intravenous route is mainly than 300mg/dL, and those whose diabetic state is difficult to distinguish reserved for hospitalized patients who require insulin drips, often only between type I and type II diabetes, such as those with significant in intensive care units. ketonuria or unplanned weight loss in association with hyperglycemia. Regular insulin can be used in subcutaneous insulin pumps. It can also Basal vs bolus insulin be mixed in the same syringe as NPH, as long as the regular insulin is Insulin can be administered as a supplement to natural basal insulin drawn up first. Regular insulin is a clear, colorless liquid, available in levels, or as bolus doses to target peaks in blood glucose after meals. vials, prefilled pens, and cartridges for reusable pens, and is available Bolus doses of rapid-acting or short-acting insulins are given before or in concentrations of 100 units/mL (U-100), as well as 500 units/mL with meals to cover extra insulin requirements after food from meals is (U-500). absorbed. Another unique feature of regular insulin is that it is available without a Basal dosing helps to increase resting insulin levels in order to prescription, in the U-100 concentration only. The majority of patients maintain normal blood glucose levels during periods of fasting, such do not take advantage of this option unless they have an urgent need as overnight. Intermediate and long-acting insulins can help patients for regular insulin and do not have an active prescription, as insurance increase basal insulin levels. Continuous infusion of a rapid acting cannot be billed for over the counter purchases. insulin can also provide basal coverage, though this is typically reserved for type I diabetic patients. Intermediate-acting insulin Intermediate-acting insulin products, known as NPH insulin, have a Preparations of insulin slower onset of action than rapid acting and regular insulin. It typically There are a number of types of insulin available in the United States. onsets within 1 to 2 hours of administration, peaks within 4 to 14 hours, One way of categorizing insulin subtypes is by their speed of action. and lasts between 16 to 24 hours. It is typically administered twice Rapid acting insulin daily, to provide coverage for both basal and post-prandial insulin Rapid acting insulins typically have a very quick onset of action, taking needs. effect within 10 to 20 minutes of administration. Their peak effects There are two commonly available NPH insulin products in the United are seen within 0.5 to 3 hours, and effects last between 3 and 6 hours. States: Rapid-acting insulins are typically administered three times daily, ●● Humulin N. immediately before eating. This is to allow the effects of rapid acting ●● Novolin N. insulin to begin when glucose absorption from the gut begins, and their peak will then correlate with the peak in glucose levels after a meal. NPH insulin products are cloudy suspensions that need to be They are designed to lower post-prandial glucose levels with bolus gently mixed prior to administration. They are only administered insulin dosing. To assess the effects of a rapid acting insulin dose, blood subcutaneously, and can be mixed in the same syringe with rapid acting sugar levels should be checked two hours after a meal. or regular insulin if necessary, so long as the rapid acting or regular insulin is drawn up first. NPH is available in vials, prefilled pens, and Several rapid acting insulin products are currently available in the cartridges for reusable insulin pens, in concentrations of 100 units/mL. United States. These include: ●● Lispro, sold under the brand name Humalog. Nocturnal hypoglycemia appears to be more common in patients using ●● Aspart, sold under the brand name Novolog. NPH insulin twice daily, due to peak insulin levels that occur overnight. ●● Glulisine, sold under the brand name Apidra. Patients experiencing significant nocturnal hypoglycemia may benefit from an alternative to NPH, such as a long-acting insulin.

Pharmacy.EliteCME.com Page 50 Diabetes consideration: When drawing up rapid or regular insulin ●● Humalog Mix 75/25 contains 75% insulin lispro protamine (similar with NPH in the same syringe, the clear insulin should always be to NPH) and 25% lispro. drawn up before the cloudy insulin! ●● Humalog Mix 50/50 contains 50% insulin lispro protamine (similar to NPH) and 50% lispro. Long-acting insulin ●● Novolog Mix 70/30 contains 70% insulin aspart protamine (similar Long-acting insulins have the longest duration of action. They are to NPH) and 30% aspart. designed to act similarly to the body’s basal insulin levels. They The following products combine regular and NPH insulin in one typically onset within 1 hour, do not have a significant peak, and last solution: between 20 and 24 hours. ●● Humulin Mix 70/30 contains 70% NPH and 30% regular insulin. There are two long-acting insulin products available in the United States: ●● Novolin Mix 70/30 contains 70% NPH and 30% regular insulin. ●● Glargine, sold under the brand name Lantus and Toujeo. While premixed insulins are relatively convenient and easy to use, ●● Detemir, sold under the brand name Levemir. they do not allow for much flexibility. Meals must be eaten at a more Glargine and detemir each have a unique method for achieving their regular schedule, and if the patient skips a meal, he or she becomes at long duration of action with minimal peak levels. When injected risk of hypoglycemia because the insulins cannot be adjusted separately. subcutaneously, glargine molecules aggregate into groups of six Premixed insulins are not commonly recommended for patients with molecules and slowly dissociate into single molecules, which can then type I diabetes, as these patients typically need the ability to make small be absorbed into the systemic circulation. On the other hand, detemir adjustments to insulin dosing based on meal intake. They are no longer is absorbed more quickly, but binds to albumin in the bloodstream to commonly used in type II diabetic patients either, due to the ease of use prolong its duration of action. with newer prefilled pen technologies and the inability for long-acting Lantus and Levemir are both clear, colorless liquids that can only be products such as Levemir and Lantus to be mixed with other insulins. administered by the subcutaneous route. They cannot be mixed in the However, premixed insulin can be considered in patients who are well same syringe with any other type of insulin. They are both available controlled on self-mixed regimens who prefer the convenience of in concentrations of 100 units/mL, in vials and prefilled pens, and having their insulin premixed. Lantus is available in a cartridge for reusable pens. Both products are Premixed insulins are cloudy solutions that can only be administered only available by prescription. Toujeo is a more concentrated form of subcutaneously. They are available in vials and prefilled pens. Similar glargine insulin, available in a concentration of 300 units/mL. to their individual components, the Humalog Mix and Novolog Mix Pre-mixed insulin require prescriptions for purchase, while the Humulin Mix and Novolin There are a number of pre-mixed insulin products available in order to Mix do not require a prescription. save patients the step of mixing two insulins in the same syringe. These Practice question #8 products act similarly to combinations of the previously mentioned Which of the following is a rapid-acting insulin? insulins, and attempt to provide insulin peaks at meal times while a. Glargine. providing a longer acting basal component as well. b. Detemir. The following products combine rapid-acting insulin with an altered c. NPH. form of rapid acting insulin that has properties similar to NPH: d. Aspart. Choosing an insulin regimen – Type I diabetic patients (McCulloch, 2016f) Type I diabetic patients will require lifelong insulin therapy, and before lunch, mid-afternoon, before the evening meal, before bedtime, the standard of care for these patients is to utilize intensive insulin and occasionally in the middle of the night. Additional tests may be regimens. The goal of insulin therapy in type I diabetics is to provide needed after certain meals and before and after exercise. Newer devices insulin in a way that mimics the body’s natural basal and bolus insulin built into insulin pumps have been developed to allow for continuous release. A basal level of insulin is provided through once or twice-daily glucose monitoring, and while it may not completely remove the need injections of an intermediate or long-acting insulin, or by continuously for an occasional fingerstick to calibrate the machine and confirm delivering short or rapid acting insulin through an insulin pump. severely abnormal levels, its immediate feedback allows for more rapid Bolus doses are administered before meals, and specific doses are responses in the event of serious high or low levels. determined by blood glucose levels before a meal, the size of the meal, Intensive insulin therapy in type I diabetes has clear benefits, but the carbohydrate composition of the meal, and by anticipated activity potential disadvantages should also be considered. The patient is levels. This type of regimen should be started as early as possible after required to put a lot of effort into managing their diet, exercise, insulin the diagnosis of type I diabetes is made. regimen, and blood glucose monitoring, which may not be ideal Intensive insulin therapy for every patient. In addition, weight gain is more likely, which can The Diabetes Control and Complications Trial was a landmark study also affect patient compliance with the intensive regimen. Risks of completed in 1998 assessing the effects of intensive insulin therapy hypoglycemia are increased with intensive therapy, up to three times in patients with type I diabetes. Intensive insulin therapy, with three higher than patients on more conventional regimens. Cost is also or more insulin injections per day or continuous infusion of insulin, a factor to consider; the Diabetes Control and Complications Trial guided by four or more blood glucose tests per day, was compared with found the cost in the 1990s was three times higher than conventional conventional therapy with one or two insulin injections per day. The treatment. With rising drug prices, inflation, and new technologies researchers found that aggressive insulin therapy beginning immediately available, that cost may actually be higher nowadays. Despite the after diagnosis had effects of maintaining the patient’s remaining beta disadvantages, intensive therapy with insulin is considered the cell function, and therefore, sustained endogenous secretion of insulin. treatment of choice in type I diabetic patients (The Diabetes Control and This action was associated with a lower risk of severe hypoglycemia Complications Trial Research Group, 1998). as well as lower A1c levels. Intensive therapy was also associated with When choosing an insulin regimen for a type I diabetic patient, the lower rates of macrovascular complications, including retinopathy, basic requirements are a basal level of insulin and bolus doses of a neuropathy, and nephropathy. The intensive therapy that was utilized rapid or short-acting insulin before meals. Choosing between multiple in the Diabetes Control and Complications Trial is now considered injections per day and an insulin pump that delivers subcutaneous standard therapy for type I diabetic patients (The Diabetes Control and insulin continuously is mostly left to patient preference and ability to Complications Trial Research Group, 1998). utilize the technology. Glycemic control and quality of life appear to Blood glucose monitoring is an integral part of intensive insulin therapy be similar between both delivery methods, but patient preference is the for type I diabetic patients, allowing the patient to make adjustments main limiting factor. to insulin dosing. Intensive insulin often requires between 4 and 7 tests per day, with tests commonly done before breakfast, mid-morning,

Page 51 Pharmacy.EliteCME.com Prandial insulin Insulin adjustments For prandial insulin administered through pre-meal injections, patients After initiating insulin in a type I diabetic patient, blood glucose levels typically prefer rapid- acting insulins to regular insulin. Rapid acting should be assessed. Patients should be instructed to record blood insulins allow the patient more flexibility and convenience with regard glucose levels four to seven times daily, at the following time periods: to meal timing, as they can administer their insulin right before the Before breakfast, mid-morning, before lunch, mid-afternoon, before meal as opposed to 30 to 45 minutes prior to a meal. Rapid-acting the evening meal, before bedtime, and in the middle of the night if products decrease the postprandial increase in blood sugar levels more the patient wakes up with symptoms of hypoglycemia. Patterns of readily than regular insulin, and are more useful than regular insulin hypoglycemia and hyperglycemia can then be assessed to determine the in lowering unexpectedly high blood glucose levels due to their rapid cause of glucose excursions. effect and shorter duration of action. Erratic blood glucose levels that do not follow a particular pattern Glycemic control does appear to be similar between rapid acting and may be due to an inconsistent eating and exercise patterns. Counseling regular insulin, with no significant differences found between the two patients on the importance of maintaining consistent levels of types of products in multiple studies. Some, but not all, studies have carbohydrates in their meals is essential to promote adequate blood shown a lower risk of severe hypoglycemia with lispro when compared glucose control. Timing of meals, frequency and timing of exercise, and to aspart and regular insulin, though it is unclear if these effects are insulin injection sites should also remain consistent in order to make clinically significant. The ultimate choice of a particular product often appropriate adjustments to the patient’s insulin regimen. depends on patient preference, insurance formulary, and overall cost. If eating consistent levels of carbohydrates at the same time every day Basal insulin is not possible, patients can be trained on counting carbohydrates and When choosing a basal insulin for daily injection, there appears to be adjusting their bolus insulin dose based on the planned carbohydrate little difference in glycemic control when comparing NPH, glargine, intake. Carbohydrate-to-insulin ratios can be used to determine how and detemir. One benefit seen with glargine in particular is that it is much insulin to use for a particular amount of carbohydrates, so if they typically administered once daily, cutting down the number of injections decide to eat a higher carbohydrate meal, they can simply increase the needed in a regimen that requires frequent injections. Glargine can be dose of insulin based on this pre-determined ratio. There is considerable given before breakfast, before dinner, or at bedtime, though studies have inter-patient variability in the amount of insulin needed to cover a set found a lower risk of nocturnal hypoglycemia with doses administered amount of carbohydrates, resulting in different carbohydrate/insulin before breakfast. Occasionally, type I diabetic patients have some ration per patient. Some patients also experience variability in their wearing off effects when glargine is administered once daily due to ratio based on the meal of the day; for example, a patient may need patient specific physiologic factors; these patients may benefit from more insulin to cover 20 grams of carbohydrates at breakfast and less to twice-daily administration to circumvent these issues. cover 20 grams of carbohydrates at dinner. The carbohydrate counting Depending on patient-specific physiologic variables, detemir can method requires a significant amount of patient effort, and may not be be administered once or twice daily. Glycemic control with detemir an appropriate method of treatment for noncompliant patients. is similar to glargine, with comparable A1c values seen with both In general, if blood sugar levels are elevated two hours after a meal, products. The duration of action with detemir appears to be somewhat the patient may need to adjust his or her carbohydrate intake, switch shorter than glargine, and twice-daily administration is necessary in simple carbohydrates like white bread with more slowly absorbed more patients on detemir than glargine due to wearing off effects. carbohydrates such as whole grain or high fiber bread, or increase the Dosing dose of insulin before a meal. The use of rapid acting insulin in place Patients newly diagnosed with type I diabetes are typically started on of regular insulin can also help to maintain postprandial glucose levels a total daily insulin dose of 0.2 to 0.4 units per kilogram per day. Most within goal ranges. patients will ultimately require more insulin, with average daily doses in Maintaining blood glucose levels near the normal range can increase the range of 0.6 to 0.7 units per kilogram per day. Adolescents typically the risk of hypoglycemia. The Diabetes Control and Complications require higher doses due to growth and activity levels. Trial found that lower A1c levels were associated with higher rates of To design a multiple daily injection regimen, the total daily dose is hypoglycemia. It also noted the risk of severe hypoglycemia is higher in typically divided in half, with half of the dose given as a basal insulin, males, adolescents, and patients with a history of severe hypoglycemia. and half given as bolus insulin, divided into three doses before meals. Hypoglycemia symptoms can occur at different blood glucose levels in different patients. For example, a 25-year-old patient with an A1c of 6.5% EXAMPLE: A 60kg patient is newly diagnosed with type I diabetes. may never experience hypoglycemia, while an 80-year-old adult may An initial total daily dose of 0.3 units per kilogram is chosen. Based experience frequent severe hypoglycemia events despite an A1c of 8%. on the patient’s weight, the total daily dose of insulin is 18 units, or 9 Therefore, patient specific factors must always be taken into consideration units given as a basal insulin dose, and 9 units for bolus insulin doses. when treating type I diabetes in order to prevent hypoglycemia (The Glargine and lispro insulins are chosen based on the patient’s insurance Diabetes Control and Complications Trial Research Group, 1998). coverage. Therefore, the patient should receive one dose of 9 units of glargine once daily, and 3 doses of 3 units of lispro before each meal. Depending on the severity of hypoglycemia, it may need treatment with The doses can then be adjusted based on the patient’s blood glucose high sugar foods, oral glucose supplements, or injectable glucagon. levels, meal size and content, and exercise levels. Patients who are experiencing hypoglycemia may need a dose reduction in their insulin. The timing and level of hypoglycemia will determine which insulin to reduce and by what amount. Treatment of hypoglycemia is discussed in the adverse events section below. Continuous subcutaneous insulin infusions via insulin pumps (McCulloch, 2016f; Pharmacist’s Letter, 2010) Insulin pumps providing a continuous subcutaneous insulin infusion and aspart, are highly preferred over regular insulin for continuous were first introduced in 1976, and were the size of a backpack. Many infusion, due to the slower absorption of regular insulin. advances in technology were made over the years, and today’s insulin Starting insulin pump therapy pumps are smaller than a cell phone and can be remotely controlled. Insulin pump therapy works best when utilized with appropriate patient Insulin pumps are used by 20 to 30% of patients with type I diabetes, populations. The ideal patient would be a type I diabetic patient, or a and less than 1% of type II diabetics use them as well. Insulin pumps type II diabetic patient with an absolute insulin deficiency who requires provide rapid acting or regular insulin as a continuous infusion to cover tighter control of blood glucose levels. Prior to initiating insulin pump the patient’s basal insulin needs, and provide pre-meal bolus doses to therapy, the patient should be on a multiple daily insulin injection cover mealtime insulin needs. Only rapid-acting and regular insulin may regimen, with at least four blood glucose checks per day. The intensity be used in insulin pumps. Rapid acting insulin products, such as lispro of a multiple daily injection regimen will prepare the patient for the

Pharmacy.EliteCME.com Page 52 requirements of insulin pump therapy. In addition, the patient should levels is seen, due to the time it takes for absorption and to reach a new be willing and motivated to improve glucose control, physically and steady state insulin level. Basal rates should be changed two to four intellectually able, and comfortable with technology. The patient should hours before the altered level is needed to accommodate these kinetic also be willing to learn the process of counting carbohydrates and how issues. to adjust insulin around carbohydrate intake. Bolus doses typically comprise about 50% of the total daily insulin The following patients may be good candidates for insulin pump dose. The specific dose to use should be based on the meal’s therapy: carbohydrate content, and administered immediately before eating. ●● Patients who fail to achieve target glucose levels due to fears of After initiating an insulin pump, close monitoring is required to ensure hypoglycemia. Insulin pumps can minimize insulin peaks, as well blood glucose levels are adequately controlled. Blood glucose levels as allow patients to tailor insulin dosing to exercise and nutritional should be monitored at least 4 to 6 times daily to allow for adjustments in intake, to minimize the risk of hypoglycemia. the insulin regimen. Catheter sites should be changed every two to three ●● Patients who cannot avoid exercise when insulin levels are peaking, days to prevent the formation of scar tissue in a particular site, which can putting themselves at risk of hypoglycemia. lead to variations in insulin absorption and blood glucose levels. ●● Many patients experience what is known as the “dawn phenomenon,” a period between 2AM and 8AM, during which How to choose an insulin pump blood glucose levels are typically higher. This is thought to be Once the decision to start insulin pump therapy has been made, the next caused by higher levels of hormones during this time period, such step in starting therapy is choosing an insulin pump. All insulin pumps as growth hormone, cortisol, glucagon, and adrenaline, which reliably deliver insulin, but they can differ in the features they offer. The blocks the effects of insulin and results in increased blood glucose following items should be taken into consideration when choosing an levels. Programming an insulin pump to increase the basal rate of insulin pump: insulin during this time period can minimize the effects of the dawn ●● Is the insulin pump easy to use? Some insulin pumps are more phenomenon. complex than others. It is important to choose an insulin pump that ●● Patients with gastroparesis can have erratic blood glucose levels. the patient can learn to use with relative ease. Insulin pumps can deliver bolus doses over longer periods of time ●● What kind of batteries are required? Many use AA, AAA, or lithium to correlate with slower absorption of glucose from food caused by batteries in 1.5 volt or 3.6 volts. Batteries often require replacement gastroparesis. every two to six weeks. ●● Pregnant patients have successfully used insulin pump therapy ●● How much memory does the insulin pump have? Insulin pumps for tighter control of blood glucose levels, preventing obstetric vary in how much memory they have, with a range of 90 events to complications. 5400 events of data storage. ●● Patients with varying meal schedules, due to varying work ●● How much does the insulin pump weigh when full? Some patients schedules or other changing obligations, can benefit from the meal experience irritation with heavier insulin pumps. Many insulin flexibility associated with insulin pumps. pumps weigh between 3.8 and 4.4 ounces when full. ●● Pediatric patients who require minute doses of insulin can benefit ●● Is the insulin pump waterproof? Many insulin pumps are water from the accuracy of insulin pumps. resistant, but submerging the insulin pump may not be possible with every available option. Practice question #9 ●● What volume does the insulin pump reservoir hold? Most insulin Which of the following patients is NOT a good candidate for insulin pumps hold between 175 and 300 units of insulin in their reservoirs. pump therapy? Patients on higher doses of insulin may prefer an insulin pump a. A type I diabetic patient with gastroparesis. that holds a larger volume of insulin to minimize the frequency of b. A 3-year-old child with type I diabetes. refilling the insulin pump. c. An athlete with type I diabetes. ●● Does the insulin pump have the capability of assisting with d. A patient with type I diabetes and dementia. carbohydrate counting? Some insulin pumps include information Most patients starting an insulin pump can do so on an outpatient basis, on common foods and their carbohydrate levels to help with but some patients, such as children with fragile diabetic conditions, may determining carbohydrate content, but not all insulin pumps have benefit from starting an insulin pump while in the hospital for close this functionality. monitoring. When starting an insulin pump, all intermediate and long- ●● Does the insulin pump have continuous glucose monitoring features? acting insulin should be stopped for 12 to 24 hours before initiating Some insulin pumps can continuously monitor glucose levels and insulin pump therapy. Rapid- acting or regular insulin can be used in the alert the user when the blood sugar level gets too low or high. interim period to control blood sugar levels. ●● How many units can be administered in bolus doses? Insulin pumps When starting an insulin pump in a patient previously controlled with a vary in the number of units that can be administered as bolus doses, multiple daily injection regimen, the blood sugar levels before insulin with most insulin pumps falling into the range of 0.05 to 35 units. pump initiation will play a role in determining the basal and bolus doses Insulin pumps can administer bolus doses through various methods: to use. For example, a patient well controlled on a multiple daily insulin All at once, over an extended period of time, or half at once and half injection regimen with an A1c of 6.5% may require an initial reduction over a longer period of time. It is important to ensure bolus doses of 10 to 20% in the total daily dose of insulin when started on the can be administered in a method the patient requires. insulin pump. A patient with poor glycemic control on a multiple daily ●● Can multiple basal rates be programmed? The products available insulin injection regimen with an A1c of 9% can typically be started on can vary in the number of basal rates they can accommodate, so it the same total daily dose of insulin when started on the insulin pump. is important to verify that the insulin pump can accommodate the number of rates a patient may need. Similar to a multiple daily insulin injection regimen, approximately ●● What is the lowest possible basal level? Some children use very low 50% of the total daily dose is administered as a basal rate in an insulin doses of insulin, so it is important to ensure the insulin pump can pump. A typical basal rate for a type I diabetic patient is 0.01 to 0.015 accommodate very low doses in these patients. Basal increments units per kilogram per hour, or 0.6 to 0.9 units per hour for a 60kg can vary from 0.025 to 0.1 units at a time. patient. Doses are then adjusted based on blood glucose levels. ●● What kind of infusion set is used with the insulin pump? Some Infusion rates may need to be different at certain times of the day. For insulin pumps have proprietary infusion sets for their brand of example, patients who experience the dawn phenomenon have higher insulin pump, while others use common Luer-Lok tubing. Some insulin needs in the middle of the night. Children under 12 years of age products do not use infusion sets, instead the insulin pump has a may experience a reverse dawn phenomenon, in which blood glucose built in set and the entire unit is discarded and replaced when empty. readings are low in the early morning hours. Most insulin pumps have Advantages of insulin pumps programming that allows for changes in the infusion rate at certain Insulin pumps allow for tighter control of blood glucose levels, and times of the day to accommodate these issues. When changing the deliver insulin in a way that more closely resembles the body’s natural infusion rate, there may be a delay before the change in plasma insulin physiologic insulin release. Tighter insulin control is correlated with a Page 53 Pharmacy.EliteCME.com reduction in the risk of microvascular and macrovascular complications blood sugar levels. Nicknamed the “artificial pancreas,” automated of diabetes. The use of insulin pumps is also associated with reduced closed loop systems require minimal user input, and attempt to learn episodes of severe hypoglycemia and nocturnal hypoglycemia, since the user’s insulin needs in order to take action to correct glucose levels most insulin pumps have built in warning systems and alarms that alert before they get out of control. Some variations of this technology the patient to low blood sugar levels. even incorporate glucagon for administration in the event of a severe Insulin pumps are being used increasingly in pediatric patients with hypoglycemic episode. This technology is still quite new and not type I diabetes. A randomized study of 32 children and adolescents with available until the spring of 2017. Studies have proven their efficacy type I diabetes found that goal A1c and pre-meal glucose levels were short-term, but long-term data is still under investigation (Medtronic, more easily achievable with insulin pumps and compared to a multiple 2016). daily injection regimen. Children with severe nocturnal hypoglycemia Disadvantages of insulin pumps may also benefit from the nighttime use of an insulin pump, and Cost is a significant disadvantage to the use of insulin pumps, because multiple daily injections during the day, to reduce the risk of nocturnal the cost of the insulin pump and associated supplies are higher than a hypoglycemia (Doyle et al., 2004). multiple daily injection regimen. In addition, system failure due to a Another advantage of insulin pumps is that there tends to be less blocked or leaking infusion set can cause a significant disruption in the variability in insulin absorption day to day when administered via an patient’s insulin therapy. Interruptions in insulin delivery via an insulin insulin pump. This is because insulin pumps deliver a relatively small pump can lead to hyperglycemia and ketoacidosis more rapidly than is volume of insulin at a time, and the injection site is consistent, two seen with multiple daily injections, with ketoacidosis seen in an average factors that can have a significant effect on insulin absorption. Less of 4 hours, due to the small subcutaneous depot of insulin. Injection site variability in absorption allows for more predictability in glucose reactions and skin infections are also a possible complication of insulin control. pumps. Insulin pumps also allow for more flexibility in meal timing. Patients Patient preference is also a significant factor in insulin pump use. Many using an NPH regimen that includes a dose before breakfast typically patients feel “tethered” to their insulin pump at all times, which can experience a peak in insulin levels around lunchtime. Delayed lunch can cause significant psychosocial issues due to perceived embarrassment lead to hypoglycemia at lunchtime. Since continuous infusion therapy and awkwardness in social situations, as well as annoyances while allows for basal rates without a peak and bolus doses administered prior sleeping. Patients using an insulin pump can often be off their insulin to a meal when needed, a late meal can be more easily accommodated pump for less than an hour without significant effects on their blood for, preventing hypoglycemia. glucose, but longer excursions without their insulin pump typically require an injection of insulin. The type of insulin and dose injected Some insulin pumps have integrated continuous glucose monitoring is patient specific and depends on the length of excursion as well. devices, which allow for real time feedback on blood sugar levels so Excursions also typically require more frequent blood glucose that the patient can make more informed decisions on their insulin monitoring to ensure glucose levels remain in control. dosing and improve glycemic control. Newer insulin pumps can even suspend the delivery of insulin based on low blood glucose levels, Diabetes consideration: The psychosocial impact of insulin pumps which can significantly reduce the risk of nocturnal hypoglycemia. should always be considered when initiating an insulin pump in a The FDA recently approved the first automated closed loop insulin diabetic patient. Patients who feel embarrassed or awkward with pump in 2016. This type of insulin pump has a continuous glucose insulin pump use may be more likely to become noncompliant. monitoring system that delivers insulin based on automatically detected Choosing an insulin regimen – Type II diabetic patients (Garber et al., 2016; McCulloch, 2016e; McCulloch, 2016g) Type II diabetic patients who are unable to control persistent Basal insulin is highly recommended for type II diabetic patients starting hyperglycemia with oral agents may benefit from adding insulin to insulin therapy, due to the simplicity of a basal regimen, lower rates of their oral regimen, or stopping their oral regimen and starting insulin. hypoglycemia, and greater patient satisfaction. Once-daily glargine or Adding insulin and continuing oral agents can be beneficial, because detemir are recommended for initial insulin treatment by the American oral agents can continue suppressing glucose production in the liver, Association of Clinical Endocrinologists and the American College of slowing gastric emptying, or removing excess glucose through the Endocrinology (AACE/ACE) in their 2016 Type II Diabetes Management urine, allowing for lower total insulin requirements and minimal Algorithm (Garber et al., 2016). The choice between these two products insulin-related weight gain. If switching completely from oral agents to often depends on cost and insurance formulary coverage, with patient insulin, it is recommended to continue oral agents until the insulin dose preference being a factor as well. The timing of the once-daily dose has been stabilized, to minimize the risk of elevated blood sugar levels should be based on when it is more likely the patient will adhere to the while the insulin dose is being adjusted. treatment regimen, as well as their pattern of hyperglycemia. Patients with Metformin is a common oral agent to leave on board when insulin consistently high blood glucose levels overnight may benefit most from is started. Other agents can be considered to keep on board if adding an evening dose of basal insulin, to minimize the risk of the dose wearing insulin; DPP-4 inhibitors and GLP-1 agonists are good choices for off before the effect is needed most. combination therapy with insulin due to their low risk of hypoglycemia Choosing a basal insulin dose depends on the patient’s initial A1c and actions in slowing gastric emptying, which may help offset level. The 2016 AACE/ACE Type II Diabetes Management Algorithm insulin-related weight gain. SGLT-2 inhibitors are also good choices for recommends starting patients with an A1c less than 8% at a total daily combination with insulin due to their mechanism of action of removing dose of 0.1 to 0.2 units per kilogram of body weight, and patients with excess glucose through the urine and low risk of hypoglycemia. an initial A1c greater than 8% at a total daily dose of 0.2 to 0.3 units per Sulfonylureas are often discontinued after initiating insulin due to the kilogram of body weight (Garber et al., 2016). higher risk of hypoglycemia with this combination. After initiation, basal insulin doses can then be adjusted every 2 to 3 Practice question #10 days based on fasting blood glucose levels, with total daily insulin doses Which of the following agents is LEAST beneficial to leave on board typically increased by 2 units at a time until goal blood glucose levels when starting insulin therapy in a type II diabetic patient? are met. Patients experiencing hypoglycemia with basal insulin should a. DPP-4 inhibitors. have their dose reduced based on fasting blood sugar levels. For patients b. SGLT-2 inhibitors. with fasting blood glucose levels consistently less than 70mg/dL, the c. Sulfonylureas. basal insulin dose should be reduced by 10 to 20%, while patients with d. GLP-1 agonists. levels consistently less than 40mg/dL should have the dose reduced by 20 to 40%.

Pharmacy.EliteCME.com Page 54 Patients with persistently high A1c levels with fasting blood glucose absorption of insulin, so it is recommended to use rotating locations on levels in the target range of 70 to 130mg/dL should have blood glucose the same site for injecting daily doses of insulin to minimize variability. levels checked before meals and before bed to assess the duration of Blood flow to the subcutaneous skin layer can also affect absorption. effects of the single daily dose of basal insulin. Patients who show signs Absorption is increased with higher skin temperatures, such as those of basal insulin wearing off too early may benefit from splitting their induced by hot showers or saunas, massage to the local area, and basal dose evenly into twice-daily injections. exercise. Blood flow rates are lower in smokers, so absorption may be Patients who have consistently high post-prandial blood sugar levels reduced in these patients. may benefit from the addition of a prandial insulin, such as a rapid Cardiovascular effects acting aspart or lispro. The 2016 AACE/ACE Type II Diabetes The Outcome Reduction with Initial Glargine Intervention (ORIGIN) Management Algorithm recommends choosing between two different trial found that oral agents combined with glargine insulin did not methods of starting prandial insulin. One method recommends starting appear to affect cardiovascular outcomes when compared with oral prandial insulin before the largest meal of the day, and adding additional agents alone. This study assessed over 12,500 patients with type injections before other meals as needed to achieve glycemic goals. The II diabetes or prediabetes who had cardiovascular risk factors, and other method involves initiating prandial before all three meals initially. randomly assigned them to receive a dose of glargine every evening or Prescribers should proceed on a case-by-case basis, depending on the standard care. After a period of 6 years, the glargine group maintained individual patient’s pattern of hyperglycemia (Garber et al., 2016). lower fasting blood sugar levels, but the rates of cardiovascular After initiating prandial insulin, doses can be adjusted every 2 to 3 days outcomes were similar between the two groups (ORIGIN Trial until glycemic goals are met, with a suggested upward dose titration of Investigators et al., 2012). 1 to 2 units at a time. Patients experiencing hypoglycemia with prandial The findings of the HEART2D trial, which evaluated effects of basal insulin regimens should have their dose reduced based on blood sugar and prandial insulin on cardiovascular outcomes in patients who had a levels two hours after meals or immediately before the next meal. myocardial infarction, found no difference between basal and prandial Patients with postprandial blood glucose levels consistently less than insulin on cardiovascular outcomes. While this study was stopped early 70mg/dL should have their dose reduced by 10 to 20%, while those with after an average follow-up period of 2.7 years, the lack of a difference levels consistently less than 40mg/dL should have their dose lowered by in cardiovascular effects between basal and prandial insulin is notable 20 to 40%. (Raz et al., 2009). Premixed formulations are not commonly recommended for initiation Adverse effects in patients with type II diabetes. While in theory they would provide The most common side effects associated with insulin therapy are two peaks of insulin activity in one injection, in practice, the peaks of hypoglycemia and weight gain. Weight gain is particularly an issue the rapid acting and intermediate acting insulins tend to merge together with more intensive insulin regimens. The UKPDS trial found an to form a single peak that is more difficult to correlate hyperglycemia average weight gain in type II diabetic patients of 7kg after 10 years timing. Studies have not shown them to have a glycemic advantage over of therapy, with rapid weight gain seen during the insulin initiation basal and bolus dosing (Garber et al., 2016). period (UK Prospective Diabetes Study Group, 1998). The magnitude Factors affecting insulin efficacy of weight gain appears to be correlated with the intensity of the insulin Fluctuations in absorption of insulin through the subcutaneous route regimen, with more weight gain seen with higher doses and more can vary from person to person, and even within the same individual, frequent administration. The Diabetes Control and Complications Trial by as much as 25 to 50%. This can lead to unexpected fluctuations in found similar increases in weight with intensive insulin therapy when blood glucose levels and suboptimal glycemic control. Longer acting compared with less frequent dosing, and also noted more weight gain insulins appear to exhibit these effects more frequently than rapid acting seen in patients with higher baseline A1c values and greater decreases insulins, particularly NPH, which may be related to inadequate mixing from baseline A1c (The Diabetes Control and Complications Trial of the insulin suspension prior to injection. Long-acting insulins, such Research Group, 1998). Weight gain associated with insulin therapy can as glargine, have also demonstrated these effects. lead to noncompliance with insulin regimens, particularly in women. Higher variability in absorption and decreased overall absorption are Despite findings of significant weight gain, the UKPDS found that noted with high doses that require a large volume of insulin to be injected microvascular complications were significantly reduced in patients for each dose. This can become a significant issue in treating high blood treated with insulin as monotherapy. Therefore, it is unclear if weight sugars in insulin resistant patients who require large doses multiple times gain associated with insulin therapy is clinically significant. Regardless, per day. Since less variability in absorption is noted with small volumes patients should be counseled on the potential for weight gain when of insulin, splitting doses or using more concentrated forms of insulin in treated with insulin, and preventative lifestyle modifications should be patients that require high doses may help to improve absorption. encouraged (UK Prospective Diabetes Study Group, 1998). Improper injection technique can also lead to variations in absorption. Hypoglycemia is a significant complication of insulin therapy, though it The depth of needle penetration can impact the location of the injection, appears hypoglycemia is more common in patients with type I diabetes and, therefore, absorption rates. Needles inserted at too shallow of a depth as compared with type II. Prandial insulin therapy is more often can lead to an intradermal injection that is not absorbed well. Too deep associated with hypoglycemia than with basal insulin, and it appears of an injection, such as in a very lean area with a thin subcutaneous layer, that glargine and detemir produce less hypoglycemia than NPH. can lead to an intramuscular injection and more rapid absorption. Hypoglycemia typically occurs with blood sugar levels less than 70mg/ Patients should be carefully trained on proper injection technique to dL, though patients experience some variation in the blood sugar minimize the risk of improper absorption. The patient should use an level at which they display symptoms of hypoglycemia. Symptoms area of the body where one inch of subcutaneous fat can be pinched of hypoglycemia include sweating, difficulty concentrating, hunger, between two fingers. The needle should be inserted perpendicularly to incoordination, weakness, lethargy, anxiety, blurred vision, confusion, the area of pinched skin up to the hilt of the syringe; then, the insulin and tremor. Early symptoms of hypoglycemia can be treated with 15 may be injected. The needle should be held in the same place for several to 20 grams of glucose, either in the form of a rapid acting glucose seconds before removal to prevent insulin from leaking out after needle product such as glucose gel or tablets, or administration of a sugary removal. food or drink, such as orange juice, soda, or sweet candy. Administering The most common sites for injecting insulin are the abdominal wall, a longer acting carbohydrate after glucose, such as encouraging the upper legs, upper arms, and buttocks. It appears that insulin is absorbed patient to eat a meal, can help prevent recurring symptoms. Hospitalized most rapidly from the abdominal wall, followed by the upper arm, and patients can be treated intravenously with 25g of 50% dextrose, which the buttock and leg appear to have the slowest absorption. Thicker typically provides a rapid response. layers of subcutaneous fat are associated with a slower absorption Severe hypoglycemia, in which the patient is unable to ingest oral rate of insulin. Switching sites randomly can lead to variability in the glucose or is unconscious, may require an injection of glucagon. Glucagon kits should be kept in an easily retrievable location that close

Page 55 Pharmacy.EliteCME.com family members or friends can find. Family and close contacts should it subcutaneously or intramuscularly. Glucagon is typically administered be trained to recognize the symptoms of hypoglycemia and understand in a dose of 0.5 to 1mg, and leads to recovered consciousness within 15 how to inject glucagon if necessary. Glucagon kits often require the user minutes. It may be followed by significant nausea and possibly vomiting to mix glucagon powder with a diluent, draw it into a syringe, and inject (Cryer, 2016). Choosing a treatment for type II diabetic patients (Garber et al., 2016) Type I diabetic patients are almost exclusively treated with insulin. Patients should be encouraged to seek support from their community. While there is research in progress assessing alternative therapies for Participation in diabetic support groups can encourage patients to the treatment of type I diabetes, there is no clear recommendation for continue on the road to good health, and minimize the risk of relapse the use of these products at this time. Therefore, this section will focus into poor lifestyle choices. Patients should be screened for mood on treatment selection for type II diabetic patients. disorders, as these can contribute to poor diet and lifestyle choices, and Choosing a treatment regimen for a type II diabetic patient can seem referred to mental health specialists if necessary. daunting with the long list of available treatment options. There are a Diabetes alone can increase the risk of cardiovascular disease, number of recommendations and guidelines for treating type II diabetes. and smoking can increase this risk. All diabetic patients should be Treatment guidelines have changed drastically over the years due to the encouraged to stop smoking and using tobacco products to minimize introduction of new medications, as well as due to continuous research the risk of cardiovascular disease. Structured programs are available to on the effects of diabetic medications on glycemic control and cardiac help patients quit smoking, as well as a variety of smoking cessation health. The American Association of Clinical Endocrinologists and products to wean down the level of nicotine they take in. the American College of Endocrinology (AACE/ACE) published a Treatment of pre-diabetes treatment algorithm in 2016 that helps clinicians decide on treatments Pre-diabetes is a significant risk factor for type II diabetes. Patients with based on a variety of factors. A summary of those recommendations will a fasting blood glucose level of 100-125mg/dL are considered to be be discussed here. pre-diabetic. Other glycemic criteria for diagnosing pre-diabetes include Glycemic goals a glucose level of 140 to 199mg/dL after an oral glucose tolerance Glycemic goals for patients with type II diabetes have changed a test and an A1c of 5.5 to 6.4%. Patients with metabolic syndrome are number of times over the years. A1c goals should be individualized for also at an increased risk of developing diabetes. Metabolic syndrome each patient, based on a variety of factors such as age, hypoglycemia is diagnosed when patients exhibit three of the following criteria risk, and comorbidities. The American Association of Clinical (American Association of Clinical Endocrinologists, 2016): Endocrinologists and the American College of Endocrinology ●● Waist circumference of more than 40 inches in men, or 35 inches in recommends a goal A1c less than or equal to 6.5% for patients who do women. not have a serious illness and are at a low risk of hypoglycemia. A1c ●● Triglyceride levels greater than 150mg/dL. greater than 6.5% can be considered for patients with serious illnesses ●● HDL cholesterol levels less than 40mg/dL in men or 50mg/dL in and those at risk of hypoglycemia. Some studies suggest goals of up to women. 8.5% for geriatric patients, as these patients are at a high risk of severe ●● Blood pressure greater than 130/85 mmHg. adverse effects from hypoglycemia, such as serious injury from falls ●● Fasting blood glucose greater than 110mg/dL. (Garber et al., 2016). Lifestyle modifications are typically the initial treatment of choice Lifestyle modifications and non-pharmacological treatments in these patients, and should be encouraged highly. Patients with one Initial treatment of type II diabetes should always begin with lifestyle criteria for pre-diabetes should have weight loss strategies intensified modifications. Optimizing nutrition is critical to decrease the effects to encourage weight loss. Patients at a high risk of the development of food on blood glucose levels as well as achieving goal body of diabetes who have more than one criteria for pre-diabetes should weight. Calorie restriction should be used to encourage weight loss in be considered for treatment with metformin or acarbose, as these are patients who are not at their goal weight. A plant-based diet should be considered low risk medications that could prevent the development encouraged, as well as whole grains, which are absorbed more slowly of diabetes. If blood sugar levels are not normalized with metformin and cause less significant peaks in blood glucose levels. Trans- fatty or acarbose, GLP-1 receptor agonists and thiazolidinediones can be acids should be avoided, and saturated fats from animal sources should considered with caution. be limited due to their negative effects on weight and cardiac health. Treatment of type II diabetes Consultation with a dietician may be beneficial for patients who are After ensuring lifestyle modifications are optimized, initial treatment of having a hard time making appropriate food choices, and counseling type II diabetes is based on the patient’s entry A1c level. Patients with may help as well in those who have behavioral issues pertaining to food. an A1c of less than 7.5%, or those who are less than 1% away from Physical activity also should be encouraged if the patient is their goal, are recommended to start with monotherapy. A variety of medically stable enough for it. The American Association of Clinical options can be chosen for monotherapy, with metformin being the most Endocrinologists and the American College of Endocrinology highly recommended. Patients who have contraindications to the use of recommends 150 minutes per week of physical activity resulting in metformin should be considered for the following first line treatments, moderate exertion. Strength training is also beneficial. Activity levels which are listed with the most highly recommended products at the top should be increased as tolerated to help patients achieve goal weights of the list: and minimize the risk of cardiovascular disease. ●● GLP-1 receptor agonists. Significantly overweight patients who have a body mass index greater ●● SGLT-2 inhibitors. than 27 who also have moderate to severe complications associated ●● DPP-4 inhibitors. with their weight may need medical therapy to help decrease their ●● Thiazolidinediones. weight. A number of drug products are available to help decrease ●● Alpha-glucosidase inhibitors. weight, including stimulants such as phentermine, antidepressants such ●● Sulfonylureas. as bupropion, and agents that discourage the absorption of fats such as Patient-specific factors should be taken into consideration when Orlistat. Patients with a body mass index greater than 35 who present choosing an antidiabetic agent, including whether weight loss is desired, with severe weight related complications may be candidates for weight their hypoglycemia risk, concurrent disease states such as renal or loss surgery, such as gastric banding or bypass surgery. hepatic disease, and concurrent medication use to avoid interactions. Sleep is an integral part to maintaining optimal health. Patients should Patients who are started on monotherapy and are not at goal glycemic be encouraged to sleep approximately 7 hours per night. They should levels after three months, those with an A1c greater than 7.5% or those also be screened for obstructive sleep apnea, as overweight and obese who are greater than 1.5% away from their A1c goal, and asymptomatic patients are at a higher risk of developing this condition. patients with an initial A1c over 9% or those who are over 2.5% away from their A1c goal should be considered for dual therapy. Dual therapy

Pharmacy.EliteCME.com Page 56 consists of using metformin or another first line agent in addition to one ●● Colesevelam. of the following second line treatments, which are listed with the most ●● Bromocriptine. highly recommended products at the top of the list: ●● Alpha glucosidase inhibitors. ●● GLP-1 receptor agonists. ●● Sulfonylureas. ●● SGLT-2 inhibitors. Patients who are not at their goal A1c level after treatment with triple ●● DPP-4 inhibitors. therapy for three months should have insulin added or intensified. ●● Thiazolidinediones. ●● Basal insulin. Patients with an initial A1c over 9%, or those who are more than ●● Colesevelam. 2.5% away from their goal A1c level, and have macrovascular or ●● Bromocriptine. microvascular complications should be initiated on insulin. Other agents ●● Alpha glucosidase inhibitors. can be added to insulin therapy as appropriate for the patient. ●● Sulfonylureas. If initiating basal insulin, patients with an A1c of less than 8% If the patient treated with dual therapy is not at their goal A1c after are recommended to begin with 0.1 to 0.2 units per kilogram of three months of therapy, a third agent should be added. Asymptomatic body weight per day, and those with an A1c of greater than 8% are patients with an initial A1c greater than 9%, or those who are more recommended to start with 0.2 to 0.3 units per kilogram of body weight than 2.5% away from their A1c goal can be considered for initial per day. Insulin should be adjusted every 2 to 3 days until glycemic therapy with triple therapy. Triple therapy consists of using metformin goals have been met. If a patient is on a sulfonylurea before initiating or another first-line agent, a second-line agent, and one of the insulin, this medication should be considered for discontinuation, due to following third line treatments, which are listed with the most highly the risk of hypoglycemia. recommended products at the top of the list: When intensifying insulin therapy, prescribers can consider adding ●● GLP-1 receptor agonists. prandial insulin, a GLP-1 receptor agonist, a SGLT-2 inhibitor, or ●● SGLT-2 inhibitors. a DPP-4 inhibitor. Depending on the patient, prandial insulin can ●● Thiazolidinediones. be added before the largest meal, or before each meal, based on ●● Basal insulin. hyperglycemia patterns. Prandial insulin should be adjusted every 2 to 3 ●● DPP-4 inhibitors. days until glycemic goals have been met. Counseling Diabetes can have a profound effect on the health and well-being of a Counseling should be patient-specific, and target the specific needs patient, and patient involvement is critical to ensuring optimal control of the patient has on the day of counseling. Pharmacists should be diabetes. Patients with diabetes manage 95% of their care themselves; involved not only in counseling of medications, but also counseling therefore, the pharmacist, in addition to the other members of the on the disease process; lifestyle modifications such as diet, exercise, patient’s health care team, is responsible for ensuring each patient has the and smoking cessation; acute complications of diabetes such as knowledge, self-confidence, and support they need to manage their own hypoglycemia; chronic complications; population specific information care. The risk of complications of diabetes can be reduced through proper applying to children, pregnancy, and elderly; glucose monitoring; and blood glucose control, which is dependent on adherence to medication self-care topics such as foot care. Additional materials may be beneficial regimens, lifestyle modifications, and blood glucose monitoring. The to the counseling pharmacist such as patient information handouts, unique role of the pharmacist as one of the most accessible members of audiovisual aids, and compliance aids such as pill boxes (Palaian, the healthcare team carries a significant responsibility to educate and 2004). counsel these patients to enhance their care. Conclusion Adequate control of diabetes is critical to the prevention of the appropriate uses of these products in order to provide optimal microvascular and microvascular complications of diabetes and their patient care. Current treatment algorithms can help guide the prescriber associated mortality. With the high number of medications available for in appropriate treatment choices, in a method that supports evidence- the treatment of diabetes, prescribers have a responsibility to understand based medicine. References American Association of Clinical Endocrinologists. (2016). Screening and Monitoring of Prediabetes. inhibitors-for-the-treatment-of-type-2-diabetes-mellitus?source=search_result&search=sglt2%20 Retrieved from http://outpatient.aace.com/prediabetes/screening-and-monitoring-prediabetes inhibitors&selectedTitle=1~38 American Diabetes Association. (2012). The History of a Wonderful Thing We Call Insulin. Retrieved Dungan, K. (2016). Amylin analogs for the treatment of diabetes mellitus. Retrieved from https:// from http://diabetesstopshere.org/2012/08/21/the-history-of-a-wonderful-thing-we-call-insulin/ www.uptodate.com/contents/amylin-analogs-for-the-treatment-of-diabetes-mellitus?source=search_ Aronoff, S.L., Berkowitz, K., Shreiner, B., & Want, L. (2004). Glucose Metabolism and Regulation: result&search=amylin%20agonists&selectedTitle=1~150 Beyond Insulin and Glucagon. Diabetes Spectrum 17(3): 183-190. Retrieved from http://spectrum. Dungan, K. & DeSantis, A. (2016). Glucagon-like peptide-1 receptor agonists for the treatment of diabetesjournals.org/content/17/3/183 type 2 diabetes mellitus. Retrieved from https://www.uptodate.com/contents/glucagon-like-peptide-1- Black, C., Donnelly, P., McIntyre, L., Royle, P.L, Shepherd, J.P., & Thomas, S. (2007). Meglitinide receptor-agonists-for-the-treatment-of-type-2-diabetes-mellitus?source=see_link analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev:CD004654. Retrieved from http:// Dungan, K. & DeSantis, A. (2016b). Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of onlinelibrary.wiley.com/doi/10.1002/14651858.CD004654.pub2/abstract type 2 diabetes mellitus. Retrieved from https://www.uptodate.com/contents/dipeptidyl-peptidase-4- Centers for Disease Control and Prevention. (2014). National Diabetes Statistics Report, 2014. dpp-4-inhibitors-for-the-treatment-of-type-2-diabetes-mellitus Retrieved from https://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf Garber, A. Abrahamson, M., Barzilay, J., Blonde, L., Bloomgarden, Z., Bush, M., Umpierrez, G. Chiasson, J.L., Josse, R.G., Gomis, R., Hanefield, M., Karasik, A., Laakso, M., & STOP-NIDDM (2016). American Association of Clinical Endocrinologists and American College of Endocrinology trial. (2003). Acarbose treatment and the risk of cardiovascular disease and hypertension in patients Type II Diabetes Management Algorithm 2016. Retrieved from https://www.aace.com/sites/all/files/ with impaired glucose tolerance: the STOP-NIDDM trial. JAMA; 290:486. Retrieved from http:// diabetes-algorithm-executive-summary.pdf jamanetwork.com/journals/jama/fullarticle/196993 Handlesman, Y. (2009). The Role of Colesevelam HCl in Type 2 Diabetes Mellitus Therapy. Journal Chiasson, J.L., Josse, R.G., Hunt, J.A., Palmason, C., Rodger, N.W., Ross, S.A., Wolever, T.M. (1994). of Postgraduate Medicine. Vol 121. Retrieved from http://www.tandfonline.com/doi/abs/10.3810/ The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. pgm.2009.05.suppl53.289 A multicenter controlled clinical trial. Ann Intern Med; 121:928. Retrieved from http://annals.org/ Hirst J.A., Farmer, A.J., Dyar, A., Lung, T.W., & Stevens, R.J. (2013). Estimating the effect of aim/article/708266/efficacy-acarbose-treatment-patients-non-insulin-dependent-diabetes-mellitus- sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia; 56:973. multicenter Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622755/ Cryer, P. (2016). Management of hypoglycemia during treatment of diabetes mellitus. Retrieved from Hollander, P. (2008). A Review of Type II Diabetes Drug Classes. US Endocrinology. Retrieved from https://www.uptodate.com/contents/management-of-hypoglycemia-during-treatment-of-diabetes- http://www.tdctoolkit.org/wp-content/uploads/2013/06/ReviewofType2DrugClasseshollander-.pdf mellitus?source=search_result&search=management%20of%20hypoglycemia&selectedTitle=1~150 Hollander, P.A., Levy, P., Fineman, M.S., Maggs, G.S., Shen, L.Z., Strobel, S.A., Kolterman, S.G. DeFronzo, R.A. (2011). Bromocriptine: A Sympatholytic, D2-dopamine Agonist for the Treatment (2003). Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight of Type 2 Diabetes. Diabetes Care;34(4):789-794. Retrieved from http://www.medscape.com/ control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care; 26:784. viewarticle/740378 Retrieved from http://care.diabetesjournals.org/content/26/3/784.long DeFronzo, R.A., & Goodman, A.M. (1995). Efficacy of metformin in patients with non-insulin- Home, P.D., Pocock, S.J., Beck-Nielsen, H., Curtis, P.S., Gomis, R., Hanefield, M., RECORD Study dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med; 333:541. Team. (2009). Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy Retrieved from http://www.nejm.org/doi/full/10.1056/NEJM199508313330902 for type 2 diabetes (RECORD): a multicentre, randomized, open-label trial. Lancet; 373:2125. Doyle, E.A., Weinzimer, S.A., Steffen, A.T., Ahern, J.A., Vincent, M., & W.V. Tamborlane. (2004). A Retrieved from http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60953-3/abstract randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with Kahn, S.E., Haffner, S.M., Heise, M.A., Herman, W.M., Holman, R.R., Jones, N.P., ADOPT Study multiple daily injections using insulin glargine. Diabetes Care; 27:1554. Retrieved from http://care. Group. (2006). Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J diabetesjournals.org/content/27/7/1554.long Med; 355:2427. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa066224#t=articleTop DeSantis, A. (2016). Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes Lebovitz, H.E., Dole, J.F., Patwardhan, R., Rappaport, E.B., Freed, M.I., & Rosiglitazone mellitus. Retrieved from https://www.uptodate.com/contents/sodium-glucose-co-transporter-2- Clinical Trials Study Group. (2001). 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Page 57 Pharmacy.EliteCME.com doi/10.1210/jcem.86.1.7157?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_ S Palaian, A., Chhetri, M., Prabhu, S., Rajan, P., & Shankar, R. (2004). Role Of Pharmacist In pub%3Dpubmed& Counseling Diabetes Patients. The Internet Journal of Pharmacology; 4:1. Retrieved from http://ispub. Li, L., Li, S., Deng, K., Liu, J., Vandvik, P.O., Zhao, P., Sun, X. (2016). Dipeptidyl peptidase-4 com/IJPHARM/4/1/3272 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of Pfeffer, M.A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H.C., Kober, L.V., & ELIXA randomized and observational studies. BMJ; 352:i610. Retrieved from http://www.bmj.com/ Investigators. (2015). Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N content/352/bmj.i610 Engl J Med; 373:2247. Retrieved from http://www.nejm.org/doi/10.1056/NEJMoa1509225 Lincoff, A.M., Wolski, K., Nicholls, S.J., & Nissen, S.E. (2007). Pioglitazone and risk of Pharmacist’s Letter. (2010). Insulin Pump Therapy. Retrieved from http://www.mission-health.org/ cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. sites/default/files/document-library/1658_0.pdf JAMA; 298:1180. Retrieved from http://jamanetwork.com/journals/jama/article-abstract/208777 Raz, I., Wilson, P.W., Strojek, K., Kowalska, I., Bozikov, V., Gitt, A.K., Jacober, S.J. (2009). Effects of Marso, S.P., Daniels, G.H., Brown-Frandsen, K., Kristensen, P., Mann, J.F., Nauck, M.A., LEADER prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Trial Investigators. (2016). Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Diabetes Care; 32:381. Retrieved from http://care.diabetesjournals.org/content/32/3/381.long Med; 375:311. Retrieved from http://www.nejm.org/doi/10.1056/NEJMoa1603827 Scheen, A.J., Charpentier, G., Ostgren, C.J., Hellgvist, A., & Gause-Nilsson, I. (2010). Efficacy and Maruthur, N.M., Tseng, E., Hutfless, S., Wilson, L.M., Suarez-Cuervo, C., Berger, Z., Bolen, S. safety of saxagliptin in combination with metformin compared with sitagliptin in combination with (2016). Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev; 26:540. Retrieved Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med; 164:740. Retrieved from http:// from http://onlinelibrary.wiley.com/doi/10.1002/dmrr.1114/abstract annals.org/aim/article/2513979/diabetes-medications-monotherapy-metformin-based-combination- Schopman, J.E., Simon, A.C., Hoefnagel, S.J., Hoekstra, J.B., Scholten, R.J., & Holleman, F. (2014). therapy-type-2-diabetes The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with McCulloch, D. (2016). Sulfonylureas and meglitinides in the treatment of diabetes mellitus. Retrieved sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev; 30:11. Retrieved from from https://www.uptodate.com/contents/sulfonylureas-and-meglitinides-in-the-treatment-of-diabetes- http://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470/abstract mellitus?source=search_result&search=meglitinide&selectedTitle=1~48 Shyangdan, D.S., Royle, P., Clar, C., Sharma, P., Waugh, N., & Snaith, A. (2011). Glucagon-like McCulloch, D. (2016b). Metformin in the treatment of adults with type 2 diabetes mellitus. Retrieved peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev:CD006423. 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Retrieved from https://www. htm?source=govdelivery&utm_medium=email&utm_source=govdelivery uptodate.com/contents/insulin-therapy-in-type-2-diabetes-mellitus?source=search_result&search=ins Whitehouse, F., Kruger, D.F., Fineman, M., Shen, L., Ruggles, J.L., Maggs, D.G., Kolterman, A.G. ulin&selectedTitle=5~130 (2002). A randomized study and open-label extension evaluating the long-term efficacy of pramlintide Medtronic. (2016). Retrieved from https://www.medtronicdiabetes.com/blog/fda-approves-minimed- as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care; 25:724. Retrieved from http://care. 670g-system-worlds-first-hybrid-closed-loop-system/ diabetesjournals.org/content/25/4/724.long Monami, M., Genovese, S., & Mannucci, E. (2013). Cardiovascular safety of sulfonylureas: a meta- Yki-Järvinen, H. (2005). Secondary prevention of macrovascular events in patients with type 2 analysis of randomized clinical trials. Diabetes Obes Metab; 15:938. Retrieved from https://www.ncbi. diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): nlm.nih.gov/pmc/articles/PMC3622755/ a randomized controlled trial. Lancet; 366:1241–2. Retrieved from http://www.thelancet.com/journals/ Nissen, S.E., & Wolski, K. (2007). Effect of rosiglitazone on the risk of myocardial infarction and lancet/article/PIIS0140-6736(05)67528-9/fulltext death from cardiovascular causes. N Engl J Med; 356:2457. Retrieved from http://www.nejm.org/doi/ Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., EMPA-REG OUTCOME full/10.1056/NEJMoa072761 Investigators. (2015). Empagliflozin, Cardiovascular Outcomes, and Mortality inType 2 Diabetes. N ORIGIN Trial Investigators, Gerstein, H.C., Bosch, J. Dagenais, G.R., Diaz, R., Jung, H., Yusuf, S. Engl J Med; 373:2117. Retrieved at http://www.nejm.org/doi/full/10.1056/NEJMoa1504720 (2012). Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med; 367:319. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa1203858 Self-assessment quiz answers 1. Answer: C. 6. Answer: C. Rationale: Ketones are not hormones; they are alternative fuels Rationale: Since linagliptin is eliminated through the hepatic route, the liver makes by breaking down fats when glucose supplies are dosage adjustments do not need to be made in patients with chronic limited. The other three options are hormones involved in the kidney disease. Sitagliptin, saxagliptin, and alogliptin all require regulation of blood sugar levels: cortisol is a stress hormone that dosage adjustments in patients with chronic kidney disease due to increases the resistance of the fat and muscle cells to the effects their elimination through the renal route. of insulin; amylin is a hormone released from the beta cells of the 7. Answer: B. pancreas with insulin, and glucagon-like peptide-1 is an incretin Rationale: Patients with chronic kidney disease should avoid using hormone released by the intestinal tract. SGLT-2 inhibitors due to their direct effects in the kidney. Patients 2. Answer: B. with a history of myocardial infarction and those with a high waist Rationale: Glyburide is a long-acting sulfonylurea that should circumference are not excluded from use of these medications, and be avoided in patients over the age of 65 due to the higher risk may see some benefit in cardiovascular risk reduction with SGLT-2 of hypoglycemia. Glipizide and glimepiride are shorter acting inhibitors. Patients with hypertension may also see some benefit sulfonylureas; their shorter duration of action allows them to carry a with the use of SGLT-2 inhibitors, as these agents may help lower lower risk of hypoglycemia. Metformin is not a sulfonylurea. blood pressure. 3. Answer: A. 8. Answer: D. Rationale: Gastrointestinal side effects, such as diarrhea, are Rationale: Aspart is a rapid-acting insulin. Glargine and detemir are common with the treatment of metformin. Lactic acidosis is a rare long-acting insulins, and NPH is an intermediate-acting insulin. but serious side effect. Injection site reactions and rhinitis are not 9. Answer: D. side effects that have been reported with metformin use. Rationale: Patients with dementia are not good candidates for 4. Answer: D. insulin pump therapy, as they often lack the cognitive ability to Rationale: Studies have shown rosiglitazone can increase the risk manage the use of an insulin pump. Children, athletes, and patients of myocardial infarction, fatal heart failure, and non-fatal heart with gastroparesis are all good candidates for insulin pump therapy. failure. The effects of rosiglitazone on hypertension have not been 10. Answer: C. assessed at this time. Rationale: Sulfonylureas are the least beneficial of the listed 5. Answer: A. agents to keep on board with insulin, due to the increased risk of Rationale: Lixisenatide should be avoided in patients with a hypoglycemia with this combination of agents. DPP-4 inhibitors, creatinine clearance of less than 30mL/min. Patients with a SGLT-2 inhibitors, and GLP-1 agonists can provide additional creatinine clearance greater than 30mL/min are eligible for use benefits when used with insulin. of lixisenatide, as well as those on basal insulin. Patients with an A1c above their goal, such as someone with an A1c of 9.5%, could benefit from the use of lixisenatide.

Pharmacy.EliteCME.com Page 58 DIABETIC MEDICATIONS AND INSULIN PUMP THERAPIES Final Examination Questions Select the best answer for questions 1 through 10 and mark your answers on online at Pharmacy.EliteCME.com

1. Which of the following is NOT a stress hormone involved in the 7. Which of the following insulin products is cloudy? regulation of blood sugar? a. NPH. a. Epinephrine. b. Glargine. b. Growth hormone. c. Aspart. c. Cortisol. d. Regular insulin. d. Antidiuretic hormone. 8. Patients newly diagnosed with type I diabetes are typically started 2. Due to the risk of lactic acidosis, metformin is contraindicated in on a total daily insulin dose of ______units per kilogram per patients with the following comorbidities EXCEPT: day. a. Active alcohol abuse. a. 1 to 2. b. Patients who have a history of lactic acidosis while taking b. 0.2 to 0.4. metformin. c. 0.8 to 1. c. Active or progressive hepatic disease. d. 0.02 to 0.04. d. A glomerular filtration rate greater than 30mL/min. 9. Similar to a multiple daily insulin injection regimens, approximately 3. How is pramlintide typically administered? _____ of the total daily dose is administered as a basal rate in an a. Once daily without regard to food. insulin pump. b. Twice daily, after meals. a. 20%. c. Three times daily, immediately before meals. b. 30%. d. Three times daily, after meals. c. 50%. 4. When compared to placebo, GLP-1 agonists showed a reduction in d. 75%. A1c levels by an average of ______. 10. Which of the following products is the most highly recommended a. 1%. for monotherapy of type II diabetes? b. 0.5%. a. Metformin. c. 0.25%. b. Sulfonylureas. d. 2%. c. DPP-4 inhibitors. 5. GLP-1 agonists exhibit the following effects EXCEPT: d. Thiazolidinediones. a. Slowing gastric emptying to slow food intake. b. Speeding up gastric emptying to slow food intake. c. Reducing postprandial glucagon levels. d. Enhancing glucose-dependent insulin secretion from the pancreatic beta cells. 6. All of the following are benefits of empagliflozin EXCEPT: a. Reduced diabetes-related blindness. b. Reduced vitreous hemorrhage. c. Reduced new or worsening nephropathy. d. Increased risk of nephropathy.

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Page 59 Pharmacy.EliteCME.com Chapter 5: Drug Administration

2 Contact Hours

By: Katie Blair, RPh, PharmD

Author Disclosure: Katie Blair and Elite do not have any actual or Questions regarding statements of credit and other customer service potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $8.00. Universal Activity Number (UAN): 0761-9999-17-079-H01-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: April 1, 2017 a provider of continuing pharmaceutical education. This Expiration Date: April 1, 2019 program is approved for 2 hours (0.2 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70 percent is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a credit. Please submit your answers either by mail, fax, or online participants who have successfully completed the post-test. Participants at Pharmacy.EliteCME.com must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives After completion of this course, healthcare professionals will be able to: Discuss the administration of medications in patients using enteral Describe the eight rights of medication administration. and parenteral nutrition. Explain the administration of enteral and parenteral medications. Discuss special considerations for administering medications in pediatric and geriatric patients. Introduction Medication errors that occur at the point of drug administration poised to reduce the frequency of medication administration errors. comprise a significant portion of the errors that can occur in the Understanding medication administration and putting best practice medication use process. As healthcare providers with a wealth of standards in place will help reduce medication administration errors and knowledge on the use of medications, pharmacists are perfectly increase patient safety. Preventing medication errors during drug administration: The eight rights of medication administration The eight rights of medication administration are used to help ensure all be crosschecked with the medication’s label to make sure the correct the necessary information is verified in order to administer a medication dose will be administered to the patient. appropriately. Historically, healthcare professionals were taught the The right time five rights of medication administration: right drug, right patient, right Before administering a medication, the provider must confirm that the dose, right time, and right route. However, an updated listing includes prescription is written for the correct time of day and frequency, and three more: right reason, right response, and right documentation. These that the scheduled administration time matches up with the prescriber’s eight practices are essential to the safe and accurate administration of order. medications. The right route The right drug The route by which the medication will be given must be documented On receipt of a prescription order, it is imperative that the correct on the prescription, and verified to ensure it is appropriate for the patient medication is selected for administration to the patient. If the name to whom it will be administered. of the drug is unfamiliar, the provider administering the medication should consult a reliable reference to ensure the correct medication is The right reason used. If necessary, the provider should consult references to identify The reason for administering a particular medication should be the purpose of administering the drug, its action, routine routes and confirmed to make sure that the prescribed drug is appropriate for the doses, interactions with other drugs, herbs, and foods, side effects, and patient’s condition. Common conditions the drug is used for should contraindications. When selecting the medication, the provider should be crosschecked against the patient’s conditions to make sure the check the medication label to ensure accuracy. medication is given for an appropriate reason. The right patient The right response The patient’s identity must be confirmed by checking two patient The patient’s response to the drug must be monitored. Pharmacy identifiers, including name, date of birth, address, or medical record staff should communicate with physicians or nurses to ensure they number. Any inconsistencies should be verified before medication are aware of the desired response and the desired response should be administration. communicated to the patient as part of providing patient counseling. The right dose The right documentation The healthcare provider must confirm that the dose is appropriate for the Documentation and record keeping are essential. Documentation of drug, the condition, and the patient. The dose being administered should what was administered to the patient as well as any patient education that was provided should be maintained (1)(2). Routes of administration Routes of administration for drugs can be classified into two categories: Drug administration that bypasses the digestive tract is considered a enteral or parenteral. Medications that are administered through the parenteral route of administration. Parenteral routes are used in many enteral route are absorbed in the digestive tract. This can apply to any circumstances, including when the patient’s gastrointestinal tract is not part of the digestive tract, from the mouth to the rectum. The common functioning, rapid effects are desired, or the patient is unconscious. enteral routes of administration are oral, buccal, sublingual, and rectal. There are many parenteral routes of administration; the most common are intravenous, intramuscular, and subcutaneous.

Pharmacy.EliteCME.com Page 60 Medications are often formulated in several different dosage forms, effects. Other women, such as women with estrogen-related cancers, to be administered by various routes. Since the various dosage forms must avoid systemic dosage forms, so vaginal preparations are used to can result in differing durations of action, onset times, and drug minimize systemic effects. concentrations, the desired effect must be taken into consideration when The patient’s condition must also be carefully considered when choosing a medication’s route of administration. For example, hormone choosing a route of administration. Pediatric and elderly patients are replacement therapy with estrogen can be administered through several particularly susceptible to medication administration errors due to their routes of administration, but the desired effect and potential side effects vulnerable conditions. The use of multiple medications and enteral or must be carefully considered before choosing a dosage form. Some parenteral nutritional support must also be taken into consideration women prefer to use oral treatments due to their desired systemic when medications are administered (1). Enteral routes of administration: Oral The oral route is the most commonly used route of medication of the stomach also have the potential to destroy certain drugs, and administration, since oral dosage forms are portable and easy to irritating medications combined with gastric acid can cause nausea and administer. Oral medications are economical, because they do not vomiting in some patients. require sterile preparation and are available in inexpensive forms. Medications given orally are also subject to the first pass effect. When Orally administered medications are versatile in that they can be medications are absorbed through the gastrointestinal tract, they are released slowly in the gastrointestinal tract, or all at once (3). transported through the portal vein to the liver where drug metabolism There are several disadvantages of the oral route of drug administration. occurs. Some medications are metabolized more than others during The effects attained through the oral route are often too slow for the first pass effect, potentially causing a significant decrease in drug emergency situations, and this route cannot be used when patients bioavailability (4). are unconscious or unable to swallow. Since orally administered medications are absorbed in the stomach and small intestine, this route Administration alert! Medications that experience significant cannot be used in patients without a functioning gastrointestinal tract first pass effects include morphine, lidocaine, diazepam, and or those on NPO orders, and oral administration can be compromised propranolol. when the patient is nauseous or vomiting. The acidic gastric secretions

Dissolution rates and gastric emptying There are many factors that affect absorption of medications that have There can be significant variations in gastric emptying speed from patient been administered orally. The physical state of the drug can have a to patient, since there are many external factors that can have an impact significant impact on the dissolution rate, or the process by which a drug on this time frame. For example, the stomach naturally has a more particle is dissolved. Medications given orally in solid dosage forms must rapid gastric emptying time when empty than immediately after a meal. be dissolved by gastrointestinal fluids before the drug particles become Therefore, medications administered on an empty stomach may remain available for absorption. Medications that rely on an acidic fluid for in the stomach for a shorter period of time than medications administered dissolution are processed in the stomach, while those medications that during or after a meal, affecting the drug’s dissolution and absorption. require a basic solution for dissolution are processed in the intestines. Concurrent medications can also impact gastric emptying time. Oral medications administered in liquid solutions or rapidly dissolving Drugs with anticholinergic properties, including amitriptyline and dosage forms are more readily available for absorption, and absorption diphenhydramine, can slow gastric emptying times, resulting in is limited only by the rate at which the medication can cross membranes increased absorption of medications absorbed from the stomach. at the absorption site. These dosage forms are more appropriate for Medications that increase gastric mobility, including laxatives, can situations where an effect is desired relatively quickly and simple move medications past their preferred site of absorption too quickly, administration is desired. resulting in reduced drug absorption. Some dosage forms are created to allow for slow dissolution, including extended release preparations. Certain medications are also known for Administration alert! When digoxin, a medication with a their slow solubility, including digoxin. Slow release preparations are slow absorption rate, is administered concurrently with milk of administered with the consideration that they may not be completely magnesia, the absorption of digoxin is significantly reduced due to absorbed due to the natural tendency of the gastrointestinal tract to increased gastrointestinal mobility. move substances along, and the effects of disease states that alter gastric emptying or gastrointestinal mobility must be taken into consideration as well. The patient’s condition can also affect gastric mobility. Elderly patients have slower gastrointestinal mobility, as well as diabetic patients. Other Gastric emptying time can have a significant impact on the absorption factors that can affect medication absorption from the gastrointestinal of orally administered medications. The average gastric emptying tract include the surface area available for medication absorption, time, or the time a medication is expected to remain in the stomach, is blood flow at the potential absorption site, the water solubility of the between two to four hours. The small intestine has a longer emptying medication being administered, and the concentration of medication at time, which can range from 4 to 10 hours on average. the absorption site (5). Sublingual route of administration The sublingual route is preferred for certain medications that must Sublingual administration is also beneficial for medications that are be absorbed rapidly for quick onset. Sublingual tablets are easily sensitive to the acidic environment in the stomach. Bypassing the dissolved and are taken by placing the tablet under the tongue where stomach via sublingual administration prevents the medication from it disintegrates for absorption. The drug is absorbed into the venous being inactivated prematurely by the low pH in the stomach. system under the tongue, which transports the medication to the Disadvantages of the sublingual route include the requirement to superior vena cava. Transit through this method protects sublingual keep the medication in the mouth until it dissolves, often imparting medications from first pass metabolism in the liver, allowing the an unpleasant taste in the process. Sublingual tablets are also fragile medication to arrive at its site of action before it is metabolized. and sensitive to moisture, often requiring specialized packaging and storage. Additionally, sublingual tablets must be designed to be small Administration alert! Nitroglycerin, commonly administered and easy to disintegrate, often resulting in higher costs than their oral in sublingual form, would never reach systemic circulation if counterparts (3). administered orally and swallowed, as it would be inactivated by hepatic metabolism (4).

Page 61 Pharmacy.EliteCME.com Buccal route of administration Similar to the sublingual route, the buccal route involves disintegrating Disadvantages of the buccal route are similar to the sublingual route, the medication in the oral cavity. In this route, the medication is and include the experience of an unpleasant taste due to keeping the dissolved on the inside of the cheek, between the cheek and the gums. medication in the mouth for a longer period of time. Buccal tablets are The absorbed medication then travels to the bloodstream, bypassing the often more expensive than more conventional dosage forms, and are acidic gastric environment and hepatic metabolism. less widely available oral or injectable dosage forms (3).

Administration alert! Fentanyl buccal tablets have been developed to bypass the first pass metabolism that can significantly reduce the effectiveness of fentanyl (6).

Rectal route of administration The rectal route of administration is another route that uses the oral medication from getting to its site of absorption in a timely manner. gastrointestinal tract for absorption, though in a less conventional way. Patients with restrictions on oral consumption of food or water and Medications administered rectally are commonly found in suppository patients who recently underwent surgery are also candidates for rectal form, which contains the drug mixed in a substance that melts at medication administration (3). body temperature. When inserted into the rectum, the suppository Rectally administered medications partially bypass the liver, with about melts, releasing the medication to be absorbed through the rectal wall. 50 percent of the drug bypassing hepatic metabolism, reducing the Enemas can also be used to apply liquid medication to the rectal tissue. effects of first pass metabolism. Disadvantages of the rectal route include The rectal wall is thin and has a rich blood supply, allowing rectally irritation of the rectal mucosa, awkward administration, and potentially administered medications to be absorbed readily. variable absorption, depending on the condition of the rectum (4). The rectal route is particularly beneficial for patients who are unconscious or are experiencing nausea or vomiting that will prevent an Parenteral routes of administration: Intravenous Administering medications through the intravenous route ensures that Drug solutions that are irritating can be administered intravenously if the drug gets into the bloodstream as quickly as possible. Absorption is injected slowly, because the circulating blood quickly and effectively bypassed when a drug is injected directly into a vein, resulting in rapid dilutes the solution, reducing irritation. An example of this can be seen and complete bioavailability. Drug delivery can be controlled more with vancomycin, a caustic drug. When administered rapidly, vancomycin precisely and adjusted based on the patient’s response, in a manner that cause phlebitis, or irritation of the veins, in addition to other reactions. It is not possible with other forms of medication administration. However, is therefore indicated to administer vancomycin over the course of at least direct access to the bloodstream requires sterile procedures to prevent 60 minutes to minimize pain, venous irritation, and infusion reactions. infections and embolisms. Unlike many enteral routes, the intravenous route can be used in Intravenous administration allows medications to be administered unconscious patients, allowing these patients to receive the medications rapidly, achieving high drug concentrations. Bolus injections can they need rapidly. Disadvantages of the intravenous route include be given to administer a high dose of a medication rapidly, and are greater potential for adverse effects of medications, since high particularly beneficial in emergency situations. concentrations are achieved rapidly. There is also the risk of embolism when air is injected into the vein with the drug, which can be potentially fatal. Pain at the injection site is also considered a disadvantage (3). Administration alert! Tissue plasminogen activators (tPA), used to break down blood clots in emergency situations, can be administered by an intravenous bolus to ensure the medication gets to the site of action quickly and efficiently, increasing the chance of positive outcomes for the patient (4).

Administering an intravenous medication The first step in administering an intravenous medication is to access this is to ensure the medication is being delivered into a vein. Then the vascular system. This can be done using either a needle or a catheter. the medication can be administered by depressing the plunger of the Needles are used for short-term vascular access. Patients needing syringe at a rate determined by the facility policies, pharmacy staff, or long-term intravenous access can have catheters placed peripherally, medication manufacturer. such as in the arm, or ports surgically placed into a more central vein, Intravenous infusions can be administered in a similar manner, but starting at the subclavian or jugular vein and ending at a point of the instead of pushing the medication through a syringe into the IV access vascular system with high blood flow. Central access often allows for a port, the medication is contained in an intravenous bag that is connected longer distance between the entry point of the catheter and its endpoint, to the port through tubing. Infusion pumps or regulator clamps can reducing the risk of infection as compared to peripheral catheters. be used to control the flow rate of the medication into the patient, and Central catheters are often more durable than peripheral catheters (3). should be used according to manufacturer recommendations, pharmacy Before administering an intravenous bolus or pushed medication to a instruction, and facility guidelines. patient, the nurse should ensure the medication is administered to the correct patient by verifying two patient identifiers. Then the correct Guidelines for administering IV medications can vary based on the medication must be selected and prepared in an appropriate dosage practice location; facility guidelines should always be followed to calculated for the patient. Next, the patient’s intravenous access point ensure proper delivery of these products. Intravenous medications should be located and cleaned with an alcohol swab. Once cleaned, the administered in the same line as other medications should be verified for syringe can be connected to the intravenous access line and should be compatibility before administration by checking the facility’s guidelines drawn back gently to pull a small amount of blood into the syringe; or various references, including Trissel’s Stability of Compounded Formulations (5). Subcutaneous route of administration Subcutaneous administration is used for various types of medications and layer under the skin, directly below the dermis and above the muscular vaccinations, and involves injecting the product into the subcutaneous layer. After injection into the subcutaneous layer, the drug can cross into

Pharmacy.EliteCME.com Page 62 the bloodstream. Absorption rates following a subcutaneous injection are Medications administered subcutaneously must not be irritating to slow, allowing for a prolonged effect of the medication. the tissue. Irritants injected subcutaneously can cause pain, tissue Drugs that are designed for subcutaneous injection can be developed sloughing, and necrosis (4). Short needles should be chosen for in ways that can alter the absorption time through modifications to the subcutaneous injections, such as a 5/8- to ½-inch needle length, to medication’s pH or particle size. Medications can also be developed as ensure drug delivery to the proper layer. No more than two milliliters implantable pellets that release medication into the subcutaneous layer of solution should be injected into the subcutaneous tissue at any one slowly over weeks or months, such as contraceptives. Drug products time, and the needle can be inserted into the skin at a 45-degree (if can also be pumped into the subcutaneous layer slowly through using a longer needle) or 90-degree angle (if using a shorter needle) catheters, as in the case of insulin pumps (4). after pinching the skin. Injection sites should be rotated to prevent lipohypertrophy and lipoatrophy (3). Intramuscular route of administration Medications administered intramuscularly are injected into the muscle Intramuscular injections require a longer needle length to ensure delivery and absorbed into the bloodstream. Rapid absorption occurs if the to the proper tissue, and 1- to 1½-inch needles are commonly used. After drug product is contained in an aqueous solution, with some variation cleaning the skin with an alcohol swab, the needle should be inserted into based on the blood flow and fatty content of the injection site.Aqueous the muscle at a 90-degree angle, and the solution should be injected at a solutions injected into the deltoid muscle are absorbed faster than rate of approximately 1 mL every 10 seconds. The most common adverse solutions injected into the gluteus maximus, particularly in females. reaction to intramuscular injections is injection site pain. Absorption is slower with depot or oil based forms, allowing for a slow, constant release of medication. Heat, massage, and exercise can also have an effect on drug absorption through the intramuscular route (3)(4). Intradermal route of administration Intradermal injections deliver medications into the dermis, the layer of the skin directly under the epidermis. To administer an intradermal injection, the skin is cleansed with an alcohol swab, then the needle is Administration alert! Diagnostic skin testing and certain inserted into the skin at a 10- to 15-degree angle, to prevent injection vaccinations are administered intradermally. into incorrect layers of the skin. Since large fluid volumes create discomfort for the patient, intradermal injections are limited to less than 0.5 mL per injection (3). Intrathecal route of administration When rapid effects are needed in the meninges or cerebrospinal administering intrathecal therapies, the medication preparation cannot areas, injections into the spinal subarachnoid space may be necessary. contain preservatives and must be sterile to ensure infectious agents are This route of administration bypasses the blood–brain barrier to not introduced into the cerebrospinal area (5). ensure delivery of medication to the central nervous system. When Pulmonary route of administration The pulmonary route of administration can be used for various types of rapid absorption into the bloodstream. First pass metabolism is avoided inhaled medications and gasses, both to directly treat the lungs as well in this route of administration (5). as for absorption into the bloodstream. Medications are inhaled with Most medications inhaled into the pulmonary system are designed for the breath and are either applied to or absorbed through the pulmonary topical application to the lungs rather than systemic absorption. There epithelium and respiratory mucous membranes. Since the alveoli of are several methods used to apply medication to the lungs, including the lungs create a large surface area, absorption can be rapid, but the metered dose aerosol inhalers, dry powder inhalers, and nebulized complicated path from the mouth to the alveoli presents a physical solutions. These methods involve breathing the medication with the barrier, preventing large drug particles from reaching the alveoli for breath into the lungs to deliver drug particles to the bronchioles (1). absorption. Gaseous anesthetics are vapors that can reach the alveoli for Intranasal route of administration The intranasal route is used to apply medications to the nasal cavity nasal cavity by pressing the actuator or squeezing the bottle, depending for local treatment. They can be delivered through metered dose nasal on the type of device. If necessary, dosing can be repeated in the other actuators, nasal aerosols, and nasal inhalers. nostril. After application, a gentle sniff can help to move the medication Before administering an intranasal spray, the nose should be gently higher into the nasal cavity. The tip of the device should be rinsed with blown first to clear the nostrils, then the hands should be washed.Then hot water before replacing the cap (1). the patient’s head should be held upright, and the tip of the applicator inserted into one nostril. The medication can then be released into the Administration alert! Antihistamines, corticosteroids, and decongestants are commonly used to treat conditions involving the nasal mucosa.

Ocular route of administration Ophthalmic medications can be applied topically for local effects in the point. Ointments can be applied by pulling the lower eyelid down to eye. Many of these medications must be absorbed through the cornea form a small sac, then drawing the ointment in a small ribbon into the for effectiveness; infections or trauma to the cornea can increase the sac. The eyes should not be rubbed after application. If more than one rate of absorption. Suspensions and ointments, as well as ocular inserts, agent is being used in the eye, wait 5 minutes after instilling eye drops, can delay the absorption of the medication to increase the duration of its and 10 to 15 minutes after using ointments before administering another action (4). product. After applying the medication to the eye, the cap should be Prior to administering ophthalmic medications, the hands should be replaced quickly and carefully, while avoiding touching the tip of the washed to prevent the spread of infection or the introduction of foreign applicator (1). substances into the eye. Drops should be applied to the conjunctiva carefully, while ensuring the applicator does not touch the eye at any

Page 63 Pharmacy.EliteCME.com Otic route of administration When local action of a medication is desired in the outer ear, drugs When ready to administer, the patient’s affected ear should be tilted so may be administered through the otic route. Liquid formulations of the ear canal is perpendicular to the ground. Then the ear canal must be antibiotics, earwax removers, and numbing agents are commonly straightened; for children younger than 3 years of age, the ear lobe should indicated for use in the ear. If a desired medication is not available be pulled down and back, for anyone older than 3 years of age, the upper in an otic dosage form, ophthalmic products may be used, but otic part of the ear should be pulled up and back. Liquid otic drops may then products should never be used in the eye due to the higher acidity of be administered into the straightened ear canal, and care should be used otic formulations. to ensure the dropper does not touch the ear to prevent contamination. Before administering otic medications, the hands should be washed If possible, the patient should keep their head with the ear canal thoroughly. The medication may be warmed to body temperature by perpendicular to the ground for five minutes; if not possible, a cotton ball holding the bottle in the hands before application to reduce discomfort. can be inserted gently into the outer part of the ear (1)(7). Vaginal route of administration The vaginal route is similar to other parenteral routes of administration include creams, ointments, foams, tablets, suppositories, solutions, and in that it bypasses the degradation of drug products by gastric acid intrauterine devices. Disadvantages of this route include the potential and first pass metabolism. However, absorption through this route can for toxic shock syndrome when vaginal dosage forms are used during be variable due to changes in fluid secretion level and pH relatively menstruation, and the possibility of some dosage forms being expelled quickly. This route is commonly used for the topical application of from the vagina after insertion (1). medications to treat conditions of the vagina, with dosage forms that Transdermal route of administration The transdermal route is used to allow medications to penetrate intact improved when the medication is suspended in oil and applied to the skin for absorption into the bloodstream. Transdermal medications skin. Absorption can also be improved by covering the skin with an are available as patches and tapes that can be stuck to the skin for occlusive dressing after medication is applied. absorption into the bloodstream. There are two types of transdermal The transdermal route is beneficial for patients who have trouble systems: those that contain methods to control the release of medication remembering to take medications, as well as unconscious patients. within the transdermal system, and those that allow the skin to control They are simple to use, as they only need to be stuck onto the skin in a the rate of absorption. designated area, dictated by the drug manufacturer. Disadvantages of The skin is penetrable by many types of drug products, but absorption transdermal systems include skin sensitivity at the application site as is dependent on the surface area of the skin where medication is well as issues with adhesion of the system to the skin for the required applied, as well as the lipid solubility of the drug. Highly lipid soluble period of application time (4). medications are readily absorbed, so transdermal absorption can be Dermal route of administration Topical agents are commonly used for their local effects on the treatment of various skin conditions. These products are relatively easy skin. Creams, ointments, gels, solutions, powders, and aerosols are to apply, and can often be easily removed if necessary. commonly used to apply medication directly to the dermal layer for the Administering medications with parenteral nutrition Parenteral nutrition is often used in patients who do not have functioning Chemical and physical compatibility of the medication and parenteral gastrointestinal tracts, or in patient who cannot tolerate oral or enteral nutrition should also be documented. nutrition. Patients receiving parenteral nutrition are commonly receiving Using parenteral nutrition as a vehicle for drug administration is other IV medications as well. When attempting to administer medications advantageous because it consolidates dosage administration, conserves with parenteral nutrition, it is important to ensure these medications are fluid volume in fluid-restricted patients, requires fewer venous compatible with parenteral nutrition solutions to ensure both drug and catheterizations, and decreases administration times. However, there nutritional therapies are safe and effective. is a significant lack of safety and compatibility data for combining Intravenous medications are often administered as a separate solution intravenous medications with parenteral nutrition, limiting the piggybacked on the parenteral nutrition line, though some medications versatility of this practice (7). can be added directly to the nutrition solution. There are several factors to consider when administering medications in this fashion, since there can be physiochemical incompatibilities between the drug and Administration alert! Medications commonly added to parenteral nutritional solution. Before combining IV medications and parenteral nutrition include H2 antagonists and regular insulin. nutrition, compatibility should be evaluated to ensure the combination will be stable for 24 hours and able to endure continuous infusion. Administering medications with enteral nutrition Enteral nutrition is often chosen to deliver nutritional solutions through medication to the small intestines. The type of feeding schedule the tubing to the stomach or small intestine in patients who cannot consume patient is receiving can also affect absorption; continuous feeding food orally but have a functional gastrointestinal tract. There are several into the stomach may need to be stopped to allow medications to be types of enteral feeding tubes that are classified by the placement of absorbed on an empty stomach, while dosing regimens can often be each end of the tubing, including nasogastric tubes, nasojejunal tubes, arranged around intermittent feeding schedules. and gastrostomy tubes. When administered incorrectly, medications can clog feeding tubes, Medications can also be administered through feeding tubes when increase adverse reactions, alter medication efficacy, or create patients cannot swallow. However, several factors must be taken into pharmacokinetic incompatibilities between the drug and nutritional consideration when medications are administered through this route to solution. The dosage form of the medication administered through a prevent complications. Feeding tubes that deliver medications directly feeding tube is particularly important. Liquid medications, including to the stomach allow for medications to be broken down by stomach suspensions, solutions, and elixirs, are preferable as they are less likely acid, but tubing that bypasses the stomach does not allow medications to clog the tubing. However, some liquid formulations have properties to dissolve in the same fashion. Medications that require action in the that can increase the potential for adverse effects, including containing stomach, such as antacids, would not be effective in tubing that delivers high concentrations of sorbitol or being hypertonic.

Pharmacy.EliteCME.com Page 64 Solid dosage forms can also be administered to a patient with a feeding interact with enteral nutrition solutions may need to be administered at tube, but tablets must be crushed and capsules must be opened to a different time than nutritional solutions, or alternative therapies may minimize the risk of clogging the feeding tube. The medication should need to be explored (8). not be added to enteral feeding solutions; they should be administered Since certain medications cannot be crushed or opened, caution must be separately and the tubing should be flushed with approximately 30 mL used to ensure the medication will be effective once manipulated. A full of water before and after administration (7). Some medications interact list of medications that cannot be crushed is available from the Institute with enteral feeding solutions, such as warfarin, fluoroquinolones, for Safe Medication Practices, at http://www.ismp.org/tools/donotcrush. proton pump inhibitors, phenytoin and carbamazepine. Medications that pdf (9). Considerations for drug administration in pediatric patients Pediatric patients experience several unique considerations when it their young age, small body surface area, low weight, and incomplete comes to medication administration; these considerations are due to body development. Oral administration Full-term infants have a gastric pH between 6 and 8 at birth, which generally declines to between 1 and 3 within 24 hours of birth. Premature infants generally have an elevated gastric pH that can remain Administration alert! Acid-labile medications, or those that are high for up to 4 months after birth due to undeveloped gastric acid easily destroyed by gastric acid, such as penicillin and ampicillin, secretion systems. This can have a significant impact on the absorption result in higher serum concentrations in premature infants. and metabolism of orally administered medications and must be taken into account when administering medications to premature newborns. Gastric emptying is also slower in premature infants, resulting in increased contact times with the gastrointestinal mucosa. This can increase absorption of medications and have a significant impact on their effect in premature infants (7). Intramuscular administration Intramuscular drug absorption can also be altered in premature infants. result in unpredictable drug absorption, so the intramuscular route is This population experiences lower muscle mass, more vasomotor avoided in neonates unless there is an emergency or intravenous sites instability, lower blood perfusion to various muscles, and inadequate cannot be used (7). muscle contraction in comparison to full-term infants. These issues can Topical administration Topical drug absorption can also be altered in newborn infants. At birth, infants have a poorly developed epidermal barrier and experience higher levels of skin hydration, which can lead to increased drug absorption. Administration alert! Theophylline, for example, can be applied as a topical gel to premature infants less than 30 weeks gestation In infants, the ratio of body surface area to body weight is the highest to achieve therapeutic serum concentrations for the treatment of of any age group, resulting in higher systemic exposure to topical apnea (7). medications. This can be a disadvantage when it comes to medications such as corticosteroids and rubbing alcohol, increasing the risk of toxic effects associated with these products. However, this effect can be used advantageously with other topical agents (7). Rectal administration Rectal administration can be used as an alternative route for pediatric Rectally administered acetaminophen is commonly used to treat fevers patients who are vomiting or otherwise unable to take oral medications. in infants, and ensures the medication gets absorbed effectively (7). Otic administration Otic administration in children is different depending on the age and back in children younger than 3 years of age. Children older than of the child, since the anatomy of the ear is slightly different in age 3 years, should have the upper part of the ear pulled up and back younger children than older children. To straighten the ear canal for before medication administration (1). administration of otic medications, the ear lobe should be pulled down Altering dosage forms for pediatric patients Many medications used to treat pediatric patients are not available in solution to other solutions containing propylene glycol should be pediatric dosage forms. Adult drug products are often used in very avoided to prevent toxic side effects (7). small amounts to allow for administration to pediatric patients. Care Orally administered medications that are only available in tablet form must be used when calculating these dosages and administering to may need to be altered for administration to pediatric patients. These young patients to ensure the proper dosage is administered, to prevent products can often be crushed and mixed into applesauce or pudding medication errors. to make the medication palatable for pediatric patients. However, Medications can be diluted into alternative solutions for administration not every type of tablet can be crushed. Extended-release tablets, to pediatric patients. When diluting medications for pediatric tablets with enteric coatings, and effervescent tablets are examples administration, appropriate vehicles must be selected to avoid of medications that cannot be crushed. A full list of medications that unnecessary adverse effects. For example, phenobarbital is available cannot be crushed is available from the Institute for Safe Medication in a solution that contains propylene glycol, a substance that can result Practices, as referenced in the section on altering dosage forms for in hyperosmolality if administered to infants. Adding phenobarbital patients using enteral nutrition (9). Medication adherence Medication adherence in pediatric patients can be more complex than to the patient’s denial of having severe asthma. Approximately 80% in adults. A study of adolescent asthma patients sought to examine of patients in this study were found to be in denial of their condition, the causes of near-fatal asthma attacks. Medication adherence was resulting in significantly increased morbidity in these patients (10). considered an issue in many of the studied adolescents, and was related

Page 65 Pharmacy.EliteCME.com Adherence can also be negatively affected by several other factors in ●● Fear of adverse effects from treatment. children and adolescents. These include (7): ●● Lack of interest in the healthcare of the child. ●● Inadequate communication between the physician and the patient/ ●● Inconvenient medication dosing schedules or dosage forms. caregiver. ●● Poor palatability of oral medications. ●● Poor understanding of the severity of the patient’s disease state. Dosing requirements in pediatric patients Calculating the dosage of medication needed for pediatric patients can patients aged 2 to 19 years were found to be obese in 2011–2012, be challenging. Dosages should be carefully calculated based on weight according to the U.S. Centers for Disease Control (11). The use of ideal or body surface area, as required by the chosen medication. Calculated body weight to calculate medication dosages can produce significantly dosages should be assessed for accuracy and compared to common different dosages than using actual body weight. Additional studies are adult dosages to assess the appropriateness of the chosen dosage (7). needed to determine the effects of childhood obesity on drug absorption, Obesity in children presents another challenge to calculating medication metabolism, and excretion; in the meantime, the pharmacist’s best dosages in pediatric patients. Approximately 17 percent of pediatric judgment should be used when calculating dosages for obese children (7). Drug interactions Due to the vulnerable nature of pediatric patients, drug interaction data information to determine the potential for drug interactions, and pay in this age group is generally lacking, with data commonly extrapolated particular attention to adolescent patients, who may use alcohol, illicit from adult studies. Healthcare providers should use the available adult drugs, or prescription medications recreationally (7). Considerations for drug administration in geriatric patients Geriatric patients, or those older than age 65 years, experience of medications administered to elderly patients, and must be taken into physiologic changes as they age that can affect their pharmacotherapy. consideration when assessing appropriate drug therapy for geriatric Many of these changes can significantly impact the pharmacokinetics patients. Absorption Absorption of medications taken orally can be affected by age-related A decrease in gastrointestinal motility is also observed in geriatric changes to the gastrointestinal system. Aging can reduce gastric blood patients, which can actually increase drug absorption. First-pass flow and decrease gastric acid secretion. This combination can reduce metabolism can also be decreased in older patients, increasing the the absorption of pH-dependent medications administered orally, overall effect of medications undergoing this type of metabolism. The especially when combined with the use of antacids or proton pump net effects of these age-related gastrointestinal changes can be difficult inhibitors. to predict and vary significantly from patient to patient and based on the medication being used, requiring the provider to evaluate medication therapy carefully (12). Distribution Distribution of medications in the body is dependent on many factors, releases slowly, prolonging its effect in geriatric patients. These changes including protein binding, lipid or water solubility, and blood flow. to volume of distribution can also significantly impact the drug dosage These factors can all be affected by age-related changes. Elderly used for loading doses (7). patients generally have lower albumin levels than younger patients (12). Geriatric patients also experience a larger volume of distribution Administration alert! Using highly protein bound medications, for lipophilic drugs due to increased body fat, but a smaller volume of such as phenytoin, in elderly patients can leave significant amounts distribution for water-soluble medications due to lower levels of water. of the drug unbound, increasing the risk of adverse effects in This can affect the overall effect of these medications, as seen with geriatric patients as compared to younger patients. diazepam, a fat-soluble medication that accumulates in fatty tissue and Metabolism Geriatric patients experience several physiologic changes can have an impact on drug metabolism. The aging process can reduce hepatic blood Administration alert! Lidocaine and morphine, two medications flow, reducing the rate at which medications are delivered to the liver that are heavily metabolized in the liver, can cause more adverse from their absorption site. This can significantly reduce the metabolism effects in elderly patients than in younger patients. of medications that are heavily extracted in the liver (7).

Metabolic activity through the cytochrome P450 enzyme system is reduced, which could be related to an age-related reduction in hepatic mass (7). Although there is not a standard dosing formula to decipher the dosages of hepatically-metabolized medications in geriatric patients, it is generally recommended to start with low doses and titrate the dose until the medication is efficacious or causes adverse effects (12). Excretion Renal function tends to decline with age, due to several physiologic through hepatic metabolism that are excreted renally; accumulation changes in the kidneys. A decrease in blood flow to the kidney can of these metabolites can create adverse reactions if their excretion is be seen in elderly patients. The number and size of nephrons also impaired. This can necessitate dosage changes of medications taken by decreases, which can lead to a decrease in kidney mass. patients with decreased renal function (12). Since many medications are excreted renally, the age-related decrease The age-related decline in kidney function is fairly predictable and in renal function can impact the elimination of medications. As renal can be estimated in order to assess proper dosages of renally excreted function decreases, the half-life of renally excreted medications such as medications. The Cockcroft-Gault formula is commonly used to assess gentamycin increases, potentially resulting in significant adverse effects. renal function in adults whose weight is within 30% of their ideal body Other medications, including meperidine, have metabolites created weight. The Cockcroft-Gault formula is as follows:

Pharmacy.EliteCME.com Page 66 (140 – age in years) x weight in kilograms clearance such as the Modification of Diet in Renal Disease (MDRD) Creatinine Clearance = ------(× 0.85 if female) formula or an actual 24-hour urine creatinine collection may be more Serum Creatinine (mg/dL) × 72 accurate. Since many drug manufacturers provide dosing information based on estimated creatinine clearance calculated with the Cockcroft- While the Cockcroft-Gault formula is the most widely used formula Gault formula, this formula remains commonly used (7)(12). to estimate creatinine clearance, other ways of assessing creatinine References 1. The American Pharmacist’s Association. The Pharmacy Technician, 4th Edition. Englewood, CO: Morton 7. Dipiro JT et al. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; Publishing Company. 2010. 2011. 2. Schlesselman, LS. 10 Strategies to Reduce Medication Errors. 2008. Accessed November 30, 2014 at 8. Williams N. Medication Administration Through Enteral Feeding Tubes. Am J Health Syst Pharm. https://secure.pharmacytimes.com/lessons/200809-01.asp. 2008;65(24):2347-2357. Accessed November 30, 2014 at http://www.medscape.com/viewarticle/585397. 3. Stein S. Boh’s Pharmacy Practice Manual: A Guide to the Clinical Experience. Accessed November 24, 9. Institute for Safe Medication Practices. Oral Dosage Forms That Should Not Be Crushed. January 2014. 2014 at https://www.inkling.com/read/bohs-pharmacy-practice-manual-stein-3rd/chapter-8/routes-of- Accessed November 30, 2014 at http://www.ismp.org/tools/donotcrush.pdf. administration. 10. Campbell DA et al. Psychiatric and Medical Causes of Near Fatal Asthma. Thorax: 1995; 254-259. 4. Shri Shankaracharya Institute of Pharmaceutical Science. Routes of Drug Administration. International Accessed November 30, 2014 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1021188/pdf/ Journal of Pharmaceutical Studies and Research. 2010. Accessed November 24, 2014 at http://www. thorax00308-0048.pdf. technicaljournalsonline.com/ijpsr/VOL%20I/IJPSR%20VOL%20I%20ISSUE%20I%20JULY%20 11. Centers for Disease Control. Childhood Obesity Facts. September 2014. Accessed November 30, 2014 at SEPTEMBER%202010/IJPSR%20VOL%20I%20ISSUE%20I%20Article%208.pdf. http://www.cdc.gov/obesity/data/childhood.html. 5. Allen L, Popovich N, Ansel H. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 12. Wooten J. Pharmacotherapy Considerations in Elderly Adults. South Med J. 2012;105(8):437-445. Philadelphia: Lippincott Williams & Wilkins. 2011. Accessed December 1, 2014 at http://www.medscape.com/viewarticle/769412_2. 6. Mystakidou K et al. Oral Transmucosal Fentanyl Citrate: Overview of Pharmacological and Clinical Characteristics. Drug Delivery. 2006:13(4):269-276. Accessed November 30, 2014 at http:// informahealthcare.com/doi/abs/10.1080/10717540500394661%20. DRUG ADMINISTRATION Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. Which of the following is NOT one of the eight rights of medication 7. When administering an intramuscular injection, the needle should administration? be inserted into the muscle at a ______angle. a. Right drug. a. 45-degree. b. Right dose. b. 90-degree. c. Right nurse. c. 10-degree. d. Right documentation. d. 15-degree. 2. Medications that are administered through the enteral route are 8. Intradermal injections are limited to less than ______per injection. absorbed in the ______. a. 0.1 mL. a. Digestive tract. b. 0.5 mL. b. Bloodstream. c. 1 mL. c. Liver. d. 2 mL. d. Skin. 9. If a patient is using an eye drop and an eye ointment, how long 3. Which of the following factors does NOT affect medication should the patient wait after instilling the eye ointment before using absorption from the gastrointestinal tract? the eye drop? a. The color of the medication administered. a. 5 minutes. b. The surface area available for medication absorption. b. 2 minutes. c. Blood flow at the potential absorption site. c. 30 minutes. d. The water solubility of the medication being administered. d. 10 to 15 minutes. 4. The ______is particularly beneficial for patients that are 10. The aging process can reduce hepatic blood flow, ______unconscious or are experiencing nausea or vomiting. the rate at which medications are delivered to the liver from their a. Oral route. absorption site. b. Sublingual route. a. Reducing. c. Buccal route. b. Increasing. d. Rectal route. c. Not affecting. 5. Administering medications through the ______d. Improving. ensures that the drug gets into the bloodstream as quickly as possible. a. Oral route. b. Intravenous route. c. Intramuscular route. d. Rectal route. 6. Short needles should be chosen for subcutaneous injections, including a ______needle length, to ensure drug delivery to the proper layer. a. 5/8-inch. b. 1-inch. c. 1½-inch. d. 2-inch.

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Page 67 Pharmacy.EliteCME.com Chapter 6: Law and Ethics: What the Pharmacy Professional Should Know

3 Contact Hours

By: Katie Blair, PharmD, RPh Author Disclosure: Katie BLAIR and Elite do not have any actual or Questions regarding statements of credit and other customer service potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $12.00. Universal Activity Number (UAN): 0761-9999-18-002-H03-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: January 11, 2018 a provider of continuing pharmaceutical education. This Expiration Date: January 11, 2020 program is approved for 3 hours (0.3 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70% is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a statement of credit. Please submit your answers online at participants who have successfully completed the post-test. Participants Pharmacy.EliteCME.com must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives Discuss the federal pharmacy laws that govern pharmacy practice. Discuss the ethical principles that apply to pharmacy practice. Describe the Comprehensive Drug Abuse, Prevention, and Control Discuss the code of ethics for pharmacists. Act of 1970 and its impact on the dispensing of controlled substances. Overview of federal pharmacy laws 4,5,6 Many federal and state laws govern the practice of pharmacy, and these Federal laws may be more or less restrictive than state laws; the more laws are constantly changing. It is important for pharmacy professionals stringent law should always be followed. Pharmacy professionals are to familiarize themselves with both the federal and state regulations responsible for knowing the state laws in the states they work in, and governing their daily responsibilities in the pharmacy, and keep up to are responsible for ensuring laws are followed in the workplace. date on new laws as well as amendments to existing laws. Pure Food and Drug Act of 1906 This act was enacted in 1906 to address public concerns about improperly Drug safety issues continued, because false or incorrect claims of efficacy labeled and unsanitary food and medications. It prohibited food and were not prohibited, labeling was not regulated, safety was not required medications from being misbranded or adulterated if they are bought and to be proven, and the FDA did not have the right to ban unsafe products. sold across state lines. This was the first act to address the safety risks This resulted in the sulfanilamide tragedy of 1937, when the toxic solvent associated with contaminated and inappropriately labeled food and drug diethylene glycol was used to make sulfanilamide elixir, resulting in 107 products, but it was not found to be comprehensive enough. deaths. This tragedy, as well as other safety issues, prompted a more comprehensive act to be passed in 1938. The Harrison Narcotics Tax Act of 1914 Because of the increasing abuse and trafficking of opium, the also required a prescription for opium to be given to patients as well as International Opium Convention met in 1912 to discuss potential requiring providers to be registered to prescribe opium. Prescriptions for international limitations on its use and transport. In 1914, the U.S. and the dispensing of opium had to be documented, and restrictions on passed its own regulations to regulate opium and narcotic use. the sale, importation, and distribution of opium and narcotic derivatives The Harrison Narcotics Tax Act gave authority to the Internal Revenue were implemented. Service (IRS) to collect tax on opiates, and anyone that produced, While the Comprehensive Drug Abuse, Prevention, and Control Act of dispensed, or sold opiates had to be registered with the IRS. This act 1970 largely replaced this act, it was the first of its kind to attempt to regulate and decrease the prevalence of narcotic use and addiction. The Food, Drug, and Cosmetic Act of 1938 This act was created to attempt to correct some of the pitfalls of the The Food, Drug, and Cosmetic Act also established clear definitions Pure Food and Drug Act of 1906. The passing of this act established for adulteration and misbranding, and established that these actions are that the FDA must approve all new medications that are to be sold illegal. It required medication labels to state adequate directions for in the U.S., and that drugs will not be approved until they have been using the product as well as warnings if the medication is habit forming determined to be safe to use. to avoid misbranding. In addition, it established that labeling must It also moved cosmetics under the jurisdiction of the FDA. It include the quantities of active ingredients, alcohol content, and name established greater authority for the FDA to oversee the safety of drugs, and location of the manufacturer. food, and cosmetics, in an effort to improve medication safety and Products were considered adulterated if they contained any dirty or prevent further disasters like the sulfanilamide tragedy. This act allowed decayed substances, were manufactured in an unsanitary environment, medications marketed before 1938 to be exempt from the requirement contained any dangerous coloring additives, were prepared in containers to prove their safety. created of unsafe materials, or if they did not have consistent purity. This legislation brought vast improvements to the safety of medications sold in the United States. The Durham-Humphrey Amendment of 1951 Many medications were unable to establish appropriate directions for The Durham-Humphrey Amendment to the Food, Drug, and Cosmetic use under the Food, Drug, and Cosmetic Act of 1938, because use under Act was passed in 1951 to resolve this issue. It established two classes the direction of a prescriber was not considered adequate. of medications, prescription (legend) drugs that require a prescriber’s Pharmacy.EliteCME.com Page 68 order to dispense, and over-the-counter (non-legend) drugs that The Durham-Humphrey Amendment allowed for prescriptions to be can be purchased without a prescription. After passing this act into called in to the pharmacy over the telephone for ease of receipt at the law, prescription medications were allowed to have the prescriber’s pharmacy. It also established that prescription drugs could be refilled if directions for use on the label if they had the wording “Caution: Federal indicated by the prescriber. law prohibits dispensing without a prescription” on the label. Kefauver-Harris Amendment of 1962 Another medication tragedy that occurred in the late 1950s prompted The Kefauver-Harris Amendment established that drugs must be proven the establishment of the Kefauver-Harris Amendment in 1962. The to be effective, in addition to being pure and safe, to receive approval medication thalidomide (Thalomid), a popular sedative, was marketed from the FDA for sale in the U.S. This was groundbreaking legislation; in Europe, and the manufacturers sought approval for sale in the United no laws prior to this had required proof that medications are effective. States as well. The FDA withheld approval pending further information This act was also retroactively applied to medications approved by the on the safety of the drug, which turned out to be a great decision when FDA between 1938 and 1962. safety information showed it was linked to birth defects. In addition, this amendment gave the FDA the authority to oversee Pregnant women who had taken thalidomide gave birth to children with prescription medication advertising, transferring this responsibility from short or missing limbs, known as phocomelia, and thousands of children the Federal Trade Commission. It also established good manufacturing around the world were born with this condition. Because the FDA did practices (GMP) for the manufacture of medications to place the not grant approval, the number of children born with phocomelia in the responsibility of creating quality drug products on the drug manufacturers. U.S. was low, but this worldwide disaster prompted the government to Lastly, it established more control over clinical trials, requiring informed reconsider the regulations in place to prevent similar tragedies. consent of participants in drug trials and adverse event reporting. Comprehensive Drug Abuse, Prevention, and Control Act of 1970 Commonly known as the Controlled Substance Act, this act was the first ●● Schedule II: These products have a high abuse potential but have to establish regulations on the prescription and dispensing of controlled an accepted medical use in the U.S. Prescriptions may be written substances as well as their importation, possession, and use. It was for these products, but they are regulated by not allowing refills, created to prevent drug abuse and dependence as well as to strengthen requiring a new prescription for each order. the authority of law enforcement on drug abuse. It led to the creation ○○ Examples of Schedule II controlled substances include: of the Drug Enforcement Agency (DEA), which is supervised by the ■■ Oxycodone. ■■ Methylphenidate. Department of Justice. ■■ Morphine. ■■ Cocaine. Registration ■■ Amphetamine salts. The Controlled Substance Act established that every facility dispensing ●● Schedule III: These drugs have a lesser abuse potential than controlled substances and every provider prescribing controlled schedule I and II controlled substances, and have an accepted substances must be registered with the DEA. Pharmacies can register medical use in the U.S. These medications may be prescribed for up by completing DEA form 224, and registration must be renewed every to six months at a time. three years. Registration must also be completed for those who wish to ○○ Examples of Schedule III controlled substances include: distribute or manufacture controlled substances and those who wish to ■■ Ketamine. ■■ Anabolic steroids. manage a controlled substance treatment program. ■■ Testosterone. Scheduling ●● Schedule IV: These medications have a lesser abuse potential than This legislation established five schedules to categorize controlled schedule III drugs, though use is still associated with psychological substances based on their abuse potential and accepted medical use. and physical dependence. They have an accepted medical use in the This system allowed for stricter regulations for potent and heavily U.S. These medications may be prescribed for up to six months at a abused medications at the top of the list in Schedule I, and decreasing time. severity of regulations as the schedule level decreases. ○○ Examples of Schedule IV controlled substances include: The Controlled Substance Act granted the attorney general the power to ■■ Clonazepam. ■■ Diazepam. move medications between schedules, remove a drug from scheduling, ■■ Alprazolam. ■■ Lorazepam. and to add a drug to the scheduling system. ■■ Carisoprodol. ■■ Midazolam. Packaging for scheduled products must contain a symbol or notation ●● Schedule V: These drugs have a lower abuse potential than identifying the schedule each medication is categorized in. Schedule IV drugs, though still have the potential for abuse and dependence. They have an accepted medical use in the U.S. These ●● Schedule I: Extremely high abuse potential and no recognized medical medications may be prescribed for up to six months at a time. use in the U.S. Prescriptions may not be written for these products. ○○ Examples of Schedule V controlled substances include: ○○ Examples of Schedule I controlled substances include: ■■ Cough syrups containing codeine. ■■ Marijuana. ■■ Crack cocaine. ■■ Anti-diarrheals containing diphenoxylate. ■■ Heroin. ■■ Methamphetamine. ■■ Pregabalin. ■■ Ecstasy. ■■ Psilocybin. ■■ Lacosamide. ■■ LSD. ■■ Rohypnol. ■■ PCP. Ordering controlled substances Schedule II controlled substances must be ordered by completing the The pharmacy retains the blue copy of the 222 form and sends the green triplicate DEA form 222 in writing. The 222 form has space to order 10 and brown copies to the wholesaler for ordering. The wholesaler then keeps unique items and is valid for 60 days from the date written on the form. the brown copy after filling the order, and sends the green copy to the DEA. The number of lines completed must be noted at the bottom of the form, Once Schedule II medications are received, the pharmacist must verify and a pharmacist who has authority to order Schedule II medications that the items received match what was ordered. The pharmacist should must sign it. initial the quantity received and the date it was received on each item’s line on the blue copy of the 222 form. The invoice should be kept with the 222 form and stored for at least two years. Maintaining DEA records All DEA records must be maintained for at least two years, or longer, controlled substances received, and records of controlled substances depending on state law. These include inventory records, records of that left the pharmacy’s inventory. They must be maintained separately

Page 69 Pharmacy.EliteCME.com from other records and be easily retrievable. Defective 222 forms recordkeeping requirements in their state of employment, because they and those completed incorrectly and not used should be kept for at vary significantly from state to state. least two years as well. Pharmacy professionals must be aware of the Controlled substance inventories The Controlled Substance Act also initiated the requirement to conduct packages of less than 1,000 doses. Records of these inventories must be inventories of controlled substances on a regular basis. An initial maintained for at least two years. inventory of all controlled substances must be conducted before the start A perpetual inventory system must be used for Schedule II controlled of business on the first day the pharmacy is open. Biennial controlled substances. A perpetual inventory system is a method of recording the substance inventories must be conducted thereafter. quantity of a particular medication continuously as prescriptions are filled When completing controlled substance inventories, an exact count so the on-hand count is constantly up to date and accurate. All additions must be completed for Schedule II controlled substances, and an and subtractions from the controlled substance inventory should be estimated count may be done for Schedule III through V medications in recorded as they occur to ensure the on-hand count is accurate. Returning controlled substances Returns of controlled substances can only occur between two entities maintained at both the receiving and transferring pharmacy, and the registered with the DEA. A completed DEA 222 form must accompany green copy of the 222 form should be sent to the DEA field office within any transfer of Schedule II controlled substances with records 60 days of transfer. Destroying controlled substances Any pharmacy that wants to destroy controlled substances that are destruction, and the names of the witnesses who will be present for the damaged or outdated must first apply for permission to destroy these items destruction, and must be sent to the DEA at least two weeks before drug by completing and submitting DEA form 41. This form should include destruction. Hospitals may apply for a “blanket authorization” to destroy the date of intended destruction, the name, concentration, and quantity damaged products and unused portions of injectable controlled substances. of any controlled substances to be destroyed, the method to be used for Controlled substance theft If a pharmacy discovers controlled substances have been stolen from the purchase value of the products, and the name, dose, and quantity the pharmacy, the pharmacy must inform the closest DEA diversion of all controlled substances that were stolen. The original copy of this office as well as the local police, and complete DEA form 106. This form should be sent to the DEA and a copy should be maintained at the form should include the pharmacy’s DEA registration information, pharmacy along with its controlled substance records. Filling prescriptions for controlled substances The Controlled Substance Act also created regulations for filling Partial fills can be completed for these prescriptions, as long as the controlled substances. Schedule II medications must be ordered on remaining quantity is dispensed within 60 days of the issue date of the paper prescriptions that are handwritten or printed from a computer, order. Schedule II prescriptions may also be faxed for products that and must be signed in ink by the prescriber. Refills are not allowed on need to be compounded. Schedule II medications. Schedule III through V medications can be handwritten or computer If the pharmacy does not have the full quantity of a Schedule II controlled generated and signed in ink, or transmitted to the pharmacy orally or by substance on hand, a partial fill can be given if the remaining quantity of fax. The prescription may be refilled up to five times within six months medication is made available within 72 hours. If the remaining quantity of the written date on the prescription. cannot be supplied to the patient within 72 hours, a new prescription must Partial fills may be given on Schedule III through V medications as long be obtained from the patient’s prescriber. as the total amount dispensed does not exceed the quantity ordered by Under emergency conditions, an oral prescription may be used for the prescriber and no fills are given out more than six months after the Schedule II medications if the following conditions are met: written date on the prescription. ●● The pharmacist makes every possible effort to identify the prescriber. Certain Schedule V cough syrups and antidiarrheal agents may be ●● The quantity is limited to that needed to treat the patient during the purchased without a prescription, depending on state law. The following emergency period. requirements must be met when dispensing Schedule V drugs without a ●● The pharmacist must record the oral prescription in writing. prescription: ●● The prescriber must provide a written prescription for the ●● Dispensing may only be completed by a pharmacist. emergency order to the pharmacy within seven days of dispensing ●● The person purchasing Schedule V drugs must be at least 18 years old. the emergency order. ●● The pharmacy must obtain identification from the purchaser and Schedule II prescriptions may be faxed to the pharmacy for patients in record in a logbook the name and address of the person purchasing long-term care facilities or those who are terminally ill, and the faxed the medication, the date purchased, the name and quantity of the copy may be maintained as the original written prescription. To be product purchased, the price, and the pharmacist’s signature. accepted as a fax, the prescription must have a notation that the patient ●● No more than 240 mL or 48 dosage units of opiate-based products is terminally ill or in a long-term care facility. and no more than 120 mL or 24 dosage units of other controlled substances may be purchased within 48 hours. Transferring prescriptions for controlled substances The Controlled Substance Act allows prescriptions for Schedule III to The receiving pharmacy must write the word “Transfer” on the face V controlled substances to be transferred between pharmacies one time, of the prescription, as well as the original date of the prescription, the unless the pharmacies share a real-time online database. If a database is original number of refills, the original date of dispensing, the number shared between pharmacies, prescriptions may be transferred up to the of refills remaining and the dates of previous refills, the prescription maximum number of refills given by the prescriber. number given at the transferring pharmacy, the name, address, and DEA The transfer must occur between two licensed pharmacists. The number of the pharmacy sending the prescription, and the name of the pharmacy transferring the prescription out must write the word VOID pharmacist responsible for transferring the prescription. on the face of the prescription to invalidate it, and must record on the Both pharmacies involved in the transfer must keep their copy of the back of the prescription the name, address, and DEA number of the prescription for at least two years from the last refill date. receiving pharmacy as well as the transfer date and the name of the pharmacist transferring the prescription.

Pharmacy.EliteCME.com Page 70 Poison Prevention Packaging Act of 1970 This act was created to decrease the risk of accidental poisoning in children ●● Medications that are administered to patients in an institution, if and prevents hundreds of deaths that were occurring annually from children administered by an employee of the facility. accidentally ingesting medications and household chemicals. ●● Specific medications do not require child-resistant packaging, It requires that most prescription and over-the-counter products be including: packaged in materials that are resistant to opening by children. Containers ○○ Less than 12.6 mg of betamethasone per package. are considered by this act to be child-resistant if they cannot be opened by ○○ Less than 16 g of erythromycin ethylsuccinate tablets per package. 80 percent of children under 5 but can be opened by 90 percent of adults. ○○ Aerosol sprays for inhalation. ○○ Less than 600 mg of mebendazole per package. There are some exceptions to the requirement for child-resistant ○○ Less than 85 mg of methylprednisolone tablets per package. packaging. These include: ○○ Oral contraceptives. ●● If the patient requests non-child-resistant packaging in a signed ○○ Pancrelipase products. statement, a blanket authorization may be given for all of a patient’s ○○ Cholestyramine powder. medications. ○○ Colestipol power in packets up to 5 g. ●● If the prescriber requests non-child-resistant packaging, a blanket ○○ Less than 105 mg prednisone per package. authorization may be given for all of a patient’s medications. ○○ Less than 264 mg sodium fluoride per package. ●● Over-the-counter products that contain the warning “This Package ○○ Chewable or sublingual isosorbide dinitrate in 10 mg doses or less. for Households Without Young Children” or “Package Not Child ○○ Nitroglycerin sublingual tablets. Resistant.” Occupational Safety and Health Act of 1970 (OSHA) The enactment of this law created the Occupational Safety and Health chemicals they come in contact with. It establishes standards for Administration to ensure employees have the right to a safe and healthy communicating hazardous issues, and addresses contaminants in the workplace. It allowed for the development of employee health and safety air as well as combustible and flammable materials. It requires eye and standards and a reporting system for injuries that occur on the job. skin protection when working with hazardous materials, such as when It also was created to aid in the reduction of hazardous working compounding sterile products. environments and allows the Occupational Safety and Health The Occupational Safety and Health Administration also publishes the Administration to audit workplaces to ensure they remain in compliance Guidelines for Cytotoxic (Anti-neoplastic) Drugs. This publication with the law. discusses the potential hazards of working with cytotoxic products and In the pharmacy environment, this act requires the use of material provides recommendations to decrease the risk of hazards. safety data sheets to inform employees of the risks associated with Drug Listing Act of 1972 This act created the requirement of a distinct 11-digit number to identify code, used to represent the specific drug product. The last two digits each medication, known as the National Drug Code (NDC) number. represent the package code, used to identify the package size and type. The first five digits of this number comprise the labeler code, used to The product and package codes are developed by the drug company to identify the drug manufacturer. The next four digits are for the product differentiate their products. Orphan Drug Act of 1983 Orphan drugs are those used to treat conditions that affect fewer than them exclusive licensing rights to their products for seven years after 200,000 people worldwide. Because many drug manufacturers create approval by the FDA. Research assistance and grants were also made products based on potential profitability, products for these conditions available to drug manufacturers under this act. were not being developed at the same speed as products for more Companies that produce drug products for diseases that affect more prevalent conditions. than 200,000 people could also qualify for assistance if they can prove The Orphan Drug Act created the allowance for tax incentives for that the development costs for creating a new medication could not be companies that produce orphan drug products, as well as allowing recovered by its sales. Drug Price Competition and Patent Term Restoration Act of 1984 Also known as the Hatch-Waxman Amendment, this legislation amended This decreased the amount of time necessary for the FDA to approve the Food, Drug, and Cosmetic Act to help streamline the generic drug generic drugs, as well as decreasing costs for manufacturers of generic approval process to encourage the development of new generic products. products, allowing for increased competition among generic drug It allowed for drug companies to file an abbreviated new drug application manufacturers and inevitably decreasing costs to consumers. (ANDA) when applying for FDA approval of generic drugs, to allow It also allows the first company to file an ANDA for the right to exclusively generic medications to be approved without the generic manufacturers market their generic product for 180 days before other companies may market conducting their own clinical trials to prove the medication’s efficacy. their generic versions. Lastly, it encouraged the development of new drugs by defining the conditions for patent extensions. Prescription Drug Marketing Act (PDMA) of 1987 This act was created to solidify the supply chain of prescription It prevents hospitals and medical facilities from reselling medications to medications and reinforce the standard route that drug products outside businesses, and prevents the reimportation of drug products that follow from drug manufacturers to wholesalers to pharmacies. It was have been exported unless the original manufacturer reimports them. developed to prevent counterfeit products from entering the supply This act also bans the distribution of medication samples to anyone chain and to decrease the diversion of prescription products. other than those licensed to prescribe medications. FDA Modernization Act of 1997 Because of the high burden of the drug approval process, the FDA created a fast-track approval process for medications for life-threatening Modernization Act was created to streamline the FDA’s regulatory conditions, a database of clinical trial information, and gave drug process to allow for more rapid approval of new drugs. manufacturers expanded rights in distributing information on unlabeled This act created a mission statement for the FDA to publicly define uses of drugs. its responsibilities and required the creation of a compliance plan to The FDA Modernization Act increased the FDA’s oversight of over- reduce the backlog of medications in the approval process. It also the-counter medications and required inactive ingredients to be listed

Page 71 Pharmacy.EliteCME.com on labels. This act also changed the requirement for the statement prescription” to be replaced by the abbreviation “Rx” on the packaging “Federal law prohibits the dispensing of this medication without a of prescription products. Omnibus Budget Reconciliation Act of 1987 (OBRA-87) The Omnibus Budget Reconciliation Act of 1987 was an extensive requires that psychiatric medications can only be used to treat patients piece of legislation affecting many different government programs. with a specific documented psychiatric condition. Doses of anti- Because of increasing concerns about substandard care for patients in psychotics must be gradually tapered to ensure the correct dosage is nursing homes, legislation was incorporated into this act to address the used, and drug holidays and behavioral modifications should be used quality of health care available for the elderly under Medicare. regularly to assess appropriateness of medication discontinuation. The enactment of OBRA required many changes to the Medicare and OBRA-87 also established that residents of long-term care facilities Medicaid conditions of participation for pharmacies and long-term care should be free of significant medication errors, and must be provided institutions that service Medicare and Medicaid patients, reforming routine and emergency medications as needed. nursing home care. Medications must be labeled as required by law, and stored in a locked Standards of care for Medicare and Medicaid patients living in storage area under recommended storage conditions. Lastly, it established nursing homes were established by OBRA-87. It prevents the use of that long-term care facilities must be serviced by a consultant pharmacist medications that are not necessary to treat a patient’s medical condition to ensure patients are receiving proper medication therapy. and establishes requirements for the use of anti-psychotic agents. It Anabolic Steroid Control Act of 1990 This act was created to introduce regulations for anabolic steroids to It defines anabolic steroids as any medication chemically related to establish penalties for those who abuse and misuse these products in an testosterone. It listed the medications that are to be considered anabolic, attempt to curb abuse and amended the Comprehensive Drug Abuse, and set aside money for education about the harmful effects of anabolic Prevention, and Control Act of 1970 to revise the definition of anabolic steroids and to help athletes avoid steroid use. The enactment of this steroids. legislation moved anabolic steroids to Schedule III, allowing for greater government oversight of these medications. Omnibus Budget Reconciliation Act of 1990 (OBRA-90) OBRA-90 was a large bill concerned with many aspects of government records must be maintained to track consultations. The act established funding. Only a small portion affected the practice of pharmacy, but standards for patient counseling, in which the pharmacist must offer to that small portion had a significant impact on pharmacy practice.This discuss significant drug therapy points, including: bill was the first to recognize that the duties of pharmacists include ●● Drug name and description. identifying and resolving drug therapy issues, expanding the standards ●● Dosage, administration route, and duration of therapy. of practice for pharmacy professionals. ●● Special precautions or directions for use. This act states that prospective drug utilization evaluations must be ●● Common adverse effects, interactions, and contraindications conducted before a prescription is filled to ensure safety for every including how they may be avoided and what to do if they occur. patient, and must include a review of appropriateness of medication, ●● Directions for self-monitoring medication therapy. contraindications, potential drug interactions, and accuracy of dosage ●● Medication storage information. and treatment duration. It established that drug utilization reviews ●● How and when to refill the medication. (DUR) should be completed by pharmacists and are composed of ●● What to do if a dose is missed. three steps: verification and screening of prescriptions before they Pharmacists must rely on their professional judgment to determine what are dispensed, patient counseling, and documentation of relevant information should be included in counseling. Patients have the right to information. DURs are also required to include computer programs refuse counseling. that can create alerts to notify the pharmacist of potential interactions, Failure to comply with these regulations may result in the loss of adverse events, and pertinent safety issues that may affect the patient. Medicaid funding and reimbursement for services rendered. The act also established a DUR board to retrospectively review OBRA-90 also established a board to develop and review strategies to whether ideal drug therapies are actually used. The DUR board can decrease costs, manage drug purchasing, and improve patient care for also recommend educational programs based on problems that it has Medicaid patients. The act stated that manufacturers must use the lowest identified in its retrospective reviews. pricing for Medicaid patients. This pricing can be accomplished by It also required that every patient be offered consultation with a refunding the state Medicaid agency the difference between the average pharmacist on their medications at the time of purchase, and that and lowest price on each product. Dietary Supplement Health and Education Act (DSHEA) of 1994 This act allowed the creation of regulations for herbal products. It requires Herbal products must meet standards for purity, quality, and the labeling of herbal products to list the ingredients and quantities of composition, and production of these products must comply with each ingredient, as well as the plant and part of the plant used to create the standards set by any official compendium. Guidelines were created to product, and a statement that the product is a dietary supplement. require manufacturers of herbal products to follow good manufacturing practices and prevent adulteration of these products. Health Insurance Portability and Accountability Act (HIPAA) of 1996 The enactment of HIPAA set out to acknowledge the basic privacy ●● Date of birth. rights of all patients, and to require health care professionals to explain ●● Social Security number. those rights to patients. It ensures the confidentiality of protected health ●● Payment history. information (PHI), requires the use of only the minimum amount of PHI ●● Account, license, and record numbers. necessary, and gives patients the right to see who has accessed their PHI. ●● Prescription and medical history. It also requires that all pharmacy staff and any other facility employees ●● Email address. who have access to PHI must receive formal training on HIPAA. ●● Device identifiers, such as an IP address. HIPAA applies to all covered entities, which include any person or group ●● Genetic information. who provides health care to a patient, bills for health care services, or is Written PHI must be handled, stored, and disposed of in a way that protects paid for health care services. It established the responsibility of health it against potential unauthorized releases of information. HIPAA-compliant care workers to protect a patient’s PHI. Examples of PHI include: channels must be used to electronically transmit health information, and ●● Name, address, and other demographic information. Pharmacy.EliteCME.com Page 72 computerized patient information must be protected through passwords and HIPAA requires that patients must be given a written notice of a covered protection measures for computer systems. PHI communicated orally must entity’s privacy practices. The notice should include information about also be protected from potential disclosures, and should be discussed at low the privacy practices of the pharmacy or health care provider, including volumes to prevent potential unauthorized disclosures. how they intend to use or disclose a patient’s PHI and how they will When disclosing PHI, only the minimum necessary amount of protect this information. information should be given to decrease the amount of PHI available for HIPAA established several rights for patients and their medical records. potential unauthorized disclosures, unless disclosures are made to the These are: patient themselves. ●● The right to receive a list of all non-routine disclosures of their PHI Disclosures to other individuals can be made under special within the past six years. circumstances, such as: ●● The right to receive a copy of their medical records. ●● For use by law enforcement. ●● The right to request changes to their medical records. An example of ●● To the Drug Enforcement Administration (DEA) for investigations. this would be if a prescription is filled with the incorrect prescriber ●● To the Board of Pharmacy for investigations. on the label. ●● For adverse event reporting. HIPAA also increases the portability and continuity of health insurance; ●● To workers compensation if needed. reduces health insurance fraud, waste, and abuse; and encourages the ●● For certain public health reasons. use of health savings accounts. A written and signed authorization letter stating the proposed use of disclosed information must be obtained from the patient if a patient’s information is to be used outside of these permitted disclosures. Drug Addiction Treatment Act (DATA) of 2000 This act was passed in 2000 to broaden the rights of providers prescribing Patients undergoing treatment for opiate addiction with controlled controlled substances for the treatment of opiate addiction. It allows substances must be enrolled in a treatment program that provides providers to prescribe medications in Schedules III through V to patients support services and counseling. Prescribers who wish to prescribe who are undergoing detoxification for or maintenance of opiate addiction. controlled substances to treat opiate addiction must be enrolled with It applies to controlled substances that have been shown to decrease the DEA and complete a required training course to obtain certification cravings for opiates and prevent symptoms of withdrawal, such as to dispense these products. Prescribers who work in private practice buprenorphine. It does not apply to methadone. settings can treat a maximum of 30 patients at a time for the first year, after which they may apply to treat a maximum of 100 patients. Medicare Drug, Improvement, and Modernization Act (MPDIMA) of 2003 This was one of the first acts that set out to modernize aging the lower the cost of their prescription medications. Patients are required Medicare system that was first established in 1965. When Medicare was to pay monthly premiums as well as deductibles, but have a maximum first founded, the role of prescription drugs in health care was minimal out-of-pocket expense annually to help reign in drug costs. compared to what it is today. This act also decreased the reimbursement rates that Medicare will pay With time, seniors began taking more and more prescription for durable medical equipment and created a nationwide competitive medications to control their chronic and acute disease states, greatly bidding program for these items in 2007. In addition, this act altered increasing their medical costs to often unaffordable levels. It was clear the payment system for medications that qualify for coverage under that a prescription drug benefit was needed to control drug costs for Medicare Part B in the outpatient setting. It also introduced a Medicare- patients enrolled in Medicare. approved voluntary discount card program to low-income Medicare The Medicare Modernization Act, as it is commonly known, was patients, which is available under the Medicare Advantage program. responsible for adding a prescription drug benefit to the Medicare This card allows for additional cost savings for Medicare patients, in system that seniors can choose to sign up for, Medicare Part D. This an attempt to decrease the costs associated with hospitalizations and plan allows seniors to enroll in regional or national insurance plans to unaffordable medication treatment. Isotretinoin Safety and Risk Management Act of 2004 Isotretinoin (Accutane) is a powerful medication used to treat acne ●● Patients must be educated on a monthly basis to avoid pregnancy. A that has been linked to major birth defects, spontaneous abortions, and survey must be completed monthly to re-educate the patient on the psychiatric side effects, including suicidal thoughts and attempts. potential side effects. To promote the safe use of isotretinoin, the Isotretinoin Safety and Risk ●● Patients must receive one-on-one counseling and must sign an Management Act was passed to enact the following requirements for informed consent form before beginning therapy. prescribing and using isotretinoin: ●● Prescriber offices must be certified to prescribe isotretinoin. ●● All pharmacists, patients, and practitioners involved in the use of ●● Prescriptions may be filled for a maximum of 30 days supply at a time. isotretinoin must be registered. ●● Female patients must take a pregnancy test monthly and receive a ●● All prescribers and pharmacists must receive education on the risks negative result before they may receive additional isotretinoin. involved with the use of isotretinoin, including psychiatric adverse ●● Blood testing must be done regularly during treatment and 30 days events and birth defects. after. ●● Isotretinoin may only be prescribed for severe recalcitrant nodular ●● Treatment centers must be evaluated annually to maintain program acne that is not responsive to other treatments, including antibiotics. compliance. ●● All adverse reactions associated with isotretinoin must be reported on a quarterly basis, and patient deaths related to isotretinoin must be reported within 15 days of death. Combat Methamphetamine Epidemic Act of 2005 Because of the increasing use and production of methamphetamine in establish sales restrictions and recordkeeping requirements for the sale the United States, this act was passed in 2005 to attempt to decrease the of these substances. availability of ingredients used to produce this dangerous substance. Any products containing pseudoephedrine, ephedrine, and Over-the-counter products such as pseudoephedrine, ephedrine, and phenylpropanolamine have a sales limit of 3.6 g per day, and 9 g in a phenylpropanolamine are used in the production of methamphetamine, 30-day period. These products must be sold in blister packaging under and this act set out to regulate manufacturing of these products and the supervision of a licensed pharmacist. They must be kept in a locked cabinet on the sales floor within view of the cashier, or behind the counter.

Page 73 Pharmacy.EliteCME.com A logbook of purchases must be kept for these products, and must Records of pseudoephedrine sales information must be maintained include the product name, strength, and quantity sold, the name, for at least two years. State laws on pseudoephedrine sales may be address, and signature of the person purchasing the product, and the more restrictive than federal regulations; it is imperative to know the date and time of the sale. The logbook may be electronic or written; applicable state regulations before selling pseudoephedrine products. written logbooks must be bound. Photo identification must be shown in order to purchase these products. Medicaid Tamper-Resistant Prescription Act Beginning in 2008, all handwritten prescriptions filled for patients who ●● Must contain at least one recognized feature to prevent counterfeit have Medicaid paying any part of the cost must be written on tamper- prescription pads from being used, such as serial numbers on resistant paper. prescriptions or microprinting. The tamper-resistant paper must contain each of the following qualities: Prescriptions that do not meet the tamper-resistant requirement may be ●● Must contain at least one recognized feature to prevent copying of verified by calling the prescriber’s office. Prescribers may fax prescriptions the prescription, such as thermochromatic ink or background ink. to the pharmacy if they are out of tamper-resistant paper. If the prescriber ●● Must contain at least one recognized feature to prevent the patient is not available, the pharmacy may fill the prescription as long as it verifies from erasing or modifying information written by the prescriber, the prescription with the prescriber’s office within 72 hours. such as penetrating ink. USP <797> These regulations, developed by the United States Pharmacopeia, were USP <797> requires training and evaluation for all personnel who created to decrease the transmission of infections to patients through drug are to use aseptic technique for preparing sterile products, assigning products, improve the quality of sterile products, and to protect pharmacy responsibility to the personnel involved in compounding. Risk levels personnel from exposure to potentially hazardous drug products. for compounding were assigned for compounds to help determine It was the first enforceable guideline for the preparation of sterile expiration dates and compounding requirements. products that established quality standards for the procedures used to It also created regulations to govern the air classification levels in clean create products using aseptic technique. It contains many requirements rooms, the physical construction of clean rooms, and procedures for for the preparation of sterile products, including training and quality gowning before compounding sterile products. Standards were set for assurance requirements, and affects any facility that prepares, stores, or cleaning and sanitation of compounding workspaces, as well as for dispenses sterile products. maintenance of automatic compounding devices and environmental monitoring. Pharmacy ethics Ethics refers to the branch of philosophy that concerns itself with From these ethical principles, codes of ethics have been developed distinguishing between right and wrong based on knowledge and not for each health care profession, including pharmacists and pharmacy feelings or opinions. technicians. They are designed to direct pharmacy professionals in their Medical practice has been governed by ethical principles and codes daily practice of pharmacy and publicly state the principles that guide since medicine was first established in ancient Greece. The Hippocratic their duties. During their training, pharmacy professionals are taught the principles of “doing good and avoiding evil” have combined to form the codes of ethics that govern their professions, and it is important to keep foundation of the basic ethical principles governing medical practice3. these codes in mind when working in the pharmacy. While they may not Over the years, several more principles have been added, and these provide an answer to every ethical dilemma, they should be applied in can be applied to the practice of pharmacy for both pharmacists and individual situations to help pharmacy professionals determine the most pharmacy technicians. appropriate solution. ETHICAL PRINCIPLES Autonomy Autonomy is the ethical term used to describe the right for patients While it can be difficult at times for health care professionals to respect to make decisions for themselves. It allows patients to choose what a patient’s decision, especially if they disagree, it is ultimately the medical treatments are best for them and allows them to take ownership patient’s right to decide whether he or she wants to take a medication or of their own health care. have a procedure done. For example, if a patient who has been given all After receiving all of the information necessary to make an informed of the information about the side effects of Celebrex decides he or she decision, health care choices must be made by patients themselves does not want to take it, the health care professional must respect the without coercion. When patients are unable to make an informed decision person’s decision. on their own, such as infants, children, and those with dementia, their Health care professionals do have the responsibility to provide patients with responsible family member or caregiver can make decisions for them. all of the information they need to make an informed decision, through counseling or other means, but the decision is ultimately up to patients. Beneficence Beneficence describes the ethical principle of acting in the best interest Providing patients with an opportunity to consult with a pharmacist of the patient, or “doing good.” This principle encourages health care to ensure they are informed on the use of their new medication is an providers to help patients achieve the best possible outcomes of their example of beneficence. Pharmacy professionals play an important role medical treatment, through advocating for them and providing them in encouraging positive outcomes for the patient, and should bear this with information to make informed decisions. principle in mind on a daily basis. Nonmaleficence The principle of nonmaleficence describes the concept of “doing no in many ways, such as preventing medication errors by checking for the harm.” Avoiding harm for patients has been a central idea of health care presence of drug interactions, adverse events, and duplicate therapies. for millennia, and continues to play an essential role today. Health care Pharmacy technicians can also take an active role in preventing harm to providers must constantly keep this concept in mind when providing patients by focusing on medication safety and ensuring prescriptions are care to patients to ensure the actions they are taking to help the patient filled correctly and accurately, as well as by learning from mistakes and do not end up causing harm. preventing their repetition. There are many ways pharmacy professionals can apply the principle of Nonmaleficence and beneficence often go hand in hand, because not nonmaleficence when assisting patients. Pharmacists can prevent harm harming a patient can also be considered to be acting in the best interest

Pharmacy.EliteCME.com Page 74 of the patient. However, “doing no harm” does not always mean the an alternate product. In this scenario, the pharmacist prevented harm by pharmacy professional is “doing good.” letting the patient know it can further increase their blood pressure, which For example, a patient with high blood pressure comes to the pharmacy can be dangerous, but did not act in the best interest of the patient by counter asking about the side effects of pseudoephedrine. The pharmacist recommending a safer alternative. These concepts are applicable to both tells the person it can increase the blood pressure but does not recommend pharmacists and technicians alike. Confidentiality Protecting the privacy of a patient’s medical condition and health and technicians must both take an active role in preventing unauthorized information is the definition of confidentiality. It is crucial to achieving disclosures of protected information. the best outcomes for a patient, because patients may be less likely Daily duties must be conducted in a way that prevents health information to share personal information if they feel their confidentiality will be from reaching unauthorized sources, and the pharmacy’s policies and violated, which could prevent the pharmacy team from acting in the best procedures should reflect the importance of maintaining confidentiality. To interest of the patient. maintain a patient’s trust, pharmacy personnel should respect the wishes of Private health information is protected by the Health Insurance the patient on who they want their patient information to be disclosed. Portability and Accountability Act of 1996 (HIPAA), and pharmacists Veracity Veracity is the principle of being honest with patients and always telling Being completely honest with patients is important, and this principle the truth. Both pharmacists and technicians can take an active role in can be violated in several ways. When critical information is left out of promoting veracity by conveying honest and truthful information to a conversation with a patient, it is considered an omission. Commission patients. Building trust with patients is essential to creating a solid occurs when a lie is intentionally told. relationship between the pharmacy and the patient, and this trust comes While pharmacists may need to use professional judgment when assessing with continuously being honest with patients. what and how much information to disclose to patients, the principle of Building trust also allows the pharmacy to obtain thorough information veracity should be kept in mind at all times. Technicians should refer any from patients on their health care, and helps pharmacists act in the best confusing situations to the pharmacist to ensure veracity is maintained. interest of their patients. Justice The concept of justice can be applied to pharmacy practice, and refers available. While not always perfect, this system allows patients to receive to the practice of allocating products and services to patients fairly, life-saving transplants fairly. regardless of race, gender, religion, or any other external factors. All patients have the right to be treated fairly by their medical providers, A common example of the principle of justice applies to patients who are so in the pharmacy environment, medications should be allocated in waiting for an organ transplant. These patients are added to a waiting list a first-come, first-served fashion, unless another fair system has been of patients and are served as fairly as possible based on their condition developed. This will ensure all patients have the same ability to access and organ needs. Patients are ranked based on their need, and those important medications. ranked at the top of the list are matched with donors as they become Fidelity The principle of fidelity refers to the duty to do what a person has promised to patients helps to maintain and build the patient-pharmacy relationship, to another. It requires health care professionals to be faithful to their patients allowing a pharmacy staff to better serve its patients. and to always keep the patient’s best interest in mind. Keeping promises Codes of ethics Both pharmacists and pharmacy technicians have their own codes of obligations of pharmacy professionals to their patients, society, and ethics to govern their practice of pharmacy, developed by professional other health care professionals. organizations. They are comprised of principles based on the moral Code of Ethics for pharmacists2 The Code of Ethics for pharmacists is made up of eight principles ●● A pharmacist acts with honesty and integrity in professional to guide pharmacists in their practice. They form a foundation for relationships. pharmacists’ professional behaviors, attitudes, and actions. ●● A pharmacist maintains professional competence. These principles, as stated by the American Pharmacists Association, are: ●● A pharmacist respects the values and abilities of colleagues and ●● A pharmacist respects the covenantal relationship between the other health professionals. patient and pharmacist. ●● A pharmacist serves individual, community, and societal needs. ●● A pharmacist promotes the good of every patient in a caring, ●● A pharmacist seeks justice in the distribution of health resources. compassionate, and confidential manner. A detailed explanation of each principle can be found at http://www. ●● A pharmacist respects the autonomy and dignity of each patient. pharmacist.com/code-ethics Code of Ethics for pharmacy technicians1 Similar to the code of ethics for pharmacists, this code was developed ●● Respect the privacy of patient medical records and disclose to guide pharmacy technicians in their professional lives. The pharmacy information only when authorized. technician’s code is comprised of 10 principles adopted by the ●● Refrain from promoting and distributing products of subpar quality American Association of Pharmacy Technicians. or that do not meet standards required by law. In summary, technicians should: ●● Refrain from taking part in activities that may disgrace the ●● Use their knowledge to ensure the patient’s safety and health. profession of pharmacy. ●● Endorse and support veracity and integrity. ●● Take an active role in professional pharmacy organizations. ●● Assist pharmacists in distributing resources in a safe, effective, and The complete code of ethics for pharmacy technicians can be found at cost-efficient manner. http://www.nationaltechexam.org/pdf/code-of-ethics.pdf ●● Respect the ability of pharmacists and other health professionals. ●● Continuously improve their pharmacy expertise and knowledge. ●● Respect patient dignity, privacy, and individuality.

Page 75 Pharmacy.EliteCME.com Ethical dilemmas Ethical dilemmas are complex situations involving a conflict between Stacy asks you not to tell anyone at the pharmacy; she is your best morals. They have no right or wrong answer, and are often confusing, friend and you do not want her to get in trouble. She says that she frustrating situations that require careful consideration to resolve. Many accidentally took the bottle when she was packing up her things to situations involve both ethical and legal considerations, and can be leave at the end of her shift today, and that she will take it back to the difficult to resolve without guidance. pharmacy on her next shift. What should you do? Identifying the problem is the first step towards finding a solution. The In the above example, there is a conflict between the fidelity you feel situation should then be assessed completely, and as much information towards your friend Stacy, and concept of justice. It seems as though as possible should be gathered to help with the decision-making process. Stacy may have intentionally stole the diazepam, a crime for which Ethical principles can then be considered to help develop a final decision. there are consequences, and lied about it. Removing this medication An ethical dilemma example: You are working in a busy retail from the pharmacy’s shelf is not only a crime, but it unfairly removed pharmacy with your friend, Stacy. One day after dinner, you stop by this medication from those available to patients in need. Stacy’s house to drop off her lab coat that she forgot in your car. When While there may not be a clear right or wrong answer, using ethical you use the bathroom at her house, you notice a stock bottle of diazepam principles and seeking advice when appropriate will help to resolve on a shelf by the mirror, without a prescription label on it. You remember ethical dilemmas. that there was a missing bottle of diazepam at work two weeks ago, but no one found it, and it was assumed to be a mistake on the wholesaler’s part. References 1. Institute for the Certification of Pharmacy Technicians. Code of Ethics for Pharmacy Technicians. 4. Abood R. Pharmacy Practice and the Law. Sudbury, MA: Jones and Bartlett Publishers. 2012. 2007. Accessed November 12, 2013 at http://www.nationaltechexam.org/pdf/code-of-ethics.pdf. 5. Mizner J. Mosby’s Review for the Pharmacy Technician Certification Examination, 2nd Edition. St. 2. American Pharmacists Association. Code of Ethics for Pharmacists. 1994. Accessed November 12, Louis: Elsevier. 2010. 2013 at http://www.pharmacist.com/code-ethics. 6. Hopper T. Mosby’s Pharmacy Technician Principles and Practice, 3rd Edition. St. Louis: Elsevier. 3. Buerki R, Vottero L. Ethical Responsibility in Pharmacy Practice, Second Edition. American Institute 2012. of the History of Pharmacy. Madison, Wisconsin. 2002. LAW AND ETHICS: WHAT THE PHARMACY PROFESSIONAL SHOULD KNOW Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. Which of the following pieces of legislation established two 6. ______is the ethical term used to describe the right for patients classes of medications, prescription (legend) drugs that require a to make decisions for themselves. prescriber’s order to dispense, and over-the-counter (non-legend) a. Autonomy. drugs that can be purchased without a prescription? b. Beneficence. a. The Harrison Narcotics Tax Act. c. Fidelity. b. The Food, Drug, and Cosmetic Act. d. Confidentiality. c. The Durham-Humphrey Amendment. 7. The principle of ______describes the concept of “doing no harm.” d. Kefauver-Harris Amendment. a. Nonmaleficence. 2. According to the Comprehensive Drug Abuse, Prevention, and b. Beneficence. Control Act of 1970, if the pharmacy does not have the full quantity c. Autonomy. of a Schedule II controlled substance on hand, a partial fill can be d. Fidelity. given if the remaining quantity of medication is made available 8. Protecting the privacy of a patient’s medical condition and health within _____ hours. information is the definition of ______. a. 24. a. Autonomy. b. 48. b. Veracity. c. 72. c. Fidelity. d. 96. d. Confidentiality. 3. ______created the requirement of a distinct 11-digit 9. ______refers to the practice of allocating products and number to identify each medication, known as the National Drug services to patients fairly. Code (NDC) number. a. Autonomy. a. Orphan Drug Act. b. Fidelity. b. Occupational Safety and Health Act. c. Justice. c. The Food, Drug, and Cosmetic Act. d. Confidentiality. d. The Drug Listing Act. 10. The principle of fidelity refers to ______. 4. Standards of care for Medicare and Medicaid patients living in a. Allocating products and services to patients fairly. nursing homes were established by the ______. b. The duty to do what a person has promised to another. a. FDA Modernization Act. c. “Doing no harm.” b. Omnibus Budget Reconciliation Act of 1987. d. Acting in the best interest of the patient. c. Omnibus Budget Reconciliation Act of 1990. d. Health Insurance Portability and Accountability Act. 5. The Omnibus Budget Reconciliation Act of 1990 was the first to recognize that the duties of pharmacists include ______. a. Ordering medications. b. Verifying the accuracy of prescriptions. c. Identifying and resolving drug therapy issues. d. Preventing medication theft.

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Pharmacy.EliteCME.com Page 76 Chapter 7: Methicillin-Resistant Staphylococcus Aureus: Prevention and Treatment 2 Contact Hours

By: Jodi Dreiling, PharmD, BCPS Author Disclosure: Jodi Dreiling and Elite do not have any actual or Questions regarding statements of credit and other customer service potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $8.00. Universal Activity Number (UAN): 0761-9999-17-258-H01-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: August 21, 2017 a provider of continuing pharmaceutical education. This Expiration Date: August 21, 2019 program is approved for 2 hours (0.2 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70% is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a statement of credit. Please submit your answers online at participants who have successfully completed the post-test. Participants Pharmacy.EliteCME.com must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives Summarize the mechanism of resistance of Staphylococcus aureus. Develop a treatment plan for infections caused by methicillin- Differentiate between community-acquired and health care-acquired resistant Staphylococcus aureus. methicillin- resistant Staphylococcus aureus. Demonstrate knowledge of medications used to treat methicillin- Identify prevention measures that can help prevent methicillin- resistant Staphylococcus aureus. resistant Staphylococcus aureus infections. Review the role of antimicrobial stewardship in the prevention and treatment of methicillin-resistant Staphylococcus aureus infections. Introduction Staphylococcus aureus (S. aureus) is a gram positive coccus that occurs S. aureus is still a major patient threat with approximately 40% of in grapelike clusters. It is a common pathogen involved in community strains being resistant to methicillin(Wiener et al., 2016). However, the and health care acquired infections. It is found in normal skin and Centers for Disease Control (CDC) published a study which reveals that mucosal flora in humans. S. aureus can cause infections ranging from life-threatening methicillin-resistant Staphylococcus aureus (MRSA) skin infections (i.e. folliculitis, impetigo, carbuncles, and cellulitis) to infection rates in the healthcare settings are declining. The study showed severe infections, such as pneumonia, osteomyelitis, endocarditis, and that between 2005 and 2011, invasive MRSA infections that started in the bacteremia. It is a virulent pathogen associated with significant morbidity hospital decreased by 54% with 30,800 fewer severe infections (Dantes and mortality. In 2011, there were over 80,000 invasive MRSA infections et al., 2011). Additionally, other studies have shown a decrease in overall and 11,285 related deaths per year (Dantes et al., 2011). central line bloodstream infections (Burton et al., 2009, CDC, 2011). Staphylococcus aureus resistance The introduction of penicillin in the 1940s improved the prognosis of beta-lactam affinity allows for ongoing cell wall synthesis despite the patients with S. aureus infections. However, two years later, strains of presence of a beta-lactam antibiotic. The term methicillin resistance penicillin resistant staphylococci were noted. The gene, B-lactamase, implies resistance to all beta-lactams including amoxicillin, ampicillin, hydrolyzes the beta-lactam ring rendering it inactive towards the cephalosporins, carbapenems, and monobactam antibiotics (Que & organism (Que & Morellion, 2015). Morellion, 2015; Stryjewski & Corey, 2014). Methicillin was the first semisynthetic penicillinase-resistant penicillin. The mecA gene is contained in the staphylococcal cassette cartridge Shortly after it was introduced, Methicillin-resistant Staphylococcus (SCC), which is a mobile chromosomal element that aids in the aureus (MRSA) was first described. Methicillin resistance is mediated successful chromosomal incorporation. Five SCC types (I-V) have by the mecA gene, which encodes for the novel penicillin- binding been isolated, which allows microbiologists to track resistance patterns protein (PBP), PBP-2a. This altered binding protein site with low (Stryjewski & Corey, 2014). Healthcare-acquired vs. community-acquired MRSA MRSA can be separated into two major categories: community-acquired MRSA isolates. CA-MRSA is more likely to be resistance to only beta- (CA-MRSA) and hospital-acquired (HA-MRSA). According CDC, lactams, but good susceptibility to trimethoprim-sulfamethoxazole and patients need to fulfill several criteria before they can be considered clindamycin. However, HA-MRSA is more multi-drug resistant, and not CA-MRSA (See Table 1) (Maree et al., 2007). Community-acquired susceptible to clindamycin (Maree et al., 2007; Pottinger, 2013). (CA) MRSA strains are genotypically distinct from healthcare-acquired Table 1: Diagnostic criteria of CA-MRSA. (HA) MRSA. Specifically, the molecular and antimicrobial resistance profiles differ between the two types of MRSA. CA-MRSA typically ●● Diagnosed as an outpatient. occurs in children and younger adults, compared to HA-MRSA, ●● Culture positive for MRSA within 48 hours after hospitalization. which usually occurs in the elderly, as they are more likely to live in a healthcare facility. When reviewing resistance patterns, CA-MRSA ●● No medical devices or indwelling catheters. has the SCCmec type IV, while HA-MRSA has SCCmec types I,II, III. ●● Medical history negative for MRSA. The current strains of CA-MRSA are also characterized by the presence ●● No history of recent stay (within 1 year) in long-term care of PVL (Panton-Valentine leukocidin) gene, which is thought to be a facility, hospital, nursing home. virulence factor for serious infections, and rarely identified in HA-

Page 77 Pharmacy.EliteCME.com Risk factors for MRSA Identification of risk factors for MRSA can help identify patients lead to an increased risk of community-acquired MRSA infection: who need targeted antibiotic treatment. The risk factors for acquiring community-acquired crowded living conditions, close skin-to-skin health care-associated MRSA include old age, multiple comorbidities, contact, compromised skin, contaminated items and surfaces, and lack the use of antibiotics within past 3 months, prolonged hospital stay of cleanliness. Common locations where the “5 C’s” may occur include duration, admission to long-term facility or hospital in past year, having schools, college dorms, daycare centers, correctional facilities, military undergone an invasive medical procedure, and/or having indwelling barracks, and gyms (Salgado et al., 2003). devices. The CDC identified five common factors, the “5Cs” that MRSA CONTROL INTERVENTIONS Hand hygiene MRSA is most commonly transmitted between patients via the water or alcohol-based hand gels. Providers and patients should be contaminated hands of health care workers. Hand hygiene should be the educated about the importance of hand hygiene. In addition, hand cornerstone for the prevention of MRSA, and other multi-drug resistant hygiene practices should be observed and feedback should be provided organisms. Health care workers should have easy access to soap and (Marimuthu et al., 2014). Contact precautions and isolation Contact precautions and isolation involve the use of gown and gloves be placed in single rooms or cohorted depending on room availability. for patient care. It also includes single use items such as blood pressure There is a lack of consensus on the appropriateness of isolating all cuffs, thermometers, and stethoscopes. Placing patients who are patients with MRSA infection or colonization and when to discontinue colonized or infected with MRSA may delay the colonization of other isolation (Calfee et al., 2014). patients, thus decreasing infection rates. If possible, patients should MRSA screening Surveillance screening of asymptomatic patients to identify MRSA of high risk patients. Once a positive screen has been identified, other carriage may help decrease transmission and active infection. The prevention methods must be implemented to decrease transmission precise role of screening has yet to be identified. Institutions vary (Fatkenheuer et al., 2015). widely in screening from screening all patients to targeted screening MRSA decolonization The goal of decolonization is to suppress or eradicate MRSA carriage in appropriate administration. Patients can also be given chlorhexidine order to decrease transmission between patients and decrease infection body washes (Ammerlaan et al., 2009). Although there is benefit for risk in the colonized patient. Decolonization is most commonly decolonization, resistance with mupirocin has been noted (Patel et al., performed with mupirocin intranasal ointment. Mupirocin is used 2009). Also, the utility of this prevention method is questioned because intranasally twice daily for 5 days. Mupirocin should be applied into of significant rates of patient recolonization. The evidence supports the nostril, pressed the side of the nose together and gently massaged to decolonization of patients undergoing clean surgical procedures (i.e. spread the ointment through the insides of the nostrils for approximately orthopedic or cardiothoracic surgery) (Bode et al., 2010). one minute. Pharmacists can counsel patients and educate nurses on the Environmental cleaning MRSA is often found in the environment close to the colonized patients. transmission after the colonized patient is discharged. While there is In a hospital setting, there are many surfaces that can be contaminated not strong data to support enhanced cleaning of MRSA rooms, good such as beds, keyboards, blood pressure cuffs, and medical devices. environmental cleaning can be a strong component of preventing MRSA can survive on surfaces for months and acts as a reservoir for transmission of other organisms (i.e. C. diff) (Han et al., 2015). Diagnosis MRSA can be diagnosed by various tests, such as in vitro culture on MRSA within 2 to 6 hours, compared to standard results, which take plates, cultures on special liquid broths, and polymerase chain reaction 24-48 hours to obtain. Once a diagnosis of MRSA is obtained, it allows (PCR) testing. The key to the rapid treatment of MRSA is the rapid the clinician to appropriately treat the patient by either expanding or diagnosis. Molecular diagnostic criteria can reduce the turnaround time narrowing antibiotic therapy (van Hal et al., 2007). to produce a rapid culture result. PCR testing allows the detection of Treatment Bacteremia Treatment of bacteremia with other antibiotics is uncertain, and further MRSA bacteremia and infective endocarditis warrant the most data is required. When selecting alternative agents, multiple factors immediate initiation of antibiotics. Vancomycin remains first-line must be considered (i.e. susceptibility testing, comorbidities, concurrent therapy for these invasive infections. Patients with MRSA due an medications). Additionally, treatment requires prompt source control, isolate with vancomycin MIC > 2 mcg/mL may not responds as well such as removal of vascular catheters or drainage of purulent collection to vancomycin; thus, daptomycin is a valid alternative for patients. (Habib et al., 2015). Skin infections MRSA is the most common cultured organism in the setting of skin tedizolid; however, use of these drugs is limited by cost and toxicity. infections. The majority of CA-MRSA infections are skin and soft tissue Their use should be limited to patients who do not respond to other infections. For any soft tissue infection, including those from MRSA, therapy or cannot tolerate other agents. the recommended primary management is incision and drainage of Patients should be hospitalized for intravenous antibiotics in the abscess formation. For abscess < 5 cm, antibiotics may not be needed, setting of severe or complicated skin infections. Those that would as incision and drainage may be sufficient. Oral antibiotics with empiric require hospitalization include: patients with extensive tissue coverage of MRSA are indicated in the setting of a moderate purulent involvement, signs of systemic toxicity, rapid progression of symptoms, infection with signs of systemic infection. Oral antibiotics of choice persistence or progression of symptoms after 48-72 hours of therapy, include: trimethoprim-sulfamethoxazole, tetracyclines (doxycycline or immunocompromised, or infection located near an indwelling device minocycline), and clindamycin. Alternate agents include linezolid and (i.e. prosthetic joint). Vancomycin is the drug of choice for MRSA skin Pharmacy.EliteCME.com Page 78 infections, unless contraindications exist. Daptomycin is an acceptable telavancin, linezolid, and tedizolid (Stevens et al., 2014; Daum, 2007; alternative agent. Although not first line, several alternative agents The Medical Letter, 2017). exist for treatment, including: ceftaroline, dalbavancin, oritavancin, Pneumonia MRSA is a major bacterial pathogen of hospital-acquired pneumonia Liu et al., 2011). An alternate agent is telavancin, as it was shown to be (HCAP) and ventilator associated pneumonia (VAP), with an incidence non-inferior to vancomycin in the setting of HA-MRSA (Rubinstein of 20 to 40% (Weiner et al, 2016). In the community, the risk of CA- et al., 2011). Daptomycin should be avoided due to its inactivation by MRSA is low (<5%), but has been increasing to become an emerging pulmonary surfactant. While tigecycline is approved for community- problem(Moran et al., 2012) . Clinical risk factors for CA-MRSA include acquired pneumonia (CAP), it has not been approved for CAP from end-stage renal disease, injection drug abuse, prior influenza, and prior MRSA. Also, ceftaroline should be avoided as it was approved for CAP, antibiotic therapy. When MRSA pneumonia is suspected, empiric therapy but not CAP due to MRSA, HCAP, or VAP (Liu et al., 2011). with vancomycin or linezolid should be initiated (Kalil et al., 2016; Antibiotics Vancomycin related adverse event. Red-man syndrome is described as an acute Vancomycin is the cornerstone for the treatment of MRSA infections. erythematous rash affecting the upper trunk and neck during or at It is a glycopeptide with activity against gram-positive organisms. The the end of the infusion. It can be treated with antihistamines, such as primary effect is the inhibition of the late stages of cell wall synthesis in diphenhydramine (Rybak et al., 2009). dividing bacteria (Barna & Williams, 1984). Daptomycin (Cubicin) The pharmacokinetic/pharmacodynamic parameter that best predicts Daptomycin is a cyclic lipopeptide that was approved for use in the vancomycin efficacy is the ratio of area under the curve (AUC) to United States in 2003. While its exact mechanism of action is unknown, minimum inhibitory concentration (MIC) of the infecting organism it is thought that daptomycin binds to the cell wall subsequently (AUC/MIC). A vancomycin AUC/MIC of > 400 has been recommended inhibiting intracellular synthesis of DNA, RNA, and protein. to predict successful outcomes. Trough serum concentrations of 15-20mg/ Daptomycin is bactericidal in a concentration dependent manner. It L are recommended for complicated infectious such as endocarditis, exerts its bactericidal effect on S. aureus without significant cell lysis, bacteremia, osteomyelitis, meningitis, and hospital-acquired pneumonia. which explains why there is decreased release of proinflammatory A trough concentration of that level will achieve the desired AUC/MIC > mediators when compared to vancomycin. The spectrum of 400 in patients with a MIC < 1mg/L. In patients with a MIC > 2 mg/L and antimicrobial activity of daptomycin includes Staphylococci, normal renal function (i.e. CrCl > 70ml/min) an alternate agent may need Pneumococci, E. faecalis and E. faecium, including MRSA, to be used, as desired AUC/MIC > 400 will not be attainable. A trough vancomycin intermediate S. aureus, and VRE isolates. Daptomycin is level of 10-15mg/L is acceptable with patients who have uncomplicated effective for the treatment of skin and soft tissue infections, bacteremia, infections (Rybak et al., 2009; Pea & Viale, 2006). endocarditis, and osteomyelitis. The poor penetration of daptomycin The typical dose of vancomycin for a patient with normal renal in the CNS precludes its use in meningitis. Also, daptomycin should function is 15mg/kg (actual body weight) administered every 8-12 not be used for pulmonary infections, as it is inactivated by surfactant hours. For patients with a serious illness, a loading dose of 25-30mg/ (Steenbergen et al., 2005). kg may be considered to rapidly achieve a target concentration. After Daptomycin is administered intravenous push over a two-minute period a loading dose, subsequent dosing schedules should be individualized or intravenous piggy back over 30 minutes. It must be administered for renal function and trough serum concentration (Rybak et al., 2009; with 0.9% sodium chloride, as it is incompatible with dextrose Wang et al., 2001). Vancomycin is poorly dialyzable by intermittent containing solutions. Standard dosing is 4mg/kg for skin and soft tissue hemodialysis; however, continuous renal replacement therapy increases infections and 6mg/kg for bacteremia. Higher dosing (8-10mg/kg) vancomycin clearance and requires more frequent dosing (Rybak et al., may be required for patients with severe infections (i.e. endocarditis, 2009; Launay-Vacher, 2002). vancomycin failure) (Falcone et al., 2013). Dosing is recommended Vancomycin trough concentrations are the most accurate and practical based on patient’s actual body weight. Daptomycin dosing is adjusted method for monitoring efficacy. Troughs should be obtained just prior in renal impairment. For dialysis patients, experts have recommended to the next dose at steady-state conditions. The trough should be drawn administering the recommended dose on 48-hour intradialytic days and prior to the fourth dose in patients with normal renal function. More increase the dose by 50% on 72-hour intradialytic days. For example, frequent monitoring is not recommended for course of therapy less than if the recommended dose for the patient is 6mg/kg, administer 6mg/ 5 days in length or for lower intensity dosing (vancomycin trough goal kg on Monday, Wednesday and 9mg/kg on Friday. All doses should be of 10-15mg/L). Once-weekly trough concentrations are recommended administered after dialysis is completed (Haselden, 2013). for patients who are hemodynamically stable and on long term Daptomycin is generally well-tolerated. Drug-induced myopathy and treatment. Frequent trough concentrations may be needed in critically increased levels of creatinine phosphokinase (CPK) have ranged from ill patients with unstable renal function and high vancomycin level 2.8 to 6.7% in phase 3 clinical trials, and is reported to be reversible requirements (Rybak et al., 2009). once daptomycin is discontinued (FDA, 2016). CPK levels should be When vancomycin was first developed in the late 1950s, it was called monitored weekly and more frequently in patients with elevated CPK “Mississippi Mud” due to its brown color. It was initially only about levels or renal impairment. Patients should also have more frequent 70% pure, which was thought to have led to the incidence of adverse CPK monitoring if they were on HMG-CoA reductase inhibitors prior reactions. However, the purity was increased to 92-95% in 1985 to or concomitantly. Daptomycin should be discontinued in patients when the product was manufactured by Eli Lilly. When the impurity with myopathy symptoms and CPK levels > 1,000 U/L or in patients increased, there was a decline in serious adverse drug reactions. without symptoms and CPK levels > 2,000 U/L. HMG-CoA reductase Vancomycin nephrotoxicity occurs in about 5-7% of patients(Cantu inhibitors should be held during daptomycin therapy. Since the rates of et al, 1994). It is typically mild and reversible. Risk factors for CPK elevation appear to increase with frequency of dosing, daptomycin vancomycin nephrotoxicity include: increase in total drug, pre-existing should be limited to once daily. There have been rare reports of renal impairment, concurrent administration of nephrotoxic agents, eosinophilic pneumonia in patients receiving daptomycin, usually critically illness, and obesity (Bamgbola, 2016). occurring after 10 days of therapy; it is not yet understood why this adverse reaction takes place (Steenbergen et al., 2005; FDA, 2016). Vancomycin is diluted to a maximum concentration of 5mg/mL and infused at a maximum rate of 500mg per 30 minutes. For example, Linezolid (Zyvox) a 1250mg dose would be diluted in 250mL of 5% dextrose (or 0.9% Linezolid is an oxazolidinone that inhibits bacterial protein synthesis sodium chloride) and administered over 90 minutes. This administration by binding to bacterial 23S ribosomal RNA of the 50S subunit. This strategy helps minimize the risk of red-man syndrome, an infusion prevents the formation of a functional 70S initiation complex that is needed for the bacterial translation process. Linezolid is bacteriostatic Page 79 Pharmacy.EliteCME.com against enterococci and staphylococci and bactericidal against most prolongs its half-life to 346 hours, allowing for once- weekly strains of streptococci. It has activity against the most common administration. It may be administered via two different regimens. The clinically relevant gram positive organisms, including MRSA, VRE, single-dose regimen is given as 1500mg intravenously one time over and penicillin resistant Streptococcus pneumonia. Linezolid has been 30 minutes. The two-dose regimen is 1000mg intravenously, followed approved for use in the treatment of bacteremia, pneumonia, simple by 500mg one week later. Dalbavancin dose require renal adjustment and complicated skin and soft tissue infections (i.e. osteomyelitis, for patients with a CrCl < 30mL/min, not on hemodialysis. The diabetic foot infection) (Moellering, 2003; FDA, 2007). single-dose regimen is given as 1125mg intravenously one time over Linezolid is dosed at 600mg every 12 hours for serious infections, 30 minutes. The two-dose regimen is 750mg intravenously, followed and 400mg every 12 hours for uncomplicated skin and soft tissue by 375mg one week later. No dose adjustment is required for patients infections. The bioavailability of linezolid approaches 100%, on regularly scheduled hemodialysis. Clinical trials showed that the which allows it to be administered intravenously or orally. The single-dose regimen had similar clinical response rates to the two- option oral step down therapy gives an advantage to Linezolid over dose regimen (81.4% vs. 84.2%). While not approved, dalbavancin is other products. Urinary excretion accounts for 85% of linezolid’s being investigated for the treatment of osteomyelitis, bacteremia, and elimination; however, there is no need for adjustment in renal failure endocarditis. or dialysis (FDA, 2007). Dalbavancin was well-tolerated in clinical trials, with the most common Linezolid is generally well tolerated, with the most common adverse adverse reactions being gastrointestinal (nausea, vomiting, diarrhea), effects are gastrointestinal symptoms of diarrhea, nausea, and headache, rash, pruritus. Infusion related reactions were rare, with less vomiting. There are some serious adverse effects that may occur in than 2% of patients experiencing flushing or phlebitis. Infusion reactions patients receiving linezolid. Reversible myelosuppression including were more frequent during rapid infusion (<30 minutes) of dalbavancin. thrombocytopenia, red blood cell aplasia, and pancytopenia have Patients may have increased liver function tests during therapy, but are been clearly described. Serial monitoring of complete blood counts reversible after discontinuation of dalbavancin. There are no significant is recommended for patients on linezolid longer than 2 weeks. drug interactions (Pope & Roecker, 2006). Peripheral neuropathy has been reported and is poorly reversible. Oritavancin (Orbactiv) Optic neuropathy causes gradual blurring of vision that may lead to Oritavancin is indicated for the treatment of acute bacterial skin and permanent blindness if linezolid is not discontinued (FDA, 2007). skin structure infections caused by susceptible organism, including Linezolid is a reversible, nonselective monoamine oxidase inhibitor MRSA. Similar to dalbavancin, it has a long half-life (~ 250 hours) that has been associated with serotonin syndrome in patients receiving allowing for a one time dosing regimen. It is administered as a concomitant serotonergic medications. Serotonin syndrome presents one-time dose of 1200mg over 3 hours. Oritavancin has not been with symptoms of fever, agitation, mental status changes, and tremors. studied in patients with a CrCl < 30 mL/min or in patients requiring Serotonin effecting medications such as selective serotonin reuptake hemodialysis. inhibitors (i.e. fluoxetine, citalopram), serotonin/norepinephrine The most common adverse reactions of oritavancin were similar to reuptake inhibitors (i.e. duloxetine, venlafaxine), tricyclic dalbavancin, including: gastrointestinal (nausea, vomiting, diarrhea), antidepressants, and multiple other medications should be avoided. headache, rash, and pruritus. Rarely, infusion- related reactions occurred. Tyramine-containing foods (i.e. aged cheese, smoked meats) should The use of unfractionated heparin is contraindicated for 120 hours (5 also be avoided due to small increases in blood pressure. Patients days) after the use of oritavancin due to the false elevation of activated should also monitor their blood pressure when taking concomitant partial thromboplastin time (aPTT). Oritavancin may elevate the PT/ pseudoephedrine and phenylpropanolamine (FDA, 2007). INR for 12 hours after administration, but has no effect on warfarin. Tedizolid (Sivextro) Thus, patients receiving warfarin may receive oritavancin. Serious Tedizolid is the second oxazolidinone to become available. It has the hypersensitivity reactions have been reported with a median onset of 1.2 same mechanism of action as linezolid, but has key structural differences days. If the reaction occurs during administration, the infusion should that have additional target binding site interactions, accounting for be stopped immediately. The treatment of the hypersensitivity reaction its greater potency and retained activity despite linezolid resistance. is supportive care of the reaction. The median time to resolution of Tedizolid is approved for the treatment of skin and soft tissue infections the adverse reaction was 2.4 days. Osteomyelitis was more commonly caused by susceptible organisms, including MRSA. reported in patients receiving oritavancin in a trial compared to vancomycin. If osteomyelitis is suspected, patients should be treated Tedizolid is prescribed as 200mg once daily for a short 6 day course of with an alternative antibiotic (Saravolatz & Stein, 2015). therapy. The bioavailability is 90%, allowing for equivalent dosing for intravenous and oral products. No dose adjustment is needed for renal Telavancin (Vibativ) or hepatic dysfunction. The side effect profile is similar to linezolid, Telavancin is indicated for the treatment of complicated skin and skin with the most common adverse events being gastrointestinal in nature. structure infections and for hospital-acquired or ventilator-associated Hematologic abnormalities may occur, and tedizolid use should be pneumonia caused by susceptible organisms, including MRSA. avoided in patients with baseline neutropenia (neutrophil counts < Telavancin should be reserved for use when alternative agents are not 1000 cells/mm3). Tedizolid has a lower monoamine oxidase inhibition available. when compared to linezolid. The risk of drug interaction between Telavancin does not have the extended half-life of dalbavancin and tedizolid and serotoninergic medications is low; however, clinical trials oritavancin. It is dosed 10mg/kg (actual body weight) every 24 hours. excluded patients receiving those medications (Burdette & Trotman, It is administered intravenously over 24 hours, and caution should be 2015). given for potential red-man syndrome. If it does occur, the infusion Lipoglycopeptides should be extended. Telavancin is primarily eliminated by the kidneys; Dalbavancin, oritavancin, telavancin are lipoglycopeptides. They thus, it is adjusted in renal dysfunction (see Table 2). are analogues of vancomycin with an enhanced mechanism of Table 2: Televancin renal dose adjustment. action. Similar to vancomycin, the lipoglycopeptides inhibit cell CrCl (Cockcroft – Gault) Dose of televancin wall synthesis. In addition, they have increased activity against gram positive cocci by greater binding to peptidoglycan precursors to 30 – 50mL/min 7.5mg/kg every 24 hours. prevent cell wall synthesis. Oritavancin and telavancin also disrupt the 10 - < 30mL/min 10mg/kg every 48 hours. membrane barrier function of S. aureus. The lipoglycopeptides contain a lipophilic side chain that prolongs their half-life (Pope & Roecker, < 10mL/min Not recommended/studied. 2006; Saravolatz & Stein, 2015; Saravolatz et al., 2009). Hemodialysis Not recommended/studied. Dalbavancin (Dalvance) Telavancin has several concerning warnings limiting is use in clinical Dalbavancin is indicated for the treatment of acute bacterial skin and practice. The use of telavancin for hospital-acquired or ventilator skin structure infections. The lipophilic side chain on dalbavancin pneumonia in patients with pre-existing moderate/severe renal

Pharmacy.EliteCME.com Page 80 impairment (CrCl < 50mL/min) had an increased risk of mortality 2.5% (66/2640) vs. 1.8% (48/2628), respectively(FDA, 2013). It is when compared to vancomycin(Corey et al., 2014). New onset recommended that tigecycline only be utilized for approved indications or worsening renal impairment has occurred in patients receiving and only when alternative therapies are not suitable (FDA, 2010;). telavancin. Patients should have renal function monitored at least For all indications, tigecycline is dosed as 100mg as a single dose, every 48-72 hours prior to, during, and after therapy. Patients are at a followed by 50mg every 12 hours for 5-14 days. Tigecycline is higher risk for nephrotoxicity if they have baseline renal dysfunction administered intravenously over 30-60 minutes. Tigecycline is or are receiving concomitant nephrotoxic agents. Telavancin contains extensively metabolized via the liver. There is no dose adjustment solubilizer cyclodextrin, which may accumulate in patients with for mild to moderate hepatic impairment (Child-Pugh class A or B); renal dysfunction; however, the clinical significance of this finding however, the maintenance dose should be adjusted to 25mg every 12 is unknown (Luke, 2010). QT prolongation can occur in patients hours for patients with severe hepatic impairment (Child-Pugh Class C) receiving telavancin. It should be avoided in patients with congenital (see Table 4). QT syndrome, known prolongation of QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy. The risk of QT Table 4: Child Pugh Class Scoring Chart. prolongation is similar to fluoroquinolones (Saravolatz et al., 2009). Measure 1 point 2 points 3 points Ceftraroline (Teflaro) Total bilirubin (mg/dL) < 2 2-3 >3 Ceftaroline is a novel 5th generation cephalosporin with activity against MRSA. It also has efficacy against Streptococcus pneumonia (including Serum albumin (g/dL) >3.5 2.8-3.5 < 2.8 multidrug-restraint strains), Haemophilus influenza, and Moraxella Prothrombin time (s) <4 4-6 >6 catarrhalis. Ceftaroline does not have activity against resistant gram- Ascites None Mild Moderate-severe negative bacteria such as Psuedomonas aeruginosa, Acinetobacter, or anaerobic organisms. Similar to other beta-lactams, ceftaroline’s Hepatic encephalopathy None Grade I-II Grade III-IV mechanism of action is binding to the penicillin -binding protein (PBP), Score: 5-6: Class A, 7-9: Class B; 10-15: Class C the enzyme that mediates the cross-linking transpeptidation of the peptidoglycan which are the terminal steps in completing the formation The most common adverse reactions for tigecycline are nausea, vomiting, of the bacterial cell wall. Ceftaroline also has a strong binding affinity diarrhea, abdominal pain, headache, and increased liver enzymes. While for PBP2a, a modified PBP in MRSA, which contributes to its spectrum rare, there have been cases of pancreatitis reported, including patients of activity against these bacteria. It is approved for the treatment of without risk factors. Since tigecycline is a tetracycline derivative, skin and skin structure infections (including MRSA) and community- photosensitivity may occur. Tigecycline use during tooth development acquired pneumonia (not due to MRSA). may cause permanent tooth discoloration (yellow-gray-brown); thus, should not be used in children and pregnancy. Tigecycline has limited Ceftaroline is dosed at 600mg intravenously every 12 hours. It is drug interactions, but may increase the effect of warfarin (FDA, 2010). administered over 5 to 60 minutes. It is approved for a 5-14 day course therapy for skin and skin structure infections, and 5-7 day course of Clindamycin (Cleocin) therapy for community-acquired pneumonia. Ceftaroline is primarily Clindamycin works by reversibly binding to 50S ribosomal subunits excreted through the kidneys, thus requires renal adjustment for preventing peptide bond formation, thus inhibiting bacterial protein patients with a CrCl < 50ml/min (see Table 3). synthesis. It is approved by the FDA for the treatment of S. aureus infections. It is has been widely used off label for the treatment of Table 3: Ceftaroline renal dose adjustment. skin and structure infections, osteomyelitis, septic arthritis, and CrCl (Cockcroft - Gault) Dose pneumonia caused by MRSA. It is not recommended for endocarditis due to its bacteriostatic action, nor for meningitis due to its limited > 50 mL/min 600mg q12h. CSF penetration. Due to potential resistance, the d-zone test is > 30 to < 50 mL/min 400mg q12h. recommended to identify the susceptibility of Clindamycin to MRSA. > 15 to < 30 mL/min 300mg q12h. Clindamycin is available in intravenous and oral formulations. The typical intravenous dose is 600 to 900mg IV every 8 hours and oral < 15 mL/min 200mg q12h. dosing is 300 to 450mg every 6-8 hours. The most common adverse ESRD – Hemodialysis 200mg q12h (dose after HD). effect is diarrhea, occurring in up to 20% of patients. Clostridium difficile may occur more frequently in patients receiving clindamycin There is no adjustment for hepatic dysfunction. Ceftaroline does when compared to other oral antibiotics (Van Eperen & Segreti, 2016). not go through the cytochrome P-450 system, so there are limited drug interactions. Ceftaroline does, however, interact with warfarin, Trimethoprim and sulfamethoxazole (TMP-SMX) (Bactrim) requiring dose adjustment. Trimethoprim is a tetrahydrofolate reductase inhibitor that, when added to sulfamethoxazole, provides a second-step block in the folate Based on clinical trials, ceftaroline is well tolerated with similar biosynthetic pathway. TMP-SMX is not FDA- approved to treat any adverse effects when compared to other cephalosporins. Since it is indication caused by MRSA. However, it is recommended as first-line a cephalosporin, there is a potential for hypersensitivity reactions in therapy for uncomplicated urinary tract infections, skin and soft-tissue patients allergic to cephalosporins and some patients with penicillin infections, and community associated MRSA infections according to allergies. Pharmacists should take a careful antibiotic allergy history clinical practice guidelines. prior to administration (Steed & Rybak, 2010). TMP-SMX is available in intravenous and oral formulations. The Tigecycline dose varies significantly based on intravenous and oral formulations, Tigecycline is a glycylcycline antibiotic derived from minocycline. indication, and renal function. The trimethoprim portion of TMP- It binds to the 30S ribosomal subunit of susceptible bacteria, thus SMX could potentially cause hyperkalemia. It is structurally similar to inhibiting protein synthesis. It has activity against many gram- triamterene and acts as a potassium sparing diuretic. Caution should positive organisms, including MRSA. Tigecycline is approved to treat be used when prescribing TMP-SMX in high doses or to patients complicated skin and skin structure infections, complicated intra- with renal impairment, older age, or who are receiving concomitant abdominal infections, and community-acquired pneumonia. While it has medications that could cause hyperkalemia (Adra & Lawrence, 2004). been studied in for the treatment of diabetic foot infections, hospital and ventilator associated pneumonia, it is not indicated for those infections. Doxycycline The FDA issued a safety warning in 2010 and a black box warning Doxycycline inhibits protein synthesis by binding with the 30S and in 2013 regarding increased risk of mortality in patients treated with possibly the 50S ribosomal subunit of susceptible bacteria. It is tigecycline when compared to other antibiotics. The FDA analyzed data indicated by the FDA for the treatment of skin and structure infections from 10 clinical trials that only used tigecycline from FDA- approved due to S. aureus, but not MRSA specifically. It is recommended by indications. The analysis showed increased mortality in patients clinical practice guidelines for the treatment of skin and structure receiving tigecycline when compared to other antibiotic medications: infections due to MRSA.

Page 81 Pharmacy.EliteCME.com Doxycycline is available in intravenous and oral formulations. It to the prescriber. The pharmacist could make recommendations to is dosed 100mg every 12 hours, regardless of route. There is no continue, adjust, change, or discontinue the antibiotic based on the dose adjustment for renal or hepatic impairment. Similar to other available microbiology results and clinical status of the patient. tetracyclines, it increases the risk of photosensitivity, and is not Another activity for pharmacists to optimize antibiotics would be recommended during tooth development (last stage of pregnancy and to establish hospital specific antibiotic guidelines based on national children < 8 years of age) (Ruhe et al., 2005). guidelines and local susceptibility data. These guidelines could be Antimicrobial stewardship incorporated into standardized order forms for prescribers. These CDC has reported that 30-50% of all antibiotics utilized in hospitals guidelines require prescribers to be complaint and adhere to the hospital are either unnecessary or inappropriate. These unnecessary antibiotics guidelines. Utilization of treatment pathways in the computerized lead to bacterial resistance, increased incidence of Clostridium physician order system increases adherence. difficile, and adverse effects (CDC, 2017). In response to the antibiotic Pharmacists can assist with antibiotic stewardship by having the resistance crisis, the White House published the National Action Plan ability to convert antibiotics from IV to oral formulations for clinically for Combating Antibiotic-Resistant Bacteria(CDC, 2017b). The goals of stable patients. Switching to oral antibiotics decreases the cost and the the National Action Plan are to slow the emergence of resistant bacteria incidence of catheter related infections. There are multiple antibiotics and prevent the spread of infection, improve surveillance, develop rapid that high bioavailability including: azithromycin, ciprofloxacin, and innovative diagnostic tests, accelerate research for development clindamycin, doxycycline, fluconazole, levofloxacin, linezolid, of antibiotics and vaccines, and improve international collaboration. moxifloxacin, metronidazole, and trimethoprim/sulfamethoxazole. According to the plan, inappropriate antibiotic use should be reduced Guidelines driving IV to PO therapy should be implemented and by 50% in outpatient settings and by 20% in inpatient settings by 2020. audited by an infectious disease pharmacist. The national target is also to reduce by at least 50% overall MRSA bloodstream infections by 2020 as compared to 2011. To complete this A core component of antimicrobial stewardship is education. Education goal, the plan recommends a regulatory requirement for antimicrobial should be provided on a regular basis to all types of healthcare stewardship be in place by 2017. providers. Education can be provided in multiple formats including presentations, flyers, weekly emails, or electronic messages. Education The CDC recommends that a successful antimicrobial stewardship should highlight system goals for antibiotic stewardship; additionally, program contain 7 core elements (see Table 5). case presentations at grand rounds, resident reports, or case conferences Table 5: Requirements of a successful antimicrobial stewardship can demonstrate and reinforce the importance of antibiotic de- program (CDC, 2017b). escalation. Antibiotic stewardship education should be included in annual provider education programs, medical education and training, Core Elements for Antimicrobial Stewardship Program and orientation for all new medical staff. Information about antibiotics Leadership commitment. could be included in patient education material. Accountability through a sing physician leader. Before implementation of a stewardship program, outcome data Drug expertise through a single pharmacy leader. should be identified. Commonly collected data includes antibiotic use, expenditures, and clinical outcome variables, such as readmission for Action, including at least one intervention. specific conditions (i.e. cellulitis, community-acquired pneumonia). Tracking prescription and resistance patterns. The most common methods to evaluation drug consumption are defined daily dose (DDD) or days of therapy (DOT). The DDD is Reporting prescription and resistance information directly to health calculated as the total number of antibiotic agent used divided by the care providers. number of grams in an average daily dose. The DDD helps compare Education for health care professionals. standardized doses among hospitals, but does not account for alternative dosing regimens dose to renal dysfunction or regimens that optimized The antimicrobial stewardship team should be multidisciplinary, pharmacokinetic or pharmacodynamic dosing. The DOT is the sum of including an infectious disease physician, infectious disease pharmacist, days that any antibiotic was administered. The DOT is not affected by clinical microbiologist, infection control professional, information dosing regimen changes. The DOT is more helpful when comparing the system specialist, nursing champion, administrative leader. use of different antibiotics within a hospital. After the data are collected, There are multiple types of interventions that can be implemented the findings should be reported to prescribers, nurses, pharmacists, and by the antimicrobial stewardship team. Pharmacists can play a key other appropriate staff. Prescriber specific reports should be provided to role in many of these activities, including formulary restrictions and help improve antibiotic prescribing. management, education, and monitoring. Antimicrobial stewardship is the key to combat the ever-growing Formulary restrictions are common among health-care systems to problem of antibiotic resistance. An antimicrobial stewardship control antibiotic use. Restrictions that require prior authorization by program has been shown to improve patient outcomes, reduce an infectious disease physician or pharmacist helps deter inappropriate antibiotic resistance, and decrease healthcare costs. Pharmacists have broad spectrum antibiotic use. Alternately, an institution could require a responsibility to be a prominent member of the stewardship team documentation of indication and duration for all antibiotics prescribed. as well as implement antimicrobial stewardship into our everyday Also, an antimicrobial steward, typically a pharmacist, could review activities (Nagel et al., 2016; ASHP, 2010; National Quality Forum, all antibiotics prescribed for more than 48 hours and provides feedback 2017; Fellner, 2016). Potential antibiotic approvals for MRSA The pipeline for antibiotics that treat MRSA is strong. Currently, it (delafloxacin), and an oral fusidic acid. Finding new treatments for includes three products that have new mechanisms of action: brilacidin, MRSA is a goal of the National Action Plan for Combating Antibiotic- debio 1450, and lefamulin. Other future agents include a new macrolide Resistant Bacteria (Fellner, 2016). (solithromycin), tetracycline derivative (omadacylcine), fluoroquinolone Conclusion MRSA continues to be an important pathogen with a high prevalence in in the setting of MRSA infection is imperative due to the high rate of the community and hospital settings. Identification of patients at high morbidity and mortality. Antimicrobial stewardship is key to improve risk for infection helps improve care. Timely and appropriate antibiotics patient outcomes and reduce antibiotic resistance. References Adra, M., & Lawrence, K.R. (2004). Trimethoprim/sulfamethoxazole for the treatment of severe Ammerlaan, H.S., Kluytmans, J.A., Wertheim, H.F., Nouwen, J.L., & Bonten, M.J. (2009). Staphylococcus aureus infections. Ann Pharmacotherapy; 38:338-341. Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis;48:922-930.

Pharmacy.EliteCME.com Page 82 ASHP. (2010). ASHP statement on the pharmacist’s role in antimicrobial stewardship and infection society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults prevention and control. Am J Health Syst Pharm; 67:575-576. and children. Clin Infect Dis; 52:e18. Bamgbola, O. (2016). Review of vancomycin-induced renal toxicity: an update. Therapeutic Advances Luke DR, Tomaszewksi K, Damle B, & Schlamm HT. (2010). Review of the basic and clinical in Endocrinology and Metabolism; 7(3):136-147. pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci; 99:3291-3301. Barna, J.C., & Williams, D.H. (1984). The structure and mode of action of glycopeptide antibiotics of Maree, C.L., Daum, R.S., Boyle-Vavra, S., Matayoshi, K., & Miller, L.G. (2007). Community- the vancomycin group. Annu Rev Microbiol; 38:339-357. associated methicillin-resistant staphylococcus aureus isolates and healthcare-associated infections. Bode, L.G., Kluytmans, J.A., Wertheim, H.F., Bogaers, D., Vanderbroucke-Grauls, C.M., Roosendaal, Emerging Infectious Diseases. 13(2):236. R., & Vos, M.C. (2010). Preventing surgical site infections in nasal carriers of Staphylococcus aureus. Marimuthu, K., Pittet, D., & Harbarth, S. (2014). The effect of improved hand hygiene on nosocomial N Engl J Med; 362:9-17. MRSA control. Antimicrob Resist Infect Control; 3:34. Burdette, S.D., & Trotman, R. (2015). Tedizolid: the first once-daily oxazolidinone class antibiotic. Moellering, R.C. (2003). Linezolid: the first oxazolidinone antimicrobial.Ann Intern Med; 128:135- Clin Infect Dis; 61:1315-1321. 142. Burton DC, Edwards JR, Horan TC, Jernigan JA, Fridkin SK. Methicillin-Resistant Staphylococcus Moran GJ, Krishnadasn A, Gorwitz RJ, Fosheim GE, Albrecht V, Limbago B, & Talan DA for the aureus Central Line–Associated Bloodstream Infections in US Intensive Care Units, 1997-2007. EMERGEncy ID NET Study Group. (2012) Prevalence of Methicillin-Resistant Staphylococcus JAMA. 2009;301(7):727-736. aureus as an Etiology of Community-Acquired Pneumonia. Clin Infect Dis; 54: 1126-1133. Calfee, D.P., Salgado, C.D., Milstone, A.M, Harris, A.D., Kuhar, D.T., Moody, J., & Yokoe, Nagel JL, Kaye KS, LaPlante KL, & Pogue, J.M. (2016). Antimicrobial stewardship for the infection D.S. (2014). Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and control practitioner. Infect Dis Clin N Am; 30:771-784. infection in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol; 35:772-796. National Quality Forum. (2017). Partners Playbook: Antibiotic Stewardship in Acute Care. Retrieved Cantu TG, Yamanka-Yuen NA, & Leitman PS. (1994) Serum vancomycin concentrations: reappraisal from: qualityforum.org/NQP_Antibiotic_Stewardship_.aspx of their clinical value. Clin Infect Dis; 18:533-543. Patel, J.B., Gorwitz, R.J., & Jernigan, J.A. (2009). Mupirocin resistance. Clin Infect Dis; 49:935-941. CDC (2011). Vital signs: central line–associated blood stream infections—United States, 2001, 2008, Pea, F., & Viale, P. (2006).The antimicrobial therapy puzzle: could pharmacokinetic pharmacodynamic and 2009. MMWR Morb Mortal Wkly Rep. 2011;60:243-248. relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill CDC. (2017). Get smart for healthcare. Retrieved from cdc.gov/getsmart/healthcare. patients? Clin Infect Dis; 42:1764. CDC. (2017b). National Action Plan for Combating Antibiotic – Resistant Bacteria. Retrieved from Pope, S.D., & Roecker, A.M. (2006). Dalbavancin: a novel lipoglycopeptides antibacterial. cdc.gov/drugresistance/pdf/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Pharmacotherapy; 26:908-918. Corey GR, Kollef MH, Shorr AF, Rubinstien E, Stryjewski ME, Hopkins A, & Barriere SL (2014). Pottinger, P.S. (2013). Methicillin-resistant Staphylococcus aureus infections. 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Skin and soft-tissue infections caused by methicillin resistant M.E.; ATTAIN Study Group. (2011). Telavancin versus vancomycin for hospital-acquired pneumonia Staphylococcus aureus. N Engl J Med; 357:380. due to gram-positive pathogens. Clin Infect Dis; 52:31-40. FDA. (2013). FDA drug safety communication: FDA warns of increased risk of death with IV Ruhe, J.J., Monson, T., Bradsher, R.W., & Menon, A. (2005). Use of long-acting tetracyclines for antibacterial Tygacil (tigecycline) and approves new boxed warning. Retrieved from https://www.fda. methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin gov/Drugs/DrugSafety/ucm369580 Infect Dis; 40:1429-1434. FDA. (2016). Daptomycin: prescribing information. Retrieved from https://www.accessdata.fda.gov/ Rybak, M., Lomaestro, B., Rotschafer, J.C., Moellering, R. Jr., Craig, W., Billeter, M., drugsatfda_docs/nda/2016/021572Orig1s052.pdf Dalovisio, J.R., & Levine, D.P. (2009). Therapeutic drug monitoring of vancomycin in adult patients: FDA. (2010). Tygacil (tigecycline): prescribing information. Retrieved from https://www.accessdata. A consensus review of the American Society of Health-System Pharmacist, the Infectious Diseases fda.gov/drugsatfda_docs/label/2010/021821s021lbl.pdf. Society of America, and the Society of Infectious Disease Pharmacists. Am J Health-Syst Pharm; FDA. (2007). Zyvox (linezolid): prescribing information. Retrieved from https://www.accessdata.fda. 66:82-98. gov/drugsatfda_docs/nda/2007/021131Orig1s012.pdf. Salgado, C. D., Farr, B.M., & Calfee, D.P. (2003). Community-Acquired Methicillin-Resistant Falcone, M., Russo, A.,Venditti, M., Novelli, A., & Pai, M.P. (2013). Considerations for Higher Staphylococcus aureus: A Meta-Analysis of Prevalence and Risk Factors. Clin Infect Dis; 36 (2): Doses of Daptomycin in Critically Ill Patients with Methicillin-Resistant Staphylococcus aureus 131-139. Bacteremia. Clin Infect Dis; 57: 1568-1576. Saravolatz, L.D. & Stein, G.E. (2015). Oritavancin: a long half-life lipoglycopeptides. Clin Infect Dis Fatkenheuer, G., Hirschel, B., & Harbarth, S. (2015). Screening and isolation to control methicillin- 2015; 61:627-632. resistant Staphylococcus aureus: sense, nonsense, and evidence. Lancet;385:1146-1149. Saravolatz, L.D., Stein, G.E., & Johnson, L.B. (2009). Telavancin: a novel lipoglycopeptide. Clin Fellner C. (2016). Companies take aim at MRSA infections. P&T; 41:126-128. Infect Dis; 49:1908-1914. Habib, G., Lancellotti, P., Antunes, M.J., Bongiorni, M.G., Casalta, J.P., Del Zotti, F., & Walker, D.M. Steed, M.E., & Rybak, M.J. (2010). Ceftaroline: a new cephalosporin with activity against resistant (2015). 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the gram-positive pathogens. Pharmacotherapy; 30:375-389. Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: Steenbergen, J.N., Alder, J., Thorne, G.M., & Tally, F.P. (2005). Daptomycin: a lipopeptide antibiotic European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear for the treatment of serious gram-positive infections. J Antimicrob Chemother; 55:283-288. Medicine (EANM). Eur Heart J; 36:3075. Stevens, D.L., Bisno, A.L., Chambers, H.F., Dellinger, E.P., Goldstein, E.J., Gorbach, S.L., & Wade, van Hal, S.J., Stark, D., Lockwood, B., Marriott, D., & J. Harkness. (2007). Methicillin-resistant J.C.; Infectious Diseases Society of America. (2014). Practice guidelines for the diagnosis and Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA management of skin and soft tissue infections: 2014 update by the infectious diseases society of PCR assay and Geno Type MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, America. Clin Infect Dis; 59:147. MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. J Clin Microbiol; 45: Stryjewski, M.E., & Corey, G.R. (2014). Methicillin-resistant Staphylococcus aureus: an evolving 2486–2490. pathogen. Clin Infect Dis. 58(suppl1):s10-19. Halselden, M., Leach, M., & Bohm, N. (2013). Daptomycin dosing strategies in patients receiving The Medical Letter. (2017). Drugs for MRSA skin and soft-tissue infections. Retrieved from http:// thrice-weekly intermittent hemodialysis. Annals of Pharm; 1342-1347. secure.medicalletter.org/JAMA_MRSA Han, J.H., Sullivan, N., Leas, B.F., Pegues, D.A., Kaczmarek, J.L., & Umscheid, C.A. (2015). Van Eperen, A.S., & Segreti, J. (2016). Empirical therapy in methicillin-resistant Staphylococcus Cleaning hospital room surfaces to prevent health care-associated infections: a technical brief. Ann aureus infections: an up to date approach. J Infect Chemother; 22:351-359. Intern Med;163:598-607. Wang, J.T., Fang, C.T., Chen, Y.C., & Chang, S.C. (2001). Necessity of a loading dose when using Kalil, A.C., Metersky, M.L., Klompas, M., Muscedere, J., Sweeney, D.A., Palmer, L.B. & vancomycin in critically ill patients. J Antimicrob Chemother; 47:246. Brozek, J.L. (2016). Management of Adults With Hospital-acquired and Ventilator-associated Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, Edwards JR, & Siever DM. Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the (2016). Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary American Thoracic Society. Clin Infect Dis; 63:e61. of data reported to the national healthcare safety network at the Centers for Disease Control and Launay-Vacher, V., Izzedine, H., Mercadal, L., & Deray, G. (2002). Clinical review: use of Prevention, 2011-2104. Infect Control Hosp Epidemiol; 37:1288-1301. vancomycin in haemodialysis patients. Crit Care; 6:313-316. Yahav, D., Lador, A., & Leibovici, L. (2012). Efficacy and safety of tigecycline: a systematic review Liu, C., Bayer, A., Cosgrove, S.E., Daum, R.S., Fridkin, S.K., Gorwitz, R.J., Chambers, H.F.; and meta-analysis. J Antimicrob Chemother; 54:1699-1709. Infectious Diseases Society of America. (2011). Clinical practice guidelines by the infectious diseases METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: PREVENTION AND TREATMENT Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com

1. The fastest way to diagnosis a MRSA infection is polymerase chain 6. A dose of vancomycin 2000mg should be administered over 2 reaction testing. hours. a. True. a. True. b. False. b. False. 2. CA-MRSA strains can be identified via the SCCmec type IV. 7. Daptomycin should not be used for meningitis because it poorly a. True. penetrates the CNS. b. False. a. True. b. False. 3. Receipt of antibiotics within 3 months is a risk factor for HA- MRSA infection. 8. The appropriate dose of ceftaroline for a patient with a CrCl of a. True. 25mL/min is 600mg q12h. b. False. a. True. b. False. 4. Mupirocin intranasal ointment is the drug of choice for MRSA decolonization. 9. TMP-SX can cause hypokalemia. a. True. a. True. b. False. b. False. 5. Daptomycin may be used to treat HA-MRSA pneumonia. 10. Doxycycline should be avoided in patients that are under the age of a. True. 8 years of age. b. False. a. True. b. False.

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Page 83 Pharmacy.EliteCME.com Chapter 8: Pain Management Awareness for Pharmacists

2 Contact Hours

By: Bradley Gillespie, PharmD

Author Disclosure: Bradley Gillespie and Elite do not have any actual Questions regarding statements of credit and other customer service or potential conflicts of interest in relation to this lesson. issues should be directed to 1-888-666-9053. This lesson is $8.00. Universal Activity Number (UAN): 0761-9999-18-011-H01-P Educational Review Systems is accredited by the Activity Type: Knowledge-based Accreditation Council of Pharmacy Education (ACPE) as Initial Release Date: January 11, 2018 a provider of continuing pharmaceutical education. This Expiration Date: January 11, 2020 program is approved for 2 hours (0.2 CEUs) of continuing Target Audience: Pharmacists in a community-based setting. pharmacy education credit. Proof of participation will be To Obtain Credit: A minimum test score of 70 percent is needed to posted to your NABP CPE profile within 4 to 6 weeks to obtain a credit. Please submit your answers either by mail, fax, or online participants who have successfully completed the post-test. Participants at Pharmacy.EliteCME.com must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives Define pain in general terms. Be familiar with the main sources of pain experienced by patients. Recognize the individuality of pain and its perception. Be familiar with the various treatment options available to combat Distinguish between different sources and types of pain. pain, including potential indications and side effects for each. Recognize the extent of the pain problem and its cost to society. Become aware of the use of acupuncture and how it may be Adopt a general understanding of the pain signaling process. integrated into an individualized pain-management strategy. Pre-assessment questions Before beginning this activity, test your pre-course knowledge by b. Cancer. answering the following questions. Please be aware that these questions c. Hypertension. may also be included as part of the CPE final examination. d. Multiple sclerosis. 1. Nociceptive pain can be described as: 3. Which of the following statements about acupuncture is true? a. A process where stimuli are detected by peripheral nerve fibers. a. Its basis is the depression of specific points in the body. b. A type of pain resulting from the activation of pain receptors on b. Parkinson’s disease is the most common ailment leading to the surface of the body or within tissues. acupuncture use. c. A kind of pain felt as a result of injury to internal organs. c. Based on results obtained in recently conducted placebo- d. All of the above. controlled trials, acupuncture is a robust treatment modality, 2. The most common cause of nerve damage is related to: resulting in pain relief in the majority of patients. a. Diabetes. d. According to traditional Chinese medicine, it regulates the flow of vital energy (qi) along the meridians. Introduction According to the International Association for the Study of Pain (IASP), in the absence of tissue damage or pathophysiology. In these cases, the pain can be defined in general terms as an unpleasant emotional and cause is typically psychological. There is no way to distinguish this sensory experience that is associated with potential or actual damage experience from injury-related pain based on their subjective report. to tissue. It is critical to note that in some cases, people may be unable While pain is quite common, there are a number of approaches that may be to verbalize the pain they are experiencing, but still require appropriate useful in its treatment. The appropriate treatment plan can vary, depending therapy for its treatment. Further, pain is not objective; each individual on the cause of the pain. In addition to pain relievers, some patients may will have divergent pain thresholds, and will describe what he or she find relief through alternative approaches, such as acupuncture. In other is feeling differently (International Association of the Study of Pain, cases, surgery may be indicated (US National Library of Medicine, 2018). 2017). At times, people will report that they are experiencing pain even Defining pain Everyone’s pain, as well as their perception of pain, is different. This aching in nature. In general, somatic pain is typically aggravated by variation is likely due to the assortment of pathologies contributing to the increased activity and relieved by rest (Sikandar, 2012). presence of pain. Some of the main sources of pain are described below: ●● Visceral pain: Visceral pain is felt as a result of injury or damage Nociceptive pain: According to a concept paper issued by the European to internal organs. This is likely the most common form of pain. Medicines Agency, nociceptive pain is internationally defined as a Visceral pain is a reaction to activation of pain receptors located in process where intense thermal, chemical or mechanical stimuli can the pelvic, abdominal or chest areas of the body. This type of pain be detected by a group of peripheral nerve fibers called nociceptors is not easily localized and is vague in nature; it is often described (European Medicines Agency, 2011). using terms such as dull, diffuse, pressure-like or deep squeezing. Actual organ injuries leading to visceral pain can include distension, Nociceptive pain can be subdivided further into somatic pain and impaction, perforation or inflammation. Symptoms associated with visceral pain. visceral pain may include nausea, fever and malaise. On other ●● Somatic pain: Somatic pain is typically a result of pain receptors occasions, visceral pain can be caused by issues with abdominal activating on the surface of the body or within musculoskeletal muscles, such as spasm (Geber, 2009). tissues. One common cause of somatic pain is post-surgical pain Neuropathic pain: In 2009, an expert committee of the International from an incision. This type of pain is typically described as dull or Association for the Study of Pain Neuropathic Pain Special Interest

Pharmacy.EliteCME.com Page 84 Group (NeuPSIG) revised the definition of neuropathic pain as “pain fears, beliefs and strong emotions. Symptoms include headaches, arising as a direct consequence of a lesion or disease affecting the stomach pain, back pain or muscle soreness. If all organic causes of somatosensory system” (Geber, 2009). There are a variety of sources of pain are ruled out, the practitioner may establish a psychogenic pain neuropathic pain, including post-herpetic neuralgia, trigeminal neuralgia diagnosis. In most cases, a patient with psychogenic pain does not or diabetes. This pain is often described in bizarre terms, including have symptoms that correlate with nervous system functioning. Often, burning or electrical in nature. Neuropathic pain can also be associated medical practitioners will work together with mental health specialists with kin sensitivity. to reach an appropriate diagnosis. Psychogenic pain treatment often Psychogenic pain: According to an article published by the Cleveland involves psychotherapy, antidepressants with pain-relieving effects Clinic, psychogenic pain is attributed to psychological factors, including such as tricyclic antidepressants, and non-narcotic pain relievers such as NSAIDs (Cleveland Clinic, 2014). Epidemiology of pain To form a representation of the frequency, prevalence and prevalence of chronic pain was higher in females (34 percent) than sociodemographics of chronic pain in the United States, Johannes et males (27 percent), and tended to increase in frequency with age. al. surveyed 35,718 Americans 18 and older. Researchers designed a Lower back pain was the most commonly reported source of pain, secondary analysis to try to correlate chronic pain characteristics with occurring in 8 percent of respondents, with osteoarthritis-derived pain sociodemographic variables. Of all of the subjects surveyed, 27,035 occurring the second-most frequently (4 percent). Approximately one-half individuals responded. of chronic pain patients experienced pain every day, with an average pain Nearly 31 percent of respondents reported having chronic pain, defined rating of severe (>7 on a scale of 0 to 10) in 32 percent of respondents. as recurrent or long-lasting pain enduring for at least six months. These Logistical regression of all respondents suggested that low household prevalence estimates were then broken down by demographics. The income and unemployment significantly correlated with chronic pain incidence (Johannes, 2010). Pathophysiology of pain Without question, pain is a mystery. As a result, the topic generates The movement of pain signals is a highly complicated process involving intense interest and enthusiasm when considering treatment approaches. peripheral nerve activation, interactions with the spinal dorsal horn, Although it is evident that pain exists, it may be difficult to find its and activating the circuits connecting the spinal cord to supraspinal cause. Even in cases where a cause is found, there may be little or no structures. Ultimately, the nerve impulses excite nociceptive inputs at correlation between the extent of disease and the patient’s degree of the level of the spinal cord. suffering. A pathology that may bring excruciating pain to one person Although this appears to be part of a normal process of transmitting could be easily tolerated by another. In some cases, even if the cause is and interpreting pain, the system can undergo transformations when identified and removed, the suffering may continue. Pain is subjective pain is encountered over a period of time as an adaptive feedback loop. in nature, although if it exists, it is usually evident in a distressed patient Therapies aimed at disrupting any parts of the loop may be effective at (Goodman, 1983). diminishing or even abolishing the pain. The body’s pain-regulating system might be better referred to as To avoid interfering with normal sensory processing, fully the “nociceptive system” because that pain is simply the result of understanding pain circuits is critical to designing rational therapies nociception. Nociception is the act of encoding and processing noxious (Vanderah, 2007). stimuli encountered by the nervous system (Schaible, 2004). Potential causes of pain Because of the diversity in its source and patients’ perceptions, pain can some form of nerve pain over time. While some patients do stem from any number of insults to the body. While pain may be formed not experience any pain or symptoms, others develop pain, from an acute injury or illness, it can remain in the form of psychogenic tingling or numbness. Although these kinds of nerve problems pain after the original insult is removed. Some key sources of pain are can develop at any time, the incidence increases as a function of discussed below. age and duration of disease. The greatest incidence is in patients ●● Nerve pain: There are more than 100 different types of nerve who have had diabetes for at least 25 years and those with damage that may lead to nerve pain. A comprehensive discussion poorly controlled blood glucose levels. A higher frequency of of all of these is beyond the scope of this course. Nerve damage is symptoms also occurs in patients with high levels of cholesterol, quite common, with more than 20 million Americans afflicted with increased blood pressure, and those who are overweight (U.S. nerve damage to some extent. The incidence of nerve damage appears Department of Health and Human Services, 2013). to increase with advancing age. The most common cause of nerve ○○ A variety toxins and medications have the potential to damage damage (one in three cases) is related to diabetes. In another third of nerves and cause nerve pain. Examples of toxins include lead, patients, the cause of the nerve damage is never determined. Known mercury, thallium, pesticides, arsenic, acrylamide and ethanol. causes of nerve damage and nerve pain include (WebMD, 2016): Further, a number of medications may cause nerve pain. Some ○○ Various autoimmune diseases can lead to symptoms of nerve key examples include various chemotherapeutics (vincristine, pain and nerve damage. Some implicated autoimmune diseases cisplatin), isoniazid, certain antimicrobials (dapsone, include multiple sclerosis, Guillain-Barré syndrome, myasthenia metronidazole, levofloxacin), amiodarone, thalidomide, and gravis, lupus and inflammatory bowel disease (Medical News hydralazine (The Foundation for Peripheral neuropathy 2016). Today, 2016). ○○ Diseases that affect motor neurons, including amyotrophic ○○ In addition to its many deleterious effects, cancer can cause lateral sclerosis, have the potential to cause nerve pain. nerve pain and damage in a variety of ways. In some cases, Investigators at the Frenchay Hospital in Bristol, United tumors may actually press up against or crush nerves. In other Kingdom, evaluated the incidence of nerve pain in 42 patients instances, certain cancers may lead to nutritional deficiencies with motor neuron disease. They determined that of those affecting nerve function. Certain radiation and chemotherapy patients, 27 experienced significant pain. The etiology of this regimens can also lead to nerve pain in some patients (Mayo pain and its treatment are unclear (Newkirk, 1985). Clinic, 2017). ○○ Sustained low vitamin B12 levels can lead to nerve damage and ○○ Anything leading to trauma or nerve compression can lead to pain. Symptoms may include confusion or dementia (in severe nerve damage and subsequent nerve pain. Examples include cases), depression, balance issues, numbness and tingling of pinched nerves, broken bones or carpal tunnel syndrome. extremities. Such nutritional deficiencies are often linked to ○○ According to a fact sheet published by the National Institutes excessive alcohol consumption or conditions that affect vitamin of Health’s National Institute of Diabetes and Digestive and absorption such as gastric surgery. (U.S. National Library of Kidney Diseases, nearly 70 percent of diabetic patients develop Medicine, 2016).

Page 85 Pharmacy.EliteCME.com ○○ Multiple infectious diseases have the potential to affect nerves ○○ Tendonitis: Tendonitis, or inflammation of the tendon, and cause nerve pain. Such diseases include Lyme disease, commonly occurs in the wrist and fingers, though it can affect varicella zoster, herpes simplex, HIV and hepatitis (Brizzi, any tendon. Tenosynovitis, or inflammation of the lining of 2014). the tendon sheaths, can also occur. These conditions are often ●● Chest pain: This is often described in terms ranging from a sharp, related to strain, injury or overuse, as well as chronic disease stabbing sensation to a dull ache, to a crushing or burning feeling. such as diabetes or rheumatoid arthritis (University of Rochester In some cases, the pain may move throughout the body, radiating Medical Center, 2018). down the arms. Several different conditions may lead to chest pain, ●● Knee pain: This is a very common complaint occurring in patients with many having little significance. Nonetheless, chest pain can of all ages. While it may have a sudden onset, often as a result of an also be associated with life-threatening conditions involving the injury or excessive exercise, it may also begin as a mild discomfort heart or lungs. and slowly worsen over time. Being overweight is a significant Differentiating between the various pains can be difficult, so chest risk factor for knee problems and associated pain. Knee pain can pains must be carefully evaluated by a qualified health professional be caused by a variety of insults, including arthritis, gout, bursitis, (Mayo Clinic, 2017). With chest pain, it is critical to determine and dislocation, joint infection, tendinitis, meniscus or ligament tear, treat the underlying cause of the pain instead of just focusing on strain, or sprain. Less commonly, knee pain can be caused by bone treating the pain itself. tumors (U.S. National Library of Medicine, 2018). ●● Burns: Pain attributed to burns is often present from a wide variety ●● Lower leg pain: The lower leg is a common pain site. Because of burn types as well as differing levels of severity. In general, burns lower leg muscles control the foot, changes in footwear or activity are categorized into three types: level can lead to lower leg pain. While increases in activity levels ○○ First-degree burns are typically considered mild relative to are the leading cause of lower leg pain, there are a variety of other burns. First-degree burns affect only the epidermis and are medical conditions that can also contribute to the discomfort. characterized by pain and reddening. Following are some of the more common causes: ○○ Second-degree burns affect not only the epidermis but also the ○○ Muscle strain or fatigue typically results from increased activity, dermis. Second-degree burns are associated with pain, redness, and are often associated with minimal pain. Nonetheless, swelling and blistering. sudden, severe injuries can lead to muscular tears or ruptured ○○ Third-degree burns go beyond the dermis, affecting deeper tendons, which represent a more serious and painful situation. tissues. Patients with third degree burns have white or ○○ Medial tibial syndrome, also known as shin splints, is a blackened, charred skin that may be numb. common injury, often affecting runners and jumpers. The pain is Burns can be a result of contact with dry heat (fire), wet heat felt where the calf muscles attach to the bone. Stress fractures of (steam), radiation, heated objects, the sun, electricity or chemicals. the tibia are another condition often seen in these same patients. The degree of pain experienced may not be related to the severity ○○ While tendonitis of the lower leg can strike anyone, it is most of the burn; some of the most serious burns may be painless, while commonly diagnosed in sports overuse-type injuries. Tendonitis first-degree burns could be excruciating to some patients (Cleveland is an inflammation surrounding tendons, which can be found in Clinic, 2017). the lower leg. Tendonitis usually presents as pain that increases ●● Pinched nerves: Whenever surrounding tissues (bones, cartilage, with activity or stretching of the affected tendon. tendons, muscles) exert excessive pressure on a nerve, a pinched ○○ When leg veins are unable to properly return blood to the (compressed) nerve may result. In addition to causing pain, tingling, heart, edema of the leg occurs, sometimes accompanied with numbness or weakness, the pressure can disrupt the nerve’s pain or tenderness. One common problem is varicose veins. A function. A pinched nerve can occur at various sites in the body. potentially life-threatening cause of leg pain is known as deep Frequent examples include pressure on a root nerve in the lower vein thrombosis, which is a clot in a leg vein that can break off spine, leading to radiating pain down the back of the leg (sciatica). and then become lodged in the lung, brain or other organs. Carpal tunnel syndrome can cause a pinched nerve in the wrist ○○ Peripheral artery disease (PAD) is a condition where blood flow resulting in pain and numbness in the hand. In extreme cases, to the leg is restricted because of a narrowing of one or more surgery may be required to relieve the pain presented by a pinched of the arteries that supplies blood to the leg. PAD is associated nerve (Mayo Clinic, 2017). with leg pain while walking that resolves upon rest. PAD is ●● Foot pain: Pain can affect just about any part of the foot, including often also associated with a cold, pale limb with an increased the instep, arch, toes, heel or sole. There are many causes of foot sensitivity to pain. pain. Some situations pre-disposing patients to foot pain include ○○ Pregnant women are especially prone to foot and leg problems, aging, being overweight, spending extended periods of time on especially during their last trimester. Often, the pain is due the feet, congenital foot deformities, injuries, poorly fitted shoes, to increases in weight and hormonal changes that may cause inadequate shoe cushioning, and excessive walking or other the foot’s arch to compress to some extent. This increases the sporting activities. In addition, the following medical issues can workload on the leg, resulting in sore legs. Leg cramps may lead to foot pain: Gout; broken bones; arthritis; bunions; sprains; be caused by blood volume changes or from sciatic nerve plantar fasciitis; hammer toes; fallen arches; and stress fractures compression resulting from the expanded uterus. (U.S. National Library of Medicine, 2018). ○○ Miscellaneous medical conditions such as fibromyalgia, ●● Hand pain: The human hand is composed of a number of muscles, multiple sclerosis, rheumatoid arthritis and thyroid disease are ligaments and sheaths. Its complexity allows for a number of problems also sometimes associated with lower leg pain. Further, other that can lead to pain. Some of the more common ailments include: medications including diuretics and statins have been known to ○○ Arthritis: A degenerative joint disease called osteoarthritis cause lower leg pain. is the most common form of arthritis in older patients. It is ○○ Compression of the large sciatic nerve in the lower back can a slowly progressing disease that affects many parts of the lead to pain in the foot. This sort of pain typically starts in the body, particularly the hands. Associated pain can result from buttocks and is felt on the side and back of the leg. This is often inflammation, and other symptoms, such as stiffness and loss of caused by a herniated disc, spinal stenosis or irritation from a hand strength, can also occur. tight muscle (About.com: Podiatry, 2018). ○○ Ganglion cysts: These are soft, fluid-filled cysts that can mimic ●● Pelvic pain: Pain felt in the lowest part of the abdomen, or pelvis, other medical conditions or problems. Symptoms associated is usually referred to as pelvic pain. Pelvic pain may be the result with ganglion cysts include wrist pain, localized swelling with of issues in the reproductive, urinary or musculoskeletal systems. mild aching, weakness, and an apparent cyst that is rounded, Because the causes are diverse, the pain can be felt in different smooth, firm or tender. If you suspect ganglion cysts, a qualified ways; it can be sharp or dull in nature. Further, its intensity can health professional should conduct a proper diagnosis. If the range from mild to severe. On some occasions, pelvic pain can cyst grows and becomes painful or interferes with the hand’s move to the lower back, thighs or buttocks. Pelvic pain can occur functionality, treatment is typically warranted. acutely or chronically. Chronic pelvic pain is usually thought of as

Pharmacy.EliteCME.com Page 86 pain that has been present for more than a few months. Some people Lower back pain may also be a result of nerve or muscle irritation may experience pelvic pain only at certain times, such as after following a back injury, degenerative diseases, viral infections or sexual activity or during urination (Mayo Clinic, 2018). congenital abnormalities of the spine. In rare cases, lower back pain ●● Elbow pain: The elbow, a hinged joint found between the humerus can indicate a more serious medical problem, such as infections, and the radius and ulnar bones, is stabilized by ligaments on its tumors or kidney stones (National Institutes of Health- National front, back and sides. A number of issues can lead to pain, including Institute of Neurological Disorders and Stroke, 2017). osteoarthritis, rheumatoid arthritis, bursitis, trauma, infection, gout, Pain diagnosis can be complex because of its extremely personal and fractures, dislocations or repetitive strains leading to inflammation subjective nature. There is no available technology or test methodology (E Pain Assist, 2016). that can locate, characterize and measure pain with any degree of ●● Lower back pain: According to a fact sheet issued by the National precision. As a result, health professionals need to rely on the patient’s Institute of Neurological Disorders and Stroke, bone strength, description of their discomfort as a major part of a thorough pain muscle elasticity and tone can decrease as people age. Further, assessment. Defining the pain as dull/sharp, constant/on-off, burning or the discs in the spine lose their fluid and flexibility as they age, aching may be useful questions to ask when obtaining a pain history. decreasing their ability to cushion the vertebrae. Pain can then occur While some technologies may be of diagnostic value, it is usually best from heavy lifting or overstretching. More serious outcomes are to make a patient-specific diagnosis and treatment plan (U.S. National possible if a disc ruptures or bulges. Other causes of lower back Library of Medicine, 2011). pain include low fitness levels, pregnancy, obesity, occupational risks and overloaded backpacks in children. Pharmacologic treatment of pain Just like the causes of pain, available treatments are also diverse. as neuropathy, nerve damage (post-herpetic neuralgia), migraine Treatment modalities run the gamut from over-the-counter pain relievers and fibromyalgia. They may also be helpful adjuvants in lower to controlled substances to acupuncture, with many alternatives in back pain, arthritis and pelvic pain. The mechanism by which these between. Because of the many different pathologies, it is critical that if drugs address pain is not clearly understood, but they may modulate one approach fails, another is tried. When it comes to pain management, neurotransmitters that transmit pain signals. Usually, these drugs no single treatment is guaranteed to work as intended. Further, relief may take several weeks to take full effect, so some patience is required. be found using a combination treatment approach (National Institutes of Antidepressants are classified based on their chemical structure and Health-National Institute of Neurological Disorders and Stroke, 2017). how they work. Examples include (Mayo Clinic, 2016): Milder pain episodes can often be treated using over-the-counter ○○ Tricyclic antidepressants are likely the most effective medications including acetaminophen and non-steroidal anti- antidepressant used for pain. Tricyclics include amitriptyline, inflammatory agents (NSAIDs) (Freeborn, 2018): imipramine, clomipramine, nortriptyline and desipramine. Side ●● Acetaminophen is a common choice for treating fevers as well as effects of tricyclics may include blurred vision, drowsiness, easing pain. It works by acting on the areas of the brain that control dry mouth, constipation, weight gain and changes in blood pain and body temperature and is commonly used for headaches and pressure. Most patients find that they can take relatively low arthritis pain. Acetaminophen is associated with liver damage and doses of tricyclics (typically lower than the doses used to treat liver failure, particularly in high doses. depression) with only minimal side effects. ●● Non-steroidal anti-inflammatory agents (NSAIDs) such as ibuprofen ○○ In addition to tricyclics, other classes of antidepressants have and naproxen decrease pain and inflammation by decreasing become commonly used in pain treatment. Examples include: production of prostaglandins, hormone-like chemicals that are ■■ Serotonin and norepinephrine reuptake inhibitors (SNRI), involved in the body’s inflammatory response. These medications such as duloxetine, treat depression and pain at the same are helpful in types of pain with an inflammatory component, such dosages, and may be helpful adjuvants in patients with both as menstrual cramps or muscle sprains. Overuse of NSAIDs is comorbidities. associated with kidney disease and gastrointestinal bleeding. ■■ Selective serotonin reuptake inhibitors (SSRI), such as paroxetine and fluoxetine, do not appear to alleviate nerve If over-the-counter drugs are inadequate for pain control, stronger pain when used as monotherapy, but may help to boost the prescription medications may be indicated. Examples of stronger efficacy of tricyclics. medications include: ●● NSAIDs: Prescription non-steroidal anti-inflammatory drugs ●● Muscle relaxants: Although muscle relaxants, such as metaxalone, effectively reduce pain by decreasing inflammation. These have gained widespread usage as adjuvants in pain treatment, a medications are most commonly used in treating pain caused by 2012 review article showed no advantage of muscle relaxants over rheumatologic disorders, osteoarthritis, painful musculoskeletal placebo, either alone or in combination with non-steroidal anti- conditions such as back pain, and acute inflammatory conditions. inflammatory drugs. This study reviewed patients with rheumatoid Some common prescription non-steroidal anti-inflammatory arthritis, which causes chronic musculoskeletal pain. Nonetheless, drugs include diclofenac, etodolac, indomethacin, ketorolac, even short-term use of muscle relaxants was associated with naproxen sodium, piroxicam and sulindac. Side effects may significant adverse events, including drowsiness and dizziness. Use occur with large or extended doses, and most commonly include of muscle relaxants should be limited to short-term treatment of gastrointestinal symptoms, such as heartburn, upset stomach and acute musculoskeletal conditions (Richards, 2012). even gastrointestinal bleeding. In many cases, these adverse events ●● Anti-anxiety drugs: Benzodiazepines, including diazepam, can be avoided by taking the drug with food, milk or antacids alprazolam and lorazepam, can also reduce muscle spasms, and (Cleveland Clinic, 2016). are widely used in combination with other drugs to combat pain. ●● Narcotics: According to a 2002 article in the Journal of General A 2012 review article that examined several clinical studies Internal Medicine, chronic pain affects at least 50 million employing these drugs showed no advantage over a placebo, either Americans at an annual cost of $70 billion. This represents a alone or in combination with non-steroidal anti-inflammatory drugs. significant health burden to our society. While cancer pain therapy Investigators observed, though, a high incidence of significant has improved substantially, the treatment of non-malignant pain, adverse events when these anxiolytics were used. Key adverse primarily in the primary care setting, is often a challenge. This use events included drowsiness and dizziness. Due to the high risk of of narcotic drugs is less comprehensively studied than their use in abuse, benzodiazepines should be used cautiously, particularly in malignant settings and is much more controversial, with the fear of patients who are on opioid therapy (Mayo Clinic, 2016). addiction frequently cited as a barrier to their use (Olsen, 2002). ●● Antidepressants: Although not FDA-approved for treating many types of pain, antidepressants are an important modality in the Nonetheless, when used appropriately, narcotics are useful for treatment for many painful conditions. Antidepressants seem to treating pain that does not respond to weaker drugs. Narcotics work best for treating pain with a root in the nervous system, such should typically be used to treat acute pain for periods of less than seven days. Chronic pain patients should be on the lowest effective

Page 87 Pharmacy.EliteCME.com dose, for the shortest period necessary, with additional adjuvant satisfaction, fewer complications and reduced sedation. In addition medications from other drug classes to maximize pain control. to an initial loading dose, each program includes a demand dose Commonly used narcotics include codeine, fentanyl, morphine, level, a lockout interval, and a background infusion rate. Although oxycodone, tramadol, hydrocodone and hydromorphone. These other drugs are used, morphine is the most commonly studied medications are known to cause drowsiness, impaired judgment, intravenous compound used in PCA (Momeni, 2006). itching, constipation, nausea and vomiting. Nausea and vomiting ●● Nerve blocks: Several types of nerve blocks can be used for pain may be limited by taking narcotics with food (U.S. National Library management. Typically, a group of nerves referred to as a plexus of Medicine, 2015). or ganglion causes pain to a specific region or organ in the body. ●● Cortisone injections: These may be useful to treat pain and Pain can sometimes be blocked to that part of the body by injecting inflammation in a specific region of the body. In most cases, medication into that ganglion. This procedure is called a nerve cortisone injections are given directly into affected joints, such block. Nerve blocks are used in various ways to serve different as the ankle, wrist, shoulder, elbow, hip or knee. Typically, the purposes, including therapeutic nerve blocks to treat painful cortisone shot is accompanied by a local anesthetic. The total conditions, diagnostic nerve blocks to determine sources of pain, number of injections received in a one-year period is often prognostic nerve blocks to predict the outcome of treatment, and limited because of potential side effects including joint cartilage pre-emptive nerve blocks, which can sometimes prevent pain from deterioration (Mayo Clinic, 2017). a procedure. ●● Patient-controlled analgesia (PCA): This is a delivery system Like all medications and procedures, nerve blocks are not without typically used in hospitals and allows patients to self-administer risk. Common adverse events include elevated blood sugar, rash, analgesic medications to relieve their pain. Over the course of itching, soreness at injection site, bleeding and, rarely, death. Nerve the past 30 years, the use of this technology has been increasing blocks are most effective in cases where pain is emanating from a because of its proven advantages over conventional painkiller single or small group of nerves (WebMD, 2016). injections. These include improved pain relief, greater patient Acupuncture Acupuncture, part of traditional Chinese medicine, is one of the oldest Because of divergent study design, it is not straightforward to healing practices in the world. Acupuncture stimulates specific points in compare results obtained in different acupuncture studies. Main the body, usually by inserting thin needles through the skin. According differences included techniques used, comparison groups and outcome to the traditional Chinese medicine theory, this regulates the flow of measurements. Individual studies have suggested that acupuncture can vital energy (called qi) along pathways called meridians. help ease chronic pain conditions, particularly lower back pain, neck Based on the results obtained in a 2012 survey, between 2002 and 2012, pain and osteoarthritis. It is also noted that many factors can influence use rates for chiropractic, acupuncture, and massage among people who the effectiveness of acupuncture, including expectations and beliefs had no insurance coverage for these types of care increased, suggesting (National Institutes of Health-National Center for Complementary and an increased willingness to pay out-of-pocket. In 2012, partial insurance Alternative Medicine, 2016). coverage was more common than complete coverage for chiropractic In spite of the objective proof of efficacy, some success has been care, acupuncture, and massage (National Center for Complementary observed in cases where acupuncture is used alone or in combination and Integrative Health, 2017). with conventional treatment approaches. It may be appropriate to consider acupuncture in some cases of pain management. Summary and conclusions The source and pathophysiology of pain is as diverse as each patient’s mechanisms of pain and then apply this knowledge by carefully and characterization of the misery that he or she is experiencing. To further comprehensively determining individual patient needs before contributing complicate matters, with myriad of treatment options available, it to their care. Lastly, it is critical for pharmacists to be aware that, because is crucial that the effective pharmacist be familiar with them all. 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Cochrane Database Syst Rev. 2012 Jan 18;1:CD008922. doi: 10.1002/14651858. 10.1016/j.jpain.2010.07.002. Retrieved online March 5, 2018, from http://www.jpain.org/article/ CD008922.pub2. Retrieved online March 5, 2018, from http://onlinelibrary.wiley.com/ S1526-5900(10)00601-2/fulltext doi/10.1002/14651858.CD008922.pub2/abstract International Association for the Study of Pain. (2017). IASP Taxonomy. Retrieved online March 5, Schaible, H. G., Richter, F. (2004). Pathophysiology of Pain. Langenbecks Arch Surg. 2004; 389:237- 2018, from http://www.iasp-pain.org/Taxonomy 243. Mayo Clinic. (2018). Pelvic Pain. Retrieved online March 5, 2018, from http://www.mayoclinic.com/ Sikandar, S., Dickenson, A. (2012). Visceral Pain – the Ins and Outs, the Ups and Downs. Curr Opin health/pelvic-pain/MY00124 Support Palliat Care. 2012 March; 6(1): 17–26. Retrieved online March 5, 2018, from https://www. Mayo Clinic. (2017). Cancer pain, relief is possible. Retrieved online March 5, 2018, from http:// ncbi.nlm.nih.gov/pmc/articles/PMC3272481/pdf/ukmss-40443.pdf www.mayoclinic.com/health/cancer-pain/CA00021 The Foundation for Peripheral Neuropathy. (2016). Toxic Neuropathy. Retrieved online March 5, Mayo Clinic. (2017). Chest Pain. Retrieved online March 5, 2018, from http://www.mayoclinic.com/ 2018, from https://www.foundationforpn.org/what-is-peripheral-neuropathy/causes/toxins/ health/chest-pain/DS00016 The Foundation for Peripheral Neuropathy. (2016). Other Drugs. Retrieved online March 5, 2018, from https://www.foundationforpn.org/what-is-peripheral-neuropathy/causes/other-drugs/

Pharmacy.EliteCME.com Page 88 U.S. Department of Health and Human Services, National Institute of Diabetes and Digestive and U.S. National Library of Medicine, MedlinePlus. (2011). Chronic Pain: Symptoms, diagnosis & Kidney Diseases (NIDDK) (2013). Diabetic Neuropathies: The nerve damage of diabetes. Retrieved treatment. Retrieved online March 5, 2018, from http://www.nlm.nih.gov/medlineplus/magazine/ online March 5, 2018, from http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/ issues/spring11/articles/spring11pg5-6.html U.S. National Library of Medicine, MedlinePlus. (2018). Pain. Retrieved online March 5, 2018, from University of Rochester Medical Center. (2018). Hand pain & problems. Retrieved online March 5, http://www.nlm.nih.gov/medlineplus/pain.html 2018, from https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=85&Conten U.S. National Library of Medicine, MedlinePlus. (2018). Foot pain. Retrieved online March 5, 2018, tID=P00917 from http://www.nlm.nih.gov/medlineplus/ency/article/003183.htm Vanderah, T. W. (2007). Pathophysiology of Pain. Medical Clinics of North America. 2007; 91:1-12 U.S. National Library of Medicine, MedlinePlus. (2018). Knee pain. Retrieved online March 5, 2018, WebMD. (2016). Nerve pain and nerve damage. Retrieved online March 5, 2018, from https://www. from http://www.nlm.nih.gov/medlineplus/ency/article/003187.htm webmd.com/brain/nerve-pain-and-nerve-damage-symptoms-and-causes#1 U.S. National Library of Medicine, MedlinePlus. (2016). Anemia – B12 deficiency. Retrieved online WebMD. (2016). Pain management and nerve blocks. Retrieved online March 5, 2018, from http:// March 5, 2018, from http://www.nlm.nih.gov/medlineplus/ency/article/000574.htm www.webmd.com/pain-management/guide/nerve-blocks U.S. National Library of Medicine, MedlinePlus. (2015). Pain medications – narcotics. Retrieved online March 5, 2018, from http://www.nlm.nih.gov/medlineplus/ency/article/007489.htm PAIN MANAGEMENT AWARENESS FOR PHARMACISTS Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. Pain can be defined in general terms as: 7. Which of the following statements about pinched nerves is FALSE? a. A broken bone. a. They are a result of excessive pressure on a nerve. b. An unpleasant emotional and sensory experience. b. They can occur only in the legs. c. A discomfort that can always be verbalized. c. One common example is a pain radiating down the leg, called d. A response always caused by actual tissue damage or sciatica. pathophysiology. d. One type of pinched nerve in the wrist is called carpal tunnel syndrome. 2. Nociceptive pain can be described as: a. A process where stimuli are detected by peripheral nerve fibers. 8. Which of the following can cause lower back pain? b. A type of pain resulting from the activation of pain receptors on a. Nerve or muscle irritation. the surface of the body or within tissues. b. Viral infections. c. A kind of pain felt as a result of injury to internal organs. c. Abnormalities of the spine. d. All of the above. d. All of the above. 3. Which of the following statements about neuropathic pain is FALSE? 9. The most common side effect associated with the use of prescription a. It is a direct consequence of a lesion or disease affecting the non-steroidal anti-inflammatory drugs is associated with which somatosensory system. body system? b. One source is diabetes. a. Gastrointestinal. c. This type of pain is NOT associated with skin sensitivity. b. Lymphatic. d. This type of pain can be described as burning or electrical in c. Cardiovascular. nature. d. Hepatic. 4. Which of the following statements about the pathophysiology of 10. Which of the following statements about acupuncture is true? pain is true? a. Its basis is the depression of specific points in the body. a. Its cause is most always simple to determine. b. Parkinson’s disease is the most common ailment leading to b. Its cause can always be correlated to the extent of disease acupuncture use. present. c. Based on results obtained in recently conducted placebo- c. Pain is subjective in nature. controlled trials, acupuncture is a robust treatment modality, d. Similar pathologies lead to similar experiences in pain across resulting in complete pain relief in the majority of patients. patients. d. According to traditional Chinese medicine, it regulates the flow of vital energy (qi) along the meridians. 5. The most common cause of nerve damage is related to: a. Diabetes. b. Cancer. c. Hypertension. d. Multiple sclerosis. 6. Toxins associated with the incidence of nerve pain include: a. Arsenic. b. Acrylamide. c. Ethanol. d. All of the above.

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Page 89 Pharmacy.EliteCME.com Chapter 9: Patient Safety and Medication Errors

3 Contact Hours

By: Brad Gillespie, PharmD Author Disclosure: Bradley Gillespie and Elite Professional Education Questions regarding statements of credit and other customer service do not have any actual or potential conflicts of interest in relation to this issues should be directed to 1-888-666-9053. This lesson is $12.00. lesson. Educational Review Systems is accredited by the Universal Activity Number (UAN): 0761-9999-18-012-H05-P Accreditation Council of Pharmacy Education (ACPE) as Activity Type: Knowledge-based a provider of continuing pharmaceutical education. This Initial Release Date: January 11, 2018 program is approved for 3 hours (0.3 CEU’s) of Expiration Date: January 11, 2020 continuing pharmacy education credit. Proof of Target Audience: Pharmacists in a community-based setting. participation will be posted to your NABP CPE profile within 4 to 6 weeks to participants who have successfully completed the To Obtain Credit: A minimum test score of 70% is needed to post-test. Participants must participate in the entire presentation and obtain a statement of credit. Please submit your answers online at complete the course evaluation to receive continuing pharmacy Pharmacy.EliteCME.com education credit. Learning objectives At the conclusion of this knowledge-based learning activity, the Discuss additional reasons that pharmacists may cause a medication pharmacy technician will be able to: error, as defined by the Food and Drug Administration. Describe the significance of the Institute of Medicine’s 1999 and Identify the ways a patient may be responsible for initiating a 2006 report on medication errors. medication error. Define and distinguish between the following terms: safe Discuss the format for reporting a medication error. medication, drug safety, quality issues, medication errors and Identify ways to promote medication safety for patients. adverse drug events. Identify the six medication “rights” to improve patient safety. List each of the governing bodies involved in medication safety Discuss recommendations to improve patient safety during the (FDA, AHRQ, IOM, USP, NCC, ISMP, JCAHO). distribution phase of drug administration. Identify the types of medication errors made by pharmacists. Identify the consumer’s role in improving medication safety. Pre-assessment questions Prior to beginning work on this activity, test your baseline knowledge of “responsible self-treatment.” Which of the following are by answering the following questions. These questions may be repeated components of responsible self-treatment? in the final examination. a. There are no medications with guaranteed efficacy. ●● Which of the following is not a component of a safe medication b. Most medications are safe. system? c. The Internet pharmacy takes full responsibility for the patient’s a. Administration of the drug. safety. b. Preparation and dispensation of the drug. d. All medications act independent of each other. c. Selecting the generic equivalent that provides the best profit ●● FDA has determined that it is always safe to purchase medications margin. from Internet pharmacies. d. Selection and procurement of the drug by a pharmacy. a. True. ●● Many Internet pharmacies try to alleviate patient anxiety by b. False. noting that they are ordering their prescriptions under the concept Introduction Over the past decade, medication safety has been a big concern for showing that in a given week, half of U.S. adults will use prescription pharmacists who dispense or administer medications to patients. drugs, and 10 percent will take at least five different medications3. The Institute of Medicine (IOM) states that even though medication In 2006, the IOM reiterated the data, as it estimated that in any given errors can occur anywhere within a safe medication system, it occurs 1 week, four out of every five adults will use a prescription medicine, more frequently in the prescription and administration processes . over-the-counter (OTC) drug, or dietary supplement, and nearly one- Pharmacists need to be especially concerned with the prevention of third of adults will ingest five or more different medications4. errors during the process of preparing and dispensing medications. In 2001, Ernst and Grizzle estimated that the total cost of drug-related In 1999, the public learned about medication errors when the Institute of morbidity and mortality in the ambulatory care setting was more than $177 Medicine (IOM) released a report, “To Err is Human: Building a Safer billion, which is greater than the cost of the medications themselves5. Health System.” The IOM report disclosed that an estimated 44,000 to 98,000 deaths result from medical errors in hospitals alone, with 7,000 To avoid even unintentional harm to patients, health care professionals of the deaths related to medications2. The report was a revelation to must understand and abide by the expectations bestowed upon them. patients, families and the entire health care team. Patients and their families put their trust in health care professionals each time they enter a health care facility. It is our duty as pharmacists As pharmacists, it is imperative to understand the legalities, to serve and protect each patient by appreciating the power of each drug responsibilities and accountability that we have to patients while before dispensing any medication to a patient. participating in any component of the medication administration process. In 2004, the Food and Drug Administration (FDA) reported alarming data provided by the Slone Epidemiology Center at Boston University,

Pharmacy.EliteCME.com Page 90 Definitions related to the safety of medications The FDA defines “safe” medication as one whose benefits outweigh the 2006, a study showed that the most common medical errors are related to risks for patients27. The IOM uses the terms “drug safety” and “quality medications10. issues” in discussion of the safe, effective, appropriate and efficient use 6 Adverse drug events are defined as “any response to a drug which of medications . There are five components in a safe medication system: is noxious or unintended, and which occurs at doses normally used ●● Selection and procurement of the drug by a pharmacy. in humans for the prophylaxis, diagnosis, or therapy of disease11.” ●● Prescription and selection of the drug for the patient. According to the Agency for Healthcare Research and Quality (AHRQ), ●● Preparation and dispensation of the drug. more than 770,000 people are injured or die each year in hospitals from ●● Administration of the drug. 30 adverse drug events, which may cost up to $5.6 million each year per ●● Monitoring of the patient for its effect . hospital, depending on hospital size12. Although all of these items are not always under the watchful purview Although the data is alarming, this estimate did not include the effect of the pharmacist, he or she should be at least mindful, if not fully of adverse drug events on the length of the admission, malpractice and responsible, for all of these critical points. litigation costs, or the costs of injuries to patients. The AHRQ estimates A medication error is defined by the National Coordinating that the cost to U.S. hospitals to treat patients who suffer adverse drug Council (NCC) as “any preventable event that may cause or lead to events during hospitalization is between $1.56 and $5.6 billion annually35. inappropriate medication use or patient harm while the medication is in 7 According to the IOM, although adverse drug events are rising and the control of the health care professional, patient or consumer .” considered preventable, it is difficult to obtain an accurate measurement of In 1996, the NCC classified a medication error based upon the severity how often preventable adverse drug events occur in the various phases of of the outcome to ensure that all health care professionals use the same the drug use process. The IOM alludes to studies over the past few years terminology and to track errors in a consistent, systematic manner8. In estimating that anywhere from 380,000 to 800,000 preventable adverse July 2006, the National Academies of the IOM released a report that drug events occur annually – however, the committees believe that these claimed 1.5 million people are harmed annually by medication errors, are underestimates. According to the IOM committee, although the data which cost more than $3.5 billion a year9. This figure alone should be varies depending on the study, it is estimated that 1.5 million preventable adequate to get the attention of all practicing pharmacists. Further, in adverse drug events occur in the U.S. annually13. Governing bodies To have a better understanding of medication safety, it is important ●● AHRQ: The Agency for Healthcare Research and Quality (AHRQ) to understand that there are many agencies and organizations eager was established in 1989 as the Agency for Health Care Policy and to promote the safety of medications for patients and health care Research. Reauthorizing legislation passed in November 1999 professionals alike. Each is geared toward monitoring the efficacy of every established AHRQ as the lead federal agency on health care quality medication on the market, and providing education to the public and health research. AHRQ, part of the U.S. Department of Health and Human care professionals. Below are a few of the agencies and organizations that Services, is the lead agency charged with supporting research monitor adverse drug events and medication errors every year. designed to improve the quality of health care, reduce its cost, and HHS: The U.S. Department of Health and Human Services (HHS) broaden access to essential services. AHRQ has completed a vast amount of research on medication errors, medication safety and the is the government’s principal agency for protecting the health of all 20 Americans and providing essential human services, especially for those effect on patients . who are least able to help themselves. HHS encompasses more than 300 The National Academy of Sciences is an adviser on scientific and programs related to the health of Americans, including safe monitoring technological matters. It was chartered by the U.S. government under and administration of medications. the auspices of President Abraham Lincoln in 1863. In 1970, the For fiscal year 2014, the HHS budget is approximately $967.3 billion14. Institutes of Medicine (IOM) was founded as an independent, nonprofit There are two U.S. public health agencies under the HHS responsible organization that provides unbiased and highly authoritative information for the efficacy encompassing medications, the Food and Drug needed to guide government decision makers and the public. Although 15 the IOM is independent and works outside of the government, it serves Administration and the Agency for Healthcare Research and Quality . 21 ●● FDA: The Food and Drug Administration (FDA) is well known to as the health arm of the National Academy of Science . The unique the public and health care professionals. The FDA began as a single component of the IOM is that researchers and scientists are unpaid agency with a single chemist in 1862. In 1906, the Federal Food and volunteer experts, dedicated to promoting safe medication practices. Drug act was passed, but the FDA did not get its name until July IOM: The Institute of Medicine (IOM) encompasses experts and 193016. The FDA’s mission is to protect public health by assuring scientists tasked with improving the lives of millions of people around the safety, efficacy and security of human and veterinary drugs, the world using evidenced-based practice22. The IOM is mandated by biological products, medical devices, the nation’s food supply, Congress, through the Medicare Modernization Act of 2003 (Section 107 cosmetics and products that emit radiation17. (c)), to “carry out a comprehensive study of drug safety and quality issues 23 While FDA regulates and approves all medications, it does not in order to provide a blueprint for system-wide change .” usually conduct the research supporting these approvals. Within the One of the committees involved in promoting medication safety FDA, there are numerous groups responsible for ensuring patient within the IOM is formed from within the Center for Drug Evaluation safety, public knowledge and the prevention of medication errors. and Research (CDER) at FDA. CDER’s goal is to review the drug FDA has collaborated with other agencies to establish a standard information, safety surveillances and key aspects of the contributions of framework to electronically share important data about medications the pharmaceutical industry, academic research, Congress and patients to promote efficiency and safety.18 FDA has a subsidiary component, using medications24. called MedWatch, that is responsible for safety information and adverse event reporting19. For-profit organizations USP: The United States Pharmacopeia (USP) is the official public of high quality pharmaceuticals, as well as reliable pharmaceutical care, standards-setting authority for all prescription and over-the-counter for people throughout the world, for more than 185 years25. medicines, dietary supplements and other health care products NCC: In 1995, the National Coordinating Council (NCC) was manufactured and sold in the United States. USP sets standards for established to promote the safe use of medications. The mission of the the quality of these products, and works with health care providers to National Coordinating Council for Medication Error Reporting and achieve those standards. The USP standards are also recognized and Prevention (NCC-MERP) is to maximize the safe use of medications used in more than 130 countries. It has helped ensure the manufacture and to increase awareness of medication errors through open communication, increased reporting, and promotion of medication error Page 91 Pharmacy.EliteCME.com prevention strategies26. The NCC-MERP helps to heighten awareness of Further to that, NCC-MERP develops comprehensive literature reviews, medication reports within the health care system and provides education describing the safe use of medications. Its goal is to protect patients by on medication errors for consumers and health care professionals. not allowing any patient to be harmed by a medication error27. Nonprofit organizations promoting patient safety ISMP: The Institute for Safe Medication Practices (ISMP) began in updates its website, noting any incorrect data published in textbooks 1975 as a nonprofit organization that receives no advertising revenue and publications29. and is devoted entirely to medication error prevention and safe JCAHO: Joint Commission on Accreditation of Healthcare (JCAHO) 28 medication use . The ISMP took over management of the United States is a nonprofit organization that has been affiliated with monitoring Pharmacopeia-developed Medication Errors Reporting Program (USP- patients in some capacity since 1910. In 1965, Congress passed the MERP) in late 2008, re-branding it as ISMP MERP. Social Security amendment that incorporated a provision in which each ISMP MERP is designed for reporting the cause of medication errors hospital needs to be JCAHO-accredited to receive reimbursement for and provides recommendations for preventing future errors, always patient care from Medicare or Medicaid30. The goal of JCAHO is to identifying the erroneously used medication. In addition, the ISMP improve the safety and quality of care provided to the public through reports to the appropriate regulatory agency and the manufacturer of the the provision of health care accreditation and related services that company. To assess whether any medication has been incorrectly listed support performance improvement in health care organizations. anywhere, the Institute for Safe Medication Practices continuously Background As pharmacists, we enter the profession so that we may care for others, said that nearly 5 percent of errors reported to the national database for and to ensure that no harm comes as a result of this care. Although one’s medication errors from 2004 to 2006 involved medication abbreviations, intentions may be good while caring for a patient, medication errors do and the majority (81 percent) occurred during the prescribing phase31. occur on a daily basis, often at the expense of the patient. Based upon the study of nearly 30,000 abbreviation-related medication Regardless of the circumstances, while caring for another, it is important errors, JCAHO in 2005 initiated the “Official Do Not Use List” that to remember: “I am here to care for this patient and family; they have put was implemented in the hospitals nationwide (See Table 1)32. Of their trust in me.” We must remember to treat each patient as we would the common abbreviations used by many experienced health care want our loved ones to be cared for while in the hands and at the mercy of professionals, “QD” for “once daily” was associated with more errors the health care system. than any other abbreviation, followed by “U” for units (13.1 percent), Throughout our health care system, with today’s economic realities, “cc” for milliliter (12.6 percent) and “MSO4” or “MS” for morphine 28 professionals encounter shortages in their departments. Although it sulfate (9.7 percent) . The “Official Do Not Use List” is being used by may induce more stress in the workplace, that should not affect safe health care professionals nationwide, and it was also incorporated into 32 medication practices and pharmaceutical care. JCAHO’s patient safety goals . To bring change to the system, it is imperative to recognize the The ISMP recommends that health care professionals do not stop at components that contribute to medication errors. According to McLeod the minimum guidelines of JCAHO standards on abbreviations to (2007), the Joint Commission Journal on Quality and Patient Safety has avoid medication errors. Since 2006, the ISMP has offered a more comprehensive list that can be accessed on the Internet33. Types of medication errors involving health care professionals According to FDA, medication errors contribute to at least one death ●● Administering. every day, and injure approximately 1.3 million people annually in the ●● Monitoring the patient for side effects and adverse drug events. United States. Between 1993 and 1998, the FDA completed a study Additionally, FDA has provided other common causes of medication in which it found that the most common medication errors were the errors35: following: ●● Poor communication between doctors, nurse practitioners, nurses or ●● Administration of an improper dose of medicine, accounting for 41 pharmacists. percent of fatal medication errors. ●● Ambiguities in the product name, directions for use, medical ●● Administration of the wrong drug, accounting for 16 percent of fatal abbreviations or the legibility of the writing. medication errors. ●● Poor procedures and techniques. ●● Administration of medicine using the wrong route of administration, ●● Patient misuse because of poor understanding of the directions for accounting for 16 percent of fatal medication errors. use of the product. Almost half of the fatal medication errors occurred in people over the Again, pharmacists will often find themselves in a position to rectify age of 60. Older people may be at greatest risk for medication errors many of these trouble points in the medication process. because they often take multiple prescription medications34. With the pharmacist’s combination of training and experience, we are often in In 2006, new data confirmed the FDA’s study of 1990, stating that the an ideal position to identify and correct these types of errors and have a most common medication errors included nurses administering the favorable impact on overall patient well-being. wrong medications or wrong dose in an intravenous drip, physicians prescribing drugs that could cause a dangerous interaction with patient’s The FDA has stated that a medication error can occur during any of the 35 other medications, and pharmacists dispensing 100-milligram tablets following components of the drug-use process : when 50-milligram tablets were prescribed36. Through training and ●● Prescribing. intense attention to detail, pharmacists can work to eliminate errors ●● Repackaging. directly under their purview. And they are also well positioned to ●● Dispensing. collaborate with nurses and prescribers to help reduce the incidence of most errors in the prescription or administration of medications. Types of medication errors initiated by a patient Although health care professionals have made many medication Patients may perceive that a medication is simply a “quick fix” errors over the years, an error can also be committed intentionally or to a problem; as pharmacists, we need to teach them about each unintentionally by the patient. The first potential problem as noted by the medication’s purpose, potential side effects, drug-drug interactions, IOM in 2006 is that 50 percent of patients do not take their medications drug-food interactions and safety concerns. Patients should also be as prescribed10. As pharmacists, we have to change the way that we reminded that before using any OTC medication or herbal product, they communicate with our patients, sharing our education and knowledge in should check with their doctor or health care practitioner because those the hope that they will take their medications as prescribed, safely. products may interact with current medications and health conditions in the same manner as other medications. Pharmacy.EliteCME.com Page 92 Another potential problem is drug abuse. In 1999, the National Institute into the importation of medications from various countries, focusing on Drug Abuse (NIDA) reported that 4 million Americans 12 years or on the safety of the medication and the potential efficacy of these older had used a prescription medication for non-medical reasons37. imported medications for patients. The FDA investigation discovered Therefore, it is incumbent on the pharmacist to be aware of this fact and the following: assess each patient who may abuse a prescriptive or non-prescriptive Of the 2,069 drug orders examined, 88 percent appeared to be medication provided to them. prescription medications available in the United States. The A third potential medication error initiated by a patient is purchasing remaining 12 percent were dietary supplements, had illegible a medication, with or without a prescription, on the Internet. A patient or incomprehensible labeling, or were not available in the U.S. may have a preconceived notion that he or she wants or needs to be on “The most surprising finding was the motivation of patients to use a certain medication after reading or hearing an advertisement from a Internet pharmacies. FDA investigators believed that many people were not buying the drugs to save money, but to bypass the need for pharmaceutical company. If the patient’s primary care physician refuses 40 to write a prescription, a patient often can purchase the medication online a prescription .” without a prescription. In other cases, Internet pharmacies are abused by FDA recommends that patients can purchase medications safely online patients who have tendencies towards self-medication, not believing that if they are purchased through a pharmacy physically located in the they need the guidance of a qualified prescriber. United States. It also said the following medications should never be Some websites and companies attempt to alleviate patients’ concerns purchased online or from a foreign source because safety controls are about the practice by noting that they are ordering under the concept of often bypassed, placing patients at risk for adverse drug events: “responsible self-treatment”: ●● Accutane (isotretinoin) – indicated for the treatment of severe, ●● The term “self-treatment” means that the patient takes responsibility recalcitrant nodular acne. for the results obtained by controlling their own access to medication. ●● Actiq (fentanyl citrate) – indicated for the management of severe Responsible self-treatment assumes that the patient owns the cancer pain in patients who are tolerant to opioid therapy. information on an accepted preparation, and realizes the following: ●● Clozaril (clozapine) – indicated for the management of severe ○○ There is no such thing as an absolutely safe medicine. schizophrenia in patients who fail to respond to standard drug ○○ There are no medicines with guaranteed efficacy. treatments for schizophrenia. ○○ Any medicines accepted simultaneously can interact positively ●● Humatrope (somatropin for injection) – indicated for the or negatively with each other. treatment of non-growth hormone-deficient short stature. ●● Lotronex (alosetron hydrochloride) – indicated for the treatment According to the World Health Organization (WHO), responsible self- of severe irritable bowel syndrome in women. medication is a practice where patients can treat their conditions and ●● Mifeprex (mifepristone or RU-486) – indicated for the medical ailments using medicines that are approved and available in their region termination of early intrauterine pregnancy. without a prescription. Further, these medications must be proven to be ●● Plenaxis (abarelix for injectable suspension) – indicated for the safe and effective. This WHO definition does not seem to align with the treatment of advanced symptomatic prostate cancer in men who are 38 message inferred by Internet pharmacies promoting this practice . not able to receive other types of treatment. It is unfortunate that there are unprofessional, misleading and illegal ●● Thalomid (thalidomide) – indicated for the acute treatment of the sites available to encourage and promote the purchase of more cutaneous manifestations of moderate to severe erythema nodosum than 1,800 medications, including high-risk medications such as leprosum. Viagra, Vicodin and Xanax. These sites sometimes even provide a ●● Tikosyn (dofetilide) – indicated for the maintenance of normal “consultation” with a physician for the patient to obtain a prescription sinus rhythm in patients with certain cardiac arrhythmia. for a narcotic or other dangerous medications. ●● Tracleer (bosentan) – indicated for the treatment of severe Another reason why patients may consider purchasing a medication pulmonary arterial hypertension. online is concern about their rising medication costs. It is estimated ●● Trovan (trovafloxacin mesylate or alatrofloxacin mesylate that 4 percent of Americans have purchased their medications online39. injection) – an antibiotic administered at in-patient health care Because other countries do not regulate their medications to the settings for the treatment of severe, life-threatening infections. standards of the FDA, the agency conducted a research investigation ●● Xyrem (sodium oxybate) – indicated for the treatment of cataplexy in patients with narcolepsy41. Reporting a medication error If a medication error should occur in any format, as a registered According to the ISMP MERP program43, all health care professionals pharmacist, you have a professional, ethical and legal obligation to should report actual or potential medication errors that occur due to any report it to the appropriate authorities. Within the United States, the of the following reasons: Medication Error Reporting program (MER) and the FDA work in ●● Errors in the prescribing, transcribing, dispensing, administering conjunction to monitor the efficacy of each medication to prevent future and monitoring of medications and vaccines. medication errors. Since March 13, 2003, the FDA has required that all ●● Wrong drug, wrong strength, or wrong dose. actual and potential medication errors must be submitted to the agency ●● Wrong patient. within 15 calendar days42. Additionally, FDA reviews medication ●● Confusion over look-alike/sound-alike drugs or similar packaging. error reports that come from drug manufacturers using the MedWatch ●● Wrong route of administration. reporting system and ISMP MERP. ●● Calculation or preparation errors. The following organizations are obligated to track medication errors: ●● Misuse of medical equipment. ●● FDA – Accepts reports from consumers, health professionals It should be noted that a potential medication error is considered a and drug companies about products regulated by FDA, including “near-miss.” Consider this example: drugs and medical devices, through MedWatch, the FDA’s safety An order for a fourth dose of medication to be administered to a information and adverse event reporting program. patient is listed on a medication administration record (MAR). Prior ●● Institute for Safe Medication Practices (MERP) – Accepts reports to administration, the pharmacist reviews the chart and notes that from consumers and health professionals on medications and the medication was supposed to be discontinued after the third dose. publishes Safe Medicine, a consumer newsletter on medication Based on the pharmacist’s vigilance, the mistake is averted. 43 errors . This potential dosing error would be considered a near-miss, because ●● Quantros – MedMARX is an anonymous medication error reporting the potential was present for an error but it did not occur and the patient program used by hospitals that was developed by USP but managed did not receive the incorrect medication. by Quantros since late 200844. It is recommended that pharmacists adhere to the following reporting methods for an actual or potential medication error in a confidential and anonymous format45:

Page 93 Pharmacy.EliteCME.com ●● ISMP Medication Errors Reporting Program (MERP): 800-233- the FDA received in excess of 95,000 reports of actual or potential 7767 or https://www.ismp.org/orderforms/ERP_Portal.asp medication errors47. ●● U.S. Food and Drug Administration’s MedWatch Reporting FDA defines serious as any adverse event that is fatal, life-threatening, Program: 800-FDA-1088 or https://www.accessdata.fda.gov/scripts/ or associated with a disability, hospitalization or congenital anomaly48. medwatch/medwatch-online.htm The ISMP reports medication errors through a variety of newsletters to Once a medication error has been reported, the FDA’s Office of Post ensure that all health care professionals are properly targeted, regardless Marketing Drug Risk Assessment (OPDRA) will review and classify of their practice setting66. the taxonomy of the medication error using a system developed by In addition, it is imperative to thoroughly complete all reporting forms the National Coordinating Council for Medication Errors Reporting 46 to ensure the provision of appropriate data to FDA. Failure to do so and Prevention (NCC-MERP) . It is important to understand that the may lead to a delay in the investigation of the medication involved and FDA receives an abundance of reports on cases and therefore will only the reasons why the problem occurred, impeding the agency’s ability to review reports that are properly completed. Between 2000 and 2008, warn and prevent future episodes. See Table 2 for recent examples of drug safety communication advisories from FDA49. Promoting medication safety The IOM is the innovative leader in eliciting change in America’s ○○ Although some medications are contained in blister packages, medication safety guidelines. Since the IOM released data in 1999 to this is the exception, not the norm. health care professionals and the public, government agencies such as FDA ●● Patients should maintain a list of all prescription and have collaborated with the IOM to promote change. After the 1999 report, nonprescription treatments that they take and review the document FDA encouraged the IOM to review the current data and provide factual, with their health care providers to ensure that there are no potential concrete suggestions to promote medication safety for all Americans. drug interactions. Because errors are preventable, all pharmacists should take responsibility ●● Patients need to become responsible for reading, understanding and and accountability for all of their actions to ensure medication safety. abiding by the medication instructions60. In 2006, an IOM report requested that U.S. government agencies Although the IOM has provided many recommendations for U.S. take the lead in implementing steps to reduce medication errors, with government agencies to implement, the first step in promoting precise deadlines and recommendations. The IOM estimated that the medication safety is to allow and encourage each patient to take a more government should expect to spend $100 million annually to research active role in his or her own medical care. In the past, many patients the most useful and cost-effective ways to reduce medication errors36. and their families thought they would be perceived as disrespectful or The 2006 IOM recommendations (and response to them, where rude if they questioned their health care practitioner. However, a new applicable) were: way of thinking, according to the IOM 2006 brief report, is to promote a ●● FDA and the Agency for Healthcare Research and Quality should be partnership between the health care provider and the patient. charged with working with the pharmaceutical industry to address To initiate and implement this paradigm shift, doctors, nurses, and problems with drug labels and packaging by the end of 2007 and pharmacists need to communicate with patients by listening, consulting possibly implement standardized drug names and labels. and educating them appropriately about each of their medications at ○○ FDA acted on this in 2008, shifting increased responsibility to various stages of their care37. 50 the Office of Surveillance and Epidemiology . It is a wonderful idea, but many practitioners argue that restrictive ●● By 2008, all health care providers were to develop a plan to reimbursement by insurance companies, Medicaid and Medicare make it transition to electronic prescribing systems. difficult to spend a large amount of time with each patient. Many times, ○○ A report from Office of the National Coordinator for Health these professionals assume that another professional will spend the quality IT (June 2012) estimated that 45 percent of new and renewal 51 time that each patient deserves. It is a vicious cycle, but pharmacists can be prescriptions were sent electronically in 2012 . the leaders in turning it around by promoting quality communication. ●● By 2010, all health care providers were to begin using electronic prescribing systems. The governing agencies encourage health care professionals to keep up- ○○ The same report noted that 48 percent of U.S. physicians now to-date on the latest information on available technological advances. use electronic prescribing systems, compared to only 7 percent For instance, the IOM states in its 2006 brief report that it is impossible in December 200851. to remember every detail about a medication; therefore, it recommends ●● The National Library of Medicine should create a central online health care professionals use a point-of-care reference to assess 37 database for consumers to find information on medications and components of the desired medication . work with FDA and CMS to consider creation of a nationwide As a result of the IOM recommendations, there have been numerous telephone hotline for patients who cannot read printed information. positive outcomes designed to enhance patient safety. Some examples ○○ The National Library of Medicine manages a suite of drug include: information portals to provide consumers with information ●● The Center for Quality Improvement and Patient Safety (CQuIPS) on drugs, herbs and supplements52. Patients can call the FDA has been established at AHRQ to integrate patient safety into the Division of Drug Information (DDI) for drug information by broader quality framework, conduct research on how to reduce telephone at 855-543-3784 or 301-796-340053. medical errors, and educate patients about their safety. ●● All health care providers should report medication errors to patients ●● National summits have been conducted, including AHRQ’s Patient and family members, regardless of whether harm occurred. Safety Research and Practices Summit (September 2000), the ●● Pharmaceutical companies should disclose all clinical trial results Food and Drug Administration’s Drug and Device Safety Summit and limit the practice of providing physicians with free samples of (throughout 2001), and the Department of Veterans Affairs’ (VA) medications because the samples are poorly regulated. Patient Safety Practices (September 2001). ○○ Many scientific journals require the posting of all clinical ●● The Health Care Financing Administration (HCFA, now the trials prospectively (as well as results, when available) as a Centers for Medicare and Medicaid Services [CMS]) is considering condition for publication. The value of this transparency should regulations requiring hospitals participating in Medicare to have strengthen the science and preserve the integrity of the medical ongoing medical error programs in place. literature54. Although some new limitations are in place, ●● The Office of Personnel Management (OPM) will require all pharmaceutical companies still distribute samples. plans in the federal employee health benefits program to seek ●● Pharmaceutical companies should package pills in blister packs accreditation that includes the evaluation of patient safety and to simplify identification and make it easier for consumers to programs to reduce errors. remember whether they took a dose. ●● The VA and Department of Defense (DOD) are leaders in computer order entry systems55.

Pharmacy.EliteCME.com Page 94 Recommendations for improving medication safety during the dispensing phase It is imperative that pharmacists adhere to the recommendations and If the pharmacist is not familiar with a medication, he or she should guidelines of our governing agencies to improve our medication look it up in a drug reference before beginning the process of dispensing practices. This can ensure that pharmacists are more conscious about the medication. The pharmacist must never assume that the prescriber is their actions before they dispense a medication to a patient. fully aware of the medication classification, use, safe dose, side effects, All pharmacist programs emphasize the six medication “rights” before drug-drug interactions, drug-food interactions and other implications. administering any medication: There are so many medications on the market that it is impossible for ●● The right patient. anyone to fully understand the implications of all drugs that might be ●● The right medication. prescribed to a patient. ●● The right dose. In November 2005, the FDA mandated that all prescription drug ●● The right route. information had to be submitted in a searchable electronic format database ●● The right time. to provide information for health care professionals and the public48. ●● The right documentation. In January 2006, the FDA revised the format in which prescription Before dispensing any medication, one of the first precautionary steps drug inserts were to be written and laid out. During that time, the FDA to take is to always check the physician’s orders against what is known mandated that inserts be written in a clear, concise manner to provide about the patient: What is the disease; are there any concomitant each health care professional the most up-to-date and easy-to-read medications that could lead to a drug-drug interaction; does the patient information to best promote patient safety42. have any co-morbidities that could complicate the use of the medication? Every year, JCAHO releases the updated National Patient Safety Goals, Second, the pharmacist is responsible for verifying that the prescriber has customized to various inpatient and outpatient settings, to which hospitals ordered the correct medication at the correct dose, to be administered at and clinics must abide by for accreditation. In June 2007, the board of an appropriate frequency. Even though there are technologies in place commissioners at JCAHO approved the 2008 National Patient Safety to assess and scrutinize the prescriber’s orders, never assume that the goals. The third goal involves the safety of medications: available systems will detect a problem or that another colleague verified ●● Identify and, at a minimum, annually review a list of look-alike/ the order. It is better and safer to check and re-check the order. sound-alike drugs used by the organization, and take action to Once the medication on the record matches the correct, safe dose that prevent errors involving the interchange of these drugs. the prescriber ordered, the pharmacist is responsible for ensuring that ●● Label all medications, medication containers (for example, syringes, the correct quantity of the correct medication at the correct dose is medicine cups, basins) or other solutions on and off the sterile field. accurately provided to the patient at the correct time. ●● Reduce the likelihood of patient harm associated with the use of anticoagulation therapy56. Bar code label rule In February 2004, the FDA issued a final rule requiring bar codes on be illegible. Pharmacists are trained to verify the medication with the certain drugs, biologicals and blood product labels57. According to 21 ordering physician instead of making educated guesses about what the CFR 201.25, “manufacturers, repackers, relabelers, and private label doctor meant. The IOM promotes e-prescription software programs distributors of human prescription drug products, biological products, because they can also help by assessing for drug allergies, drug-drug and over-the-counter (OTC) drug products that are dispensed pursuant interactions and overly high doses during the writing phase to prevent to an order and are commonly used in hospitals are subject to the bar potential medication errors37. code requirement, regardless of the method they use to distribute their 58 According to the Health Care Quality Modernization, Cost Reduction, drug products .” and Quality Improvement Act, prescribing errors were reduced by After the initiation of bar codes, the FDA estimated that their 95 percent and hospital costs lowered by 13 percent with automated implementation would help prevent nearly 500,000 adverse events and prescribing. The government has also included e-prescribing adoption transfusion errors, while saving $93 billion in health costs over 20 years59. in the Medicare Prescription Drug Improvement and Modernization Act With the advances in technology, the governing bodies also of 2003, and many payors are sponsoring e-prescribing initiatives for recommended that facilities incorporate electronic prescriptions by their providers. E-prescribing can increase patient safety by preventing errors, improving continuity of care, and by tracking and providing 2010 to avoid mistakes with handwritten prescriptions. Over the years, 60 many pharmacists have complained that physicians’ handwriting can feedback about adverse events . Drug name confusion FDA collaborates with the ISMP to assess and review potential reported where an 8-year-old boy died because the pharmacist filled the medications that look alike, sound alike and have labels that could cause a opiate, methadone, rather than the intended methylphenidate66. 61 medication error . FDA is adamant about eliminating potential confusion As a pharmacist, it is imperative to recognize the vast array of potential because of the name, appearance or sound of the medication. The goal is errors from drug name confusion: the data is staggering. In addition, to prevent errors during the procurement of a medication. according to Meadows, other examples of drug name confusion The last time a medication name was changed was in 1994: Levoxine, reported to FDA include: used to treat hypothyroidism, was often confused with the heart ●● Serzone (nefazodone) for depression and Seroquel (quetiapine) for medication Lanoxin. Therefore, FDA recommended a name change. schizophrenia. Subsequent to this request, Levoxine was changed to Levoxyl66. ●● Lamictal (lamotrigine) for epilepsy, Lamisil (terbinafine) for nail It should be noted that after drugs are approved, FDA monitors each infections, Ludiomil (maprotiline) for depression and Lomotil medication for errors caused by name confusion. If errors or confusion (diphenoxylate) for diarrhea. are noted, FDA informs health care professionals about it in an effort ●● Taxotere (docetaxel) and Taxol (paclitaxel), both for chemotherapy. to avoid additional problems. For example, FDA has reported errors ●● Zantac (ranitidine) for heartburn, Zyrtec (cetirizine) for allergies involving the administration of methadone instead of the prescribed and Zyprexa (olanzapine) for mental conditions. ●● Celebrex (celecoxib) for arthritis and Celexa (citalopram) for Metadate ER, (methylphenidate) for the treatment of attention deficit/ 66 hyperactivity disorder (ADHD). Unfortunately, there was a case depression . Drug labeling In January 2002, a study found that consumers tend to overlook on the product’s ingredients, uses, warnings, dosage, directions and important label information on OTC drugs. Four months later, in May proper storage66. 2002, FDA mandated a standardized “drug facts” label on foods and For example, during the fall of 2007, news media reports claiming that medications to ensure that consumers have the appropriate information parents were overdosing their children led many people to believe that Page 95 Pharmacy.EliteCME.com cough medications were no longer safe to administer to children under in the format for the labeling of prescription drugs to provide health 6 years of age. Pharmaceutical companies responded by changing the care professionals clear and concise prescribing information85. The IOM labels on all cough medications, telling parents to consult with their committee recommends that the drug industry and the appropriate federal doctor before giving a child under 6 years of age the medicine. agencies work together to improve nomenclature, which encompasses drug 37 In 2000, the FDA proposed a new package insert that was more user- names, abbreviations and acronyms . It is also is critical to teach patients to recognize that if the medication does not look right based upon its color or friendly and highlighted the critical information needed for physicians 10 prescribing products66. In January 2006, the FDA initiated new changes shape, they should never assume it is the correct, prescribed medication . FDA recommendations to improve medication safety On January 30, 2007, the FDA announced 41 initiatives to improve drug ●● Avoid the use of all potentially dangerous abbreviations and dose safety based on the recommendations of the IOM27. Among them were: expressions. (See Table 1 – The Do Not Use list.) ●● List all products by generic name. ●● Do not use trailing zeros (5 mg, never 5.0 mg). ●● Do not include the salt of the chemical when expressing a generic ●● Use leading zeros for doses that are less than 1 (0.3 mg, never .3 mg). name unless there are multiple salts available (i.e., hydroxyzine ●● Spell out the word “units.” hydrochloride and hydroxyzine pamoate). ●● Use the proper, approved standard abbreviations for dosage units. ●● Use brand names in upper case letters (i.e., LANOXIN, LASIX) to ●● Do not abbreviate names (do not use Mso4 for morphine). differentiate them from their generic cohort. ●● Use upper case and lower case letters (ie., HydrOXYzine and ●● Express suffixes that are part of the brand name (i.e., SR, SA, hydrALAZINE) to help distinguish look-alike products. CR) within both the generic name field and the brand name (i.e., ●● When the drug name, strength, dosage form and dosage units appear diltiazem XR). together, avoid confusion by listing the generic name first and provide a space between them62. Additional recommendations for pharmacists to improve medication safety In addition to ensuring that the previous recommendations are found it useful to develop and use one or more forms to support the implemented, pharmacists may be able to participate in implementing medication reconciliation process.) the following guidelines to promote patient safety, as incorporated in ●● Ensure that a complete list of the patient’s medications is JCAHO’s national safety goal. communicated to the next provider of service when a patient is referred or transferred to another setting, service, practitioner or In 2006, JCAHO initiated the medication reconciliation form to help 1 prevent medication errors. The medication reconciliation form is level of care within or outside the organization . implemented upon admission, transfer to another unit, and discharge from In the second national standard, JCAHO recommended the following to the facility to ensure that all home medications and discharge medications prevent a medication error during the communication phase86. are clearly stated to avoid an overlap or drug-drug interactions. The Pharmacists are often required to take verbal orders from a doctor or other requirements for JCAHO’s national safety goals include: prescriber or their representative over the telephone, or sometimes, even ●● Implement a process for obtaining and documenting a complete list in person. Before taking a verbal order over the telephone, the pharmacist of the patient’s current medications upon the patient’s admission to should gather all available data about the patient. When given a verbal the organization, with the involvement of the patient. This process order, the pharmacist must repeat each component of the order back to includes a comparison of the medications the organization provides the caller, which includes verbalizing the medication and spelling it (if to those on the list. (Note: While this safety goal does not require appropriate), reiterating the dose and the frequency of the medication. a separate form for the medication list, many organizations have Consumers’ role to improve medication safety FDA has been diligently attempting to eradicate or reduce medication ●● Keep a list of all medications, including OTC, herbals, dietary errors for patients in a very complex medical system. To promote supplements and any other substances. In addition, patients should medication safety, FDA recommends that consumers collaborate with continuously review their medications with their primary provider their health care providers to reduce errors. FDA urges consumers to because many people have more than one physician prescribing take the following steps66: medications to them. Patients should never assume that their ●● As a patient, know the most common type of medication errors that physicians collaborate on care for an individual patient. occur. The most vulnerable populations are children and elderly ●● If in doubt, never assume anything. Ask your health care providers patients over 60 years of age. According to another report in 2007 for clarification. by FDA, more than 700,000 people go to emergency rooms every To promote medication safety for the consumer, the IOM recommends year because of a medication interaction. In the same consumer the following for the pharmaceutical industry10: health information form, the FDA said that the most commonly ●● The Food and Drug Administration should help standardize the implicated drug causing unexpected medical problems for patients 27 text and design of medication leaflets so that consumers can easily is Coumadin (warfarin) . understand them. ●● Know the name of your medication and its purpose. FDA reiterates ●● The National Library of Medicine should create a website that that the patient should never take a medication just because “the is a comprehensive, understandable source of information about doctor said so.” drugs and fund a national telephone line for people who don’t have ●● Always read and understand the directions for taking each Internet access. medication safely and properly as prescribed. According to ●● Health care organizations should tell patients about medication Weiss (2006), more than 50 percent of patients do not take their errors made in their care, even if they were not hurt by the error. medications as prescribed10. Goals for the future Although progress has been made, more providers need to begin using As pharmacists, it is an exciting time to be involved in promoting e-prescribing systems, and all pharmacies should be able to receive patient safety by reducing the risks of medication errors. Over the years, prescriptions electronically. The Agency for Healthcare Research and governing bodies have made it apparent that they want to reduce and Quality (AHRQ) should take the lead in fostering improvements in IT eventually eradicate the risk of patients coming to harm in health care systems used in ordering, administering and monitoring drug usage. settings. As pharmacists, we must also do our part! Conclusion Although there are many variables that lead to medication errors in our pharmacists to promote patient safety. It is imperative to understand the complex medical system, there are multiple actions that we can take as Pharmacy.EliteCME.com Page 96 legal responsibilities and obligations that you have to patients you care No one ever wants to be a party in a medication error, especially for directly or indirectly on a daily basis. knowing that the errors can be disabling to a patient or even cause Each health care professional can take the initiative and rise above the death. It takes just a few extra minutes to ensure that each medication is shortcomings within our health care system to promote patient safety. safely prescribed, dispensed and administered to the patient. The governing bodies have provided an abundance of research and Remember: Each patient is an individual who has a story and a family; evidence-based practice recommendations to prevent and help eradicate do not jeopardize his or her safety and life. The next time, it could be the risk of medication errors. your loved one who is the patient. TABLE 1 Official Do Not Use List by JCAHO

Do not use Potential problem Use instead U (unit). Mistaken for “0” (zero), the number “4” (four) or “cc”. Write “unit”. IU (international unit). Mistaken for IV (intravenous) or the number 10 (ten). Write “International unit”. Q.D., QD, q.d., qd (daily). Mistaken for Q.O.D. Write “daily”. Q.O.D., QOD, q.o.d, qod Mistaken for Q.D. Period after the Q mistaken for “I” and the Write “every other day”. (every other day). “O” mistaken for “I”. Trailing zero (X.0 mg).* Decimal point is missed. Write X mg. Lack of leading zero (.X mg). Write 0.X mg. MS. Can mean morphine sulfate or magnesium sulfate. Write “morphine sulfate”. MSO4 and MgSO4. Write “magnesium sulfate”. # Applies to all orders and all medication-related documentation that *Exception: A “trailing zero” may be used only where required to is handwritten (including free-text computer entry) or on pre-printed demonstrate the level of precision of the value being reported, such forms32. as for laboratory results, imaging studies that report size of lesions, or catheter/tube sizes. It may not be used in medication orders or other medication-related documentation. TABLE 2 Drug safety communications Posted by the FDA January 1, 2012-April 26, 2013

Date Product(s) Safety issue April 26, 2013 Anti-seizure drug Potiga (ezogabine). Linked to retinal abnormalities and blue skin discoloration. March 14, 2013 Incretin mimetic drugs for type 2 diabetes Byetta, Bydureon Investigating reports of possible increased risk of pancreatitis (exenatide); Victoza (liraglutide); Januvia, Janument, and pre-cancerous findings of the pancreas from incretin Juvisync (sitagliptin); Onglyza (saxagliptin); Nesina, mimetic drugs for type 2 diabetes. Kazano (alogliptin); Tradjenta, Jentadueto (linagliptin). March 12, 2013 Zithromax, Zmax (azithromycin). Risk of potentially fatal heart rhythms. February 26, 2013 Sensipar (cinacalcet). Pediatric clinical trials suspended after report of death. February 20, 2013 Codeine. Safety review update of codeine use in children; new boxed warning and contraindication on use after tonsillectomy and adenoidectomy. 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April 29, 2013 at http://www.iom.edu/Reports/2006/The-Future-of-Drug-Safety-Promoting-and- jointcommission.org/assets/1/18/Do_Not_Use_List.pdf Protecting-the-Health-of-the-Public/Change-Drug-Safety-Policy-FDA.aspx 33. ISMP’s. List of Error- Prone Abbreviations, symbols, and dose designations. Accessed online April 30, 52. The Office of the National Coordinator for Health Information Technology. (November, 2012). Accessed 2013 at http://www.ismp.org/tools/errorproneabbreviations.pdf online on April 29, 2013 at http://www.healthit.gov/sites/default/files/us_e-prescribingtrends_onc_ 35. Stoppler, M (2006). The most common medication errors. Accessed online April 28, 2013 at http://www. brief_4_nov2012.pdf medicinenet.com/script/main/art.asp?articlekey=55234 53. U.S. National Library of Medicine. Drug information from the National Library of Medicine (2013). 36. FDA. FDA-101: Medication Errors. Accessed online April 28, 2013 at http://www.fda.gov/ Accessed online April 29, 2013 at http://www.nlm.nih.gov/learn-about-drugs.html ForConsumers/ConsumerUpdates/ucm048644.htm 54. FDA. Division of Drug Information (2013). Accessed online April 29, 2013 at http://www.fda.gov/ 37. Medication Errors Harm 1.5m U.S. Residents Annually: New Institute of Medicine Report Says Medical AboutFDA/CentersOffices/ News Today (25 July 2006).Accessed online April 28, 2013 at http://www.medicalnewstoday.com/ 55. Ross GS, Gross CP, Krumholz HM. Promoting transparency in pharmaceutical industry sponsored articles/47931.php research. Am J Public Health. 2012; 102:72-80 38. Youngkin, E., Sawin, K., Kissinger, J., & Israel, D. (2005). Pharmacotherapuetics; A primary care guide. 56. AHRQ. Standardizing Medication Error Event Reporting in the U.S. Department of Defense. Accessed (2nd ed.) Pearsons: NJ. online on April 29, 2013 at http://www.ahrq.gov/news/ulp/ptsafety/ptsafety4.htm 39. WHO. The role of the pharmacist in self-care and self-medication (2013). Accessed online, April 28, 57. Joint Commission. National Patient Safety Goals: Facts About the 2008 National Patient Safety 2013 at http://apps.who.int/medicinedocs/en/d/Jwhozip32e/3.3.html#Jwhozip32e.3.3 Goals. (2007). Accessed April 29, 2013 at http://www.jointcommission.org/PatientSafety/ 40. CBS News. Few Americans Buy Drugs Online (February, 2009). Washington. Accessed online, April 29, NationalPatientSafetyGoals/08_npsg_facts.htm 2013 at http://www.cbsnews.com/2100-204_162-648495.html 58. HHS. HHS Announces New Requirements for Bar Codes on Drugs and Blood to Reduce Risks 41. FDA: FDA Says consumers continue to buy risky drugs online. Self-medication a concern; FDA of Medication Errors (February, 2004). Accessed online on May 1, 2013 at http://www.fda.gov/ approved generics may be cheaper alternative. (November 1, 2007). Accessed Online April 29, 2013 at NewsEvents/Newsroom/PressAnnouncements/2004/ucm108250.htm http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109018.htm 59. FDA. Guidance for Industry: Bar code label requirements. Questions and answers (August, 42. FDA. FDA Consumer Safety Alert: Don’t Buy these Drugs Online or From Foreign Countries. (March 2011). Accessed April 29, 2013 at http://www.fda.gov/downloads/BiologicsBloodVaccines/ 2010) Accessed online April 30, 2013 at http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ GuidanceComplianceRegulatoryInformation/Guidances/UCM267392.pdf BuyingUsingMedicineSafely/BuyingMedicinesOvertheInternet/ucm202893.htm 60. Premiere, Inc.. FDA Rule Requires Barcodes on Drug and Blood Products to Help Reduce Errors 43. Meadows M. Strategies to reduce medication errors. How the FDA is working to improve medication (2006). Accessed online April 29, 2013 at https://www.premierinc.com/safety/topics/bar_coding/ safety and what you can do to help. FDA Consum. 2003 May-Jun;37(3):20-7 61. JCAHO. Electronic prescribing within an electronic health record reduces ambulatory prescribing 44. The National Medication Errors Reporting Program (ISMP MERP) (2013). Accessed online April 29, errors (October, 2011). Accessed online April 29, 2013 at http://www.ingentaconnect.com/content/jcaho/ 2013 at https://www.ismp.org/orderforms/reporterrortoismp.asp jcjqs/2011/00000037/00000010/art00007 45. Quantros- MEDMARX ADE Data Repository (2013). Accessed online April 29, 2013 at http://quantros. 62. FDA Statement: FDA Statement on Institute of Medicine’s Report on Preventing Medication Errors com/our-products/safety-and-risk-management-srm/medmarx-medication-database (July, 2006). Accessed online April 29, 2013 at: http://www.fda.gov/NewsEvents/Newsroom/ 46. National Coordinating Council for Medication Error Reporting and Prevention. Report a Medication PressAnnouncements/2006/ucm108695.htm Error. Accessed online November 8, 2007 at http://www.nccmerp.org/reportMedError.html 63. Institute for Safe Medication Practices. It’s Time for Standards to Improve Safety with Electronic 47. Thomas, M., Holquist, C., & Phillips, J. (October 2001). FDA Safety Page: Med error reports to Communication of Medication Orders. (Feb 2003). Accessed online April 29, 2013 at www.ismp.org/ FDA show a mixed bag. Accessed online on April 29, 2013 at http://www.fda.gov/downloads/Drugs/ Newsletters/acutecare/articles/20030220.asp?ptr=y DrugSafety/MedicationErrors/ucm115775.pdf PATIENT SAFETY AND MEDICATION ERRORS Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. Which of the following is not a component of a safe medication 6. Assume the scenario where a prescriber has written an order for system? three daily doses of lorazepam, 0.5 mg, to be administered at a. Administration of the drug. bedtime, with discontinuation after the third dose. When visiting b. Preparation and dispensation of the drug. the floor on the fourth night, the pharmacist notes that the nurse has c. Selecting the generic equivalent that provides the best profit taken a dose of lorazepam from the floor stock, and is preparing to margin. administer it to the patient. The pharmacist immediately recognizes d. Selection and procurement of the drug by a pharmacy. the potential error and stops the nurse from administering the dose. This situation could be described as: 2. According to FDA, medication errors can occur during which a. Lucky. component of the drug use process? b. A near-miss. a. The dispensing phase. c. A pharmacist overstepping his or her responsibility. b. The prescribing phase. d. A safe and efficient way to run a nursing unit. c. The repackaging phase. d. All of the above. 7. Before dispensing a prescription medication, the pharmacist should ensure that: 3. Medication errors contribute to how many deaths every day? a. No relevant drug-drug interactions are present with concomitant a. One. medications. b. Three. b. The prescriber has discussed alternative therapies with the patient. c. Five. c. The prescriber has written for a drug that has an acceptable d. Ten. generic substitution. 4. Many Internet pharmacies try to alleviate patient anxiety by d. The patient is able to pay his prescriber for services rendered. noting that they are ordering their prescriptions under the concept 8. Examples of look-alike, sound-alike drug names include which of of “responsible self-treatment.” Which of the following are the following: components of responsible self-treatment? a. Serzone and Seroquel. a. There are no medications with guaranteed efficacy. b. Celebrex and Celexa. b. Most medications are safe. c. Taxotere and Taxol. c. The internet pharmacy takes full responsibility for the patient’s d. All of the above. safety. d. All medications act independently of each other. 9. In an effort to reduce medication errors, FDA has suggested all of the following advice for consumers: 5. The following organizations are obligated to track medication errors: a. Be familiar with the most common medication errors. a. FDA. b. Know the name and purpose for each medication prescribed to you. b. Institute for Safe Medication Practices. c. Assume that the different specialists that you are seeing c. Quantros. communicate with each other. d. All of the above. d. Keep a list of all medications, supplements, herbs and vitamins that you are taking. 10. Which of the following is not on the JCAHO “Do Not Use List” for prescription drug orders? a. Trailing zero, e.g., x.0 mg. b. MS. c. BID. d. IU. RPAZ03PSE18

Pharmacy.EliteCME.com Page 98 Chapter 10: Pharmacist Responsibilities in the Management of Controlled Substances 1 Contact Hour

By: Bradley Gillespie, PharmD Author Disclosure: Bradley Gillespie and Elite Professional Education Questions regarding statements of credit and other customer service do not have any actual or potential conflicts of interest in relation to this issues should be directed to 1-888-666-9053. This lesson is $4.00. lesson. Educational Review Systems is accredited by the Accreditation Universal Activity Number (UAN): 0761-9999-18-014-H01-P Council of Pharmacy Education (ACPE) as a provider Activity Type: Knowledge-based of continuing pharmaceutical education. This program is Initial Release Date: January 11, 2018 approved for 1 hour (0.1 CEU’s) of continuing pharmacy Expiration Date: January 11, 2020 education credit. Proof of participation will be posted Target Audience: Pharmacists in a community-based setting. to your NABP CPE profile within 4 to 6 weeks to To Obtain Credit: A minimum test score of 70 percent is needed to participants who have successfully completed the post-test. obtain a credit. Please submit your answers either by mail, fax, or online Participants must participate in the entire presentation and complete the at Pharmacy.EliteCME.com course evaluation to receive continuing pharmacy education credit. Course overview This course provides a practice-focused discussion on the Controlled study pages. The answers to the questions in the scenarios are provided Substance Act. Please note that this course has been developed to be to enhance the learning of the concepts of the Controlled Substance Act. an engaging CE activity. The scenarios and questions toward the end The Final exam will cover the same concepts as outlined in the learning are provided as examples of application and are not answerable on the objectives and the scenarios. Learning objectives After the pharmacist has concluded this application-based activity, he or Become familiar with the appropriate DEA forms needed to she will be qualified and able to: document the transaction of controlled substances. Understand the role of the Drug Enforcement Administration in Describe the requirements of both electronic and paper-based regulating the use of controlled substances. controlled substance record keeping systems. Appreciate the importance of a controlled system of distribution to Examine the requirements for inventorying controlled substances. best manage transactions involving controlled substances. Understand that there are requirements for Internet pharmacies Develop a general understanding of how to schedule controlled dispensing controlled substances that are unique and apart from substances. those needed to dispense non-controlled substances. Pre-assessment questions Before beginning this activity, test your pre-course knowledge by a. File DEA Form 106 within one business day with the DEA. answering the following questions. Please be aware that these questions b. Immediately replace all missing stock. will also be included as part of the CPE final examination. c. Consider a more secure alarm system. 1. Jim Walters, PharmD, has completed his residency in community d. Complete full interviews with all employees to rule out their involvement. practice and is preparing to open his own pharmacy. Before he can begin to dispense controlled substances in his pharmacy, he will 3. Davies’ Community Pharmacy is preparing for its biennial need to complete which of the following tasks? inventory of controlled substances. While Steen Davies, PharmD, a. Register his pharmacy with the DEA, using DEA Form 224. has an idea of how this should be conducted, there are a few key b. Display a certificate indicating this registration in a prominent things that he should keep in mind when completing this important place. count of all controlled substances. Some of things that he should c. Order schedule II controlled substances for inventory using think about when planning the specifics of the inventory include DEA Form 222. which of the following? d. All of the above. a. An exact count of all schedule IV substances, regardless of 2. When opening the pharmacy one morning, Jennifer Carlson, RPh, bottle size, is critical. is horrified to find that the window of the front door to the store b. All schedule II substances must be manually counted. was broken, and that the lock had been forcibly opened. When she c. All documents created summarizing the inventory must be entered the actual pharmacy area, she was further distressed to find stored for a period of at least five years. d. All papers created documenting the inventory of controlled that the shelves had been ransacked, and it appeared that a number substances must be stored together with other controlled of units of anabolic steroids, narcotics, and benzodiazepines were substance records to facilitate their simple retrieval. missing. In addition to calling the local police authorities, Jennifer will also be required to do which of the following: Introduction This course is designed to provide an overview of the Controlled This course is not designed to cover all situations. A more detailed Substances Act and allow practicing pharmacists the opportunity to and exhaustive program would be required to cover all eventualities test their knowledge by evaluating relevant case studies and applying that may be encountered by a pharmacist navigating the Controlled information they have learned in this course to answer questions Substances Act. Further to that, this course covers only federal law. specific to those cases.

Page 99 Pharmacy.EliteCME.com Pharmacists must also be familiar with the requirements laid out by to meet legitimate needs for these drugs. To carry out this important their respective state pharmacy laws. mission, DEA works hand-in-hand with state, local and other federal What is the DEA, and what is the purpose of the Controlled authorities. Substances Act (CSA)? Key concepts In 1973, the Drug Enforcement Administration (DEA) was formed, Within the confines of the CSA, it is critical that all transactions primarily to enforce all federal drug laws. The Controlled Substances involving controlled substances occur within a “closed system” of Act (CSA) and associated regulations formed its backbone, distribution. Within this controlled loop, all entities authorized to implementing federal requirements governing the disposition of both “touch” controlled substances – manufacturers, distributors, doctors, legal and illicit drugs. and pharmacies – must hold the proper DEA registration applicable to In the context of pharmacy, the DEA has two major jobs: prevention of their practice. Further, all parties must maintain a strict accounting for all transactions, and maintain their records in such a way that they are the diversion and abuse of controlled substances and at the same time, 1 ensuring that the supply of legal controlled substances remain available kept separate from other documents and are readily retrievable . Scheduling Substances that fit under the CSA are currently divided into five high psychological dependence. Schedule III drugs include products schedules based on whether they have an acceptable medical use and containing less than 15 milligrams of hydrocodone per dosage unit, their relative potential for abuse and likelihood of causing dependence. products containing not more than 90 milligrams per dosage unit of 1,4 Schedule I: codeine, buprenorphine, and anabolic steroids such as oxandrolone . Schedule I drugs either have no currently medically acceptable use or Schedule IV: have a high potential for abuse. Schedule I substances include: heroin, Compared to substances categorized in schedule II and III, substances marijuana, LSD, and methaqualone. Additionally, some materials can be in schedule IV have a low potential for abuse or dependence. Schedule temporarily included in schedule I subject to emergency scheduling1,2. IV items benzodiazepines such as alprazolam, clonazepam, and 1,5 Schedule II: midazolam . Substances categorized as schedule II all have a high potential for Schedule V: abuse. Further to that, the use of these drugs can lead to severe Compared to substances categorized into schedules I, II, III and IV, psychological or physical dependence. Schedule II drugs include substances in this schedule have a low potential for abuse and consist codeine, morphine, cocaine, amphetamine, and methylphenidate1,3. primarily of preparations containing limited quantities of certain Schedule III: narcotics. In most cases, preparations appearing in schedule V are used Substances in this schedule generally are considered to have a potential for their antitussive, antidiarrheal and analgesic properties. Examples of schedule V products include preparations containing not more than 200 for abuse less than substances listed in schedules I or II. The abuse 1,6 of these drugs may lead to moderate or low physical dependence or milligrams of codeine per 100 milliliters or per 100 grams . Registration requirements Before any controlled substances can be dispensed by a pharmacy, that publicly displayed at each pharmacy. This registration must be renewed pharmacy needs to be registered with the DEA. This is accomplished every three years using DEA Form 224a1,8. online using DEA Form 2241,7. A certificate of this registration must be Transfer or disposal of controlled substances If a pharmacy should ever need to transfer or dispose of controlled For the transfer of schedule II products, a DEA Form 222 must be substances to another properly registered facility, this transaction must completed1,9. For schedule III-V controlled substances, the transfer be documented. These records must be maintained and kept available must be documented, including the drug name, dosage form, strength, for inspection by DEA for a period of two years. quantity and date transferred. Additionally, the document must include the names, addresses, and DEA registration numbers of all parties involved in the transfer1. How to manage a significant loss or theft of controlled substances The theft of a controlled substance is a criminal event that must be ●● Date of theft, or date discovered. reported to the police and DEA within one business day. Should there be ●● Name and phone number of local police department, if notified. any question of whether a crime has occurred, pharmacists should err on ●● Type of theft. the side of conservatism and report the event1. The theft of a controlled ●● List of any markings the pharmacy makes on the labels, such as substance is documented using DEA Form 106. This documentation symbols or price codes. will include1,10: ●● List of missing controlled substances, including strength, dosage ●● Name and address of the pharmacy. form, and container size, or National Drug Code (NDC) numbers. ●● DEA number of the pharmacy. Prescription records Should the pharmacy determine there is a conflict between the The requirements governing the use of electronic prescriptions for requirements of federal and state requirements for record keeping, controlled substances are outlined in 21 C.F.R. §1311. Briefly, all the pharmacy will need to develop a filing system that complies with electronic records must be maintained for two years (although this time both federal and state law. Regardless of the filing system chosen, all requirement does not pre-empt any longer periods of retention that may prescriptions and supporting documents need to be stored in a way that be required by other applicable laws or regulations, such as state law). makes them readily retrievable for DEA inspection. If a paper-based The electronic system must allow the electronic controlled substance system is used, all schedule II prescriptions must be kept separate from prescription records to be readily retrievable from other prescriptions all other documents1. and must be easily rendered into a readable format. Lastly, electronic prescription records must be sortable by prescriber name, patient, drug and date dispensed11. Controlled substances inventory requirements An inventory is a comprehensive and accurate count of all controlled schedule II controlled substances and a reasonable estimate of schedule substances on hand. This accounting will be based on an actual count of III-V controlled substances (except in case of containers holding 1,000

Pharmacy.EliteCME.com Page 100 or more dosage units, in which case an actual count is required). The When are inventories required? CSA dictates that all inventory records be maintained for at least two ●● At the time of initial DEA registration. years. Schedule II inventory records must be kept separate from all ●● Biennially (every two years following initial inventory). other inventory documents. ●● For newly scheduled controlled substances, inventory must be completed as of the effective date of scheduling or change in schedule1. Ordering controlled substances Only schedule II controlled substances require a specific ordering confirmation of the order’s accuracy. Additionally, these receipts must protocol. DEA Form 222 is required on each occasion that a schedule also document the name of the controlled substance, the formulation, II controlled substance is distributed from a wholesaler, purchased, or the number of dosage units, and the total number of containers received. transferred between properly registered facilities9. For schedule III-V These receipts must be maintained for two years using a system that controlled substances, pharmacists are required to maintain an invoice allows them to be readily retrieved for inspection by DEA1. or packing slip stating the date that the products were received and Prescription requirements The basic elements for a controlled substance prescription do not vary any pharmacist who knowingly fills a questionable prescription for a greatly from those needed for any other prescription based on the CSA, controlled substance is committing a felony offense1,13. although states may have their own laws governing the prescription of The use of electronic prescriptions for controlled substances is these products. With that said, pharmacists must be cognizant of their permitted only after their system has obtained a third-party audit responsibility to ensure that every prescription they fill is legitimate or certification review, determining that the application meets DEA within the meaning and intent of the CSA. If a pharmacist has any doubt requirements. Refills are not permitted for schedule II controlled about the authenticity or validity of a prescription, he or she is under no substances. Up to five refills may be obtained for a schedule III-V obligation to fill it; contacting the prescriber may help the pharmacist to 1,12 controlled substances within six months of issuance of the original verify the authenticity of a questionable prescription . To the contrary, prescription1. Dispensing requirements When dispensing, controlled substances may be received only by issue electronic prescriptions for controlled substances, so long as they the actual patient or a member of the patient’s household. Schedule are using an approved software system. Pharmacies are permitted to II controlled substances may be dispensed pursuant to a written receive, dispense, and archive electronic prescriptions1,15. prescription, except in cases of a bona fide emergency, in which case the Prescriptions for schedule III-V controlled substances can be delivered prescription can be transmitted to the pharmacy telephonically. In this by paper, facsimile, orally or electronically, so long as they meet the case, the prescriber must provide a written prescription to the pharmacy DEA requirements for such prescriptions1. within seven days. In addition, the DEA now allows prescribers to The Ryan Haight Online Pharmacy Consumer Protection Act of 2008 The Ryan Haight Online Pharmacy Consumer Protection Act of 2008 pharmacy. Operating counter to this act is in violation of 21 U.S.C. § amended the CSA by including a number of new provisions designed to 841(h)(1) and subject to potential criminal prosecution and loss of the prevent the illegal distribution and dispensing of controlled substances pharmacy’s DEA registration14. over the Internet. This act, designed to counteract “rogue” Internet sites, The information contained in this section above is included only as applies to all controlled substances. a brief summary. A full description of the requirement of this act is Under this act, it is illegal to deliver, distribute or dispense a controlled beyond the scope of this course. Pharmacists and pharmacies needing substance by means of the Internet unless the online pharmacy holds more complete and comprehensive information describing the act a modified DEA registration authorizing it to operate as an online should access the actual text of the CSA and DEA regulations. Controlled Substance Act scenarios Scenario 1: controlled substances. Further, all documents on controlled substances Winter Pharmacy is preparing a record keeping system to account must be kept separate and readily retrievable from other records. for the acquisition, storage and dispensing of controlled substances. Scenario 2: To accomplish this within the guidelines set out by the Controlled Jim Walters, PharmD, has completed his residency in community Substances Act, its owners wisely choose to design a “closed” practice and is preparing to open his own pharmacy. Before he can system. Critical elements of this inventory control system will begin to dispense controlled substances in his pharmacy, he will include which of the following? need to complete which of the following tasks: a. For sake of simplicity, make sure that all prescriptions (non- a. Register his pharmacy with the DEA, using DEA Form 224. controlled and controlled substances) are filed in a single b. Display a certificate indicating this registration in a location. prominent place. b. Maintain a strict accounting of all transactions of controlled c. Order schedule II controlled substances for inventory using substances. DEA Form 222. c. Ensure that only the pharmacy has the proper DEA d. All of the above. registration permits. d. None of the above. Answer: Although many procedures must be followed to properly open a pharmacy, if that pharmacy chooses to dispense controlled substances, Answer: To comply with all provisions of the CSA, any pharmacy that the CSA requires that additional tasks must also be completed. The first dispenses controlled substances must operate within the confines of a task for Dr. Walters is to properly register his pharmacy with the DEA, “closed system.” In essence, this means that every entity that comes using DEA Form 224. After he receives this registration, the certificate into contact with the controlled substance must be properly licensed, indicating his registration needs to be prominently displayed in the registered, and follow proper guidelines. One such guideline stipulates pharmacy. In order to procure schedule II controlled substances, Jim that all involved parties, including Winter Pharmacy, must provide a Walters must do so using DEA Form 222. This form is not required for comprehensive and thorough accounting of all transactions involving acquiring schedule III-V controlled substances.

Page 101 Pharmacy.EliteCME.com Scenario 3: Scenario 6: After Jim Walters has been in business for some time, he realizes Davies’ Community Pharmacy is preparing for its biennial that due to poor inventory control, he has a number of dosages of inventory of controlled substances. While Steen Davies, PharmD, oxycodone that have reached their expiry date and are thus not has an idea of how this should be conducted, there are a few key suitable for sale to patients. In response to this finding, Jim Walters things that he should keep in mind when completing this important should: count of all controlled substances. Some of things that he should a. Mail them back to his wholesaler without documentation. think about when planning the specifics of the inventory include b. Discard the expired pills in an approved refuse receptacle. which of the following? c. Complete DEA Form 222 and transfer to a properly licensed a. An exact count of all schedule IV substances, regardless of facility. bottle size, is critical. d. Contact the manufacturer to request an extension on the b. All schedule II substances must be manually counted. expiry date. c. All documents created summarizing the inventory must be stored for a period of at least five years. Answer: The CSA makes it clear that any change in disposition of d. The paperwork created documenting the inventory of all schedule II controlled substances, including oxycodone, needs to be Schedule II-V controlled substances must be stored together documented using DEA Form 222. To either return to the wholesaler to facilitate their simple retrieval. without documentation or simply discard the doses would be a clear violation of the CSA. It would not be appropriate for Jim Walters Answer: The inventorying of all controlled substances is critical to to request an extension on the expiry date. To move these schedule maintaining compliance with the CSA. Exact counts are required only II controlled substances from his inventory, the only legal way to for schedule II controlled substances and other controlled substances in accomplish this, is to send them to another properly licensed facility. bottles containing 1,000 or more dosage units. All documents must be This transaction will need to be appropriately documented using DEA maintained for at least two years, with schedule II records kept separate Form 222. from the others. Scenario 4: Scenario 7: When opening the pharmacy one morning, Jennifer Carlson, RPh, Kim Maxon, PharmD, the pharmacist in charge of Arrow is horrified to find that the window of the front door to the store Community Pharmacy, is working with her pharmacy technician to was broken, and that the lock had been forcibly opened. When she prepare its regular medication order. In addition to non-controlled entered the actual pharmacy area, she was further distressed to find substances, this order will also call for a number of medications that the shelves had been ransacked, and it appeared that a number that are categorized as schedule III-V, as well as for some ADHD of units of anabolic steroids, narcotics and benzodiazepines were medications, which fall under schedule II. To complete the missing. In addition to calling the local police authorities, Jennifer submission and receipt of this order, Kim will need to ensure that will also be required to which of the following: which of the following tasks is accomplished? a. File DEA Form 106 within one business day with the DEA. a. All of the ADHD medications will need to be ordered using b. Immediately replace all missing stock. DEA Form 222. c. Consider a more secure alarm system. b. DEA Form 222 will need to be completed to order all of the d. Complete full interviews with all employees to rule out their controlled substances. involvement. c. For the schedule III-V controlled substances, Kim is required to sign the invoice or packing slip stating the date Answer: While there may be a number of business-related responses to that the products were ordered from the wholesaler. a theft of controlled substances that Jennifer may elect to accomplish, d. The receipts or invoices that are included with the shipment the CSA is clear that a DEA Form 106 needs to be filed with DEA must be accounted for and signed by Kim Maxon, as she is within one business day. DEA Form 106 describes the circumstances the pharmacist in charge. and details of the theft. Although items b, c and d, may be reasonable responses, they are not mandated by the CSA. Answer: According to ordering provisions laid out in the CSA, all Scenario 5: orders for schedule II controlled substances will need to be made using Mammoth Lakes Community Pharmacy, in an effort to create DEA Form 222. The other controlled substances can be ordered using greater levels of patient safety and improve efficiencies, is any type of order forms. The CSA does not require that receipts or considering replacing its antiquated paper record keeping invoices documenting the orders are signed for by the pharmacist in system with a state-of-the-art electronic system. Unfortunately, charge, but does require that the receipt date is noted on the invoice and the pharmacy manager, Jim Edwards, PharmD, finds that the that it is filed in a way that they can be readily retrieved by DEA. more vendors he speaks to, the more confused he gets about the Scenario 8: requirements of such a system. Whichever system Mammoth Lakes Lawrence Campbell, RPh, is nearing the end of his shift at the Eagle ends up using, it is critical that it addresses which of the following Community Pharmacy when a man approaches the prescription key elements? drop-off area. The well-dressed man presents a prescription to a. The selected system complies only with federal DEA Lawrence for a quantity of 150 oxycodone 10mg tablets. While regulations, as these supersede state laws. at first glance, the prescription appears legitimate, upon closer b. The system should simplify its approach to filing by making examination, Lawrence notes that the patient’s name is slightly sure that all prescriptions for controlled substances remain smeared. To try to validate the prescription, Lawrence asks the man together. why he was being prescribed the medication. The customer hesitates c. To comply with DEA regulations, all schedule II slightly, and then, without making eye contact, states that it is for prescriptions need to be maintained in a readily retrievable back pain. Based on these series of events, the best initial approach state for a period of at least two years. to managing this situation is for Mr. Campbell to: d. None of the above elements are needed. a. Dispense the medication. b. Contact the prescribing physician to verify the prescription. Answer: Electronic pharmacy data systems can be complex, creating c. Detain the customer and call the police. confusion for the people who need to select an appropriately designed d. Ask the customer whether the prescription is authentic. system. Nonetheless, whether a paper, or electronic structure is employed, the CSA is clear that prescriptions for all schedule II Answer: Lawrence was wise to question the validity of the prescription. controlled substances need to be kept separate from other documents Based on the response to his additional inquiry, the patient gave the in a readily retrievable state for no less than two years. Further to that, impression that there may be a problem with the authenticity of the systems need to be designed to be compliant with all laws, both state prescription. Based on this, Lawrence had an obligation to ensure that and federal. the prescription was genuine before filling it.

Pharmacy.EliteCME.com Page 102 The proper next steps are subjective, but there are some basic ideas other pharmacy records in an easily retrievable state. While telephonic to keep in mind when considering this situation. Dispensing the emergency prescriptions for schedule II controlled substances are prescription under these circumstances would be wrong, and a potential allowed in some circumstances, it is incumbent on the prescribing violation of the CSA. Detention of the patient, and calling the police, physician to provide a supportive written prescription within seven may be appropriate, but is likely not the best initial approach. The best days. tactic would be to simply contact the physician who allegedly wrote the Scenario 10: prescription and ask him or her to verify that it is legitimate. James Gilbert, PharmD is realizing his career goals by establishing Scenario 9: a large, Internet-based pharmacy. He believes that by opening Jeanna Andrew, pharmacist in charge of Century City Pharmacy, this service, he can provide excellent service to his customers at is putting together a list of special requirements specific to the competitive prices because of the efficiencies of scale and reduced dispensing of schedule II controlled substances. Some of the key overhead costs. In addition to regulations and laws governing elements that must be discussed in her checklist include which of all pharmacies, he should be especially concerned with the rules the following? included in which of the following acts? a. The transfer of schedule II substances must be documented a. The Ryan Haight Online Pharmacy Consumer Protection using DEA Form 222. Act of 2008. b. Schedule II inventory records must be kept separate from all b. The Consumer Protection Act. other pharmacy documents. c. The 1962 Kefauver Harris Amendment. c. If schedule II substances are dispensed under an emergency d. The 1952 Durham-Humphrey Amendment. situation without a written prescription, a paper prescription Answer: To remain current and relevant, the CSA was amended in from the prescriber must be provided to the dispensing 2008 to more closely govern the dispensing of controlled substances pharmacy within seven days. over the Internet. Under the provisions of this act, it is illegal to sell d. All of the above. controlled substances over the Internet without proper DEA registration Answer: The CSA is especially clear on the guidelines for handling (in addition to the requirements of traditional pharmacies). The acts schedule II controlled substances. All changes in disposition of identified in items b, c and d, while important to pharmacy practice in schedule II controlled substances must be documented using DEA general, are not as closely aligned with the dispensing of controlled Form 222. Regular inventorying of schedule II controlled substances is substances over the Internet as that described in item a. also required, and resultant documents must be kept separate from all Conclusion Evolving national trends in the abuse of controlled substances and the substances are scheduled by the Controlled Substance Act and their development of new regulations to combat this practice have created an responsibilities in ensuring that these potentially dangerous medications ever-changing clinical practice environment as well as laws to govern are managed throughout the prescribing system. it. It is critical that all practicing pharmacists understand how controlled References 1. U.S. Department of Justice (2010). Pharmacist’s Manual: An Informational Outline of the Controlled 8. U.S. Department of Justice: Drug Enforcement Administration (2009). DEA Form 224a. Accessed Substances Act. Accessed online March 23, 2017 at: http://www.deadiversion.usdoj.gov/pubs/ online March 24, 2017 at: http://www.deadiversion.usdoj.gov/fed_regs/notices/2009/fr08212.htm manuals/pharm2/pharm_manual.pdf 9. U.S. Department of Justice: Drug Enforcement Administration (2017). DEA Form 222. Accessed 2. Code of Federal Regulations (2013). § 1308.11. Accessed online March 23, 2017 at http://www.ecfr. online March 24, 2017 at: http://www.deadiversion.usdoj.gov/faq/dea222.htm gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&idno=21#21:9.0.1.1.9.0.26.4 10. U.S. Department of Justice: Drug Enforcement Administration (2017). DEA Form 106. Accessed 3. Code of Federal Regulations (2013). § 1308.12. Accessed online March 23, 2017 at http://www.ecfr. online March 24, 2017 at: http://www.deadiversion.usdoj.gov/21cfr_reports/theft/ gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&idno=21#21:9.0.1.1.9.0.26.4 11. U.S. Department of Justice: Drug Enforcement Administration (2013). Part 1311 digital certificates- 4. Code of Federal Regulations (2013). § 1308.13. Accessed online March 23, 2017 at http://www.ecfr. Subpart C—electronic prescriptions. Accessed online March 24, 2017 at: http://www.deadiversion. gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&idno=21#21:9.0.1.1.9.0.26.4 usdoj.gov/21cfr/cfr/1311/subpart_c100.htm 5. Code of Federal Regulations (2013). § 1308.14. Accessed online March 23, 2017 at http://www.ecfr. 12. U.S. Department of Justice: Drug Enforcement Administration (2017). Title 21 United States Code gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&idno=21#21:9.0.1.1.9.0.26.4 (USC) Controlled Substances Act: Section 829. Prescriptions. Accessed online March 24, 2017 at: 6. Code of Federal Regulations (2013). § 1308.15. Accessed online March 23, 2017 at http://www.ecfr. http://www.deadiversion.usdoj.gov/21cfr/21usc/829.htm gov/cgi-bin/text-idx?c=ecfr&rgn=div5&view=text&node=21:9.0.1.1.9&idno=21#21:9.0.1.1.9.0.26.4 13. United States v. Kershman, 555 F.2d 198 (United States Court Of Appeals, Eighth Circuit, 1977). 7. U.S. Department of Justice: Drug Enforcement Administration (2017). DEA Form 224. Accessed Accessed online March 24, 2017 at: http://openjurist.org/555/f2d/198/united-states-v-kershman online March 24, 2017 at: http://www.deadiversion.usdoj.gov/drugreg/reg_apps/224/224_instruct.htm 14. Department Of Justice, Drug Enforcement Administration. 21 CFR Parts 1300, 1301, 1304, 1306, Implementation of the Ryan Haight Online Pharmacy Consumer Protection Act of 2008 (2009). Accessed online March 24, 2017 at: http://www.deadiversion.usdoj.gov/fed_regs/rules/2009/fr0406. pdf 15. Department Of Justice, Drug Enforcement Administration. 21 CFR Parts 1300, 1304, 1306, 1311. Electronic Prescriptions for Controlled Substances. (2010). Accessed online March 24, 2017 at https:// www.deadiversion.usdoj.gov/fed_regs/rules/2010/fr0331.htm

Page 103 Pharmacy.EliteCME.com PHARMACIST RESPONSIBILITIES IN THE MANAGEMENT OF CONTROLLED SUBSTANCES Final Examination Questions Choose the best answer for questions 1 through 5 and mark your answers online at Pharmacy.EliteCME.com

1. Critical elements of a “closed” inventory control system will 4. According to the Controlled Substance Act, what is the procedure include which of the following? when a theft of a controlled substance occurs? a. For sake of simplicity, make sure that all prescriptions (non- a. Report to the police and file DEA Form 106 within one business controlled and controlled substances) are filed in a single day with the DEA. location. b. Immediately replace all missing stock. b. Maintain a strict accounting of all transactions of controlled c. Consider a more secure alarm system. substances. d. Complete full interviews with all employees to rule out their c. Ensure that only the pharmacy has the proper DEA registration involvement. permits. 5. What is one of the inventory requirements of the inventory of d. None of the above. controlled substances? 2. Before a new pharmacy can begin to dispense controlled substances, a. An exact count of all schedule IV substances, regardless of which task must the pharmacy complete? bottle size is critical. a. Register the pharmacy with the DEA, using DEA Form 224. b. All schedule II substances must be manually counted. b. Display a certificate indicating this registration in a prominent c. All documents created summarizing the inventory must be place. stored for a period of at least five years. c. Order schedule II controlled substances for inventory using d. The paperwork created documenting the inventory of all DEA Form 222. schedule II-V controlled substances must be stored together to d. All of the above. facilitate their simple retrieval. 3. If a pharmacy should ever need to transfer or dispose of controlled substances to another properly registered facility, the pharmacy must: a. Mail back the controlled substances without documentation. b. Discard the expired pills in an approved refuse receptacle. c. Complete DEA Form 222 and transfer to a properly licensed facility. d. Contact the manufacturer to request an extension on the expiry date.

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Pharmacy.EliteCME.com Page 104 Chapter 11: Shingles Disease Process and Vaccination for Pharmacists and Pharmacy Technicians

2 Contact Hours

By: Katie Blair, PharmD, RPh Author Disclosure: Katie Blair and Elite Professional Education, LLC Questions regarding statements of credit and other customer service do not have any actual or potential conflicts of interest in relation to this issues should be directed to 1-888-666-9053. This lesson is $8.00. lesson. Educational Review Systems is accredited by the Universal Activity Number (UAN): 0761-9999-18-036-H06-P Accreditation Council of Pharmacy Education (ACPE) as Activity Type: Knowledge-based a provider of continuing pharmaceutical education. This Initial Release Date: February 20, 2018 program is approved for 2 hours (0.2 CEUs) of continuing Expiration Date: February 20, 2020 pharmacy education credit. Proof of participation will be Target Audience: Pharmacy Technicians in a community-based setting. posted to your NABP CPE profile within 4 to 6 weeks to participants who have successfully completed the post-test. Participants To Obtain Credit: A minimum test score of 70 percent is needed to obtain a credit. Please submit your answers either by mail, fax, or online must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. at Pharmacy.EliteCME.com Learning objectives Discuss the characteristics of varicella zoster virus, including Discuss the efficacy, contraindications and precautions, adverse primary infection and secondary reactivation of the latent virus, reactions and administration of Shingrix. complications and treatment. Explain the recommendations of the Advisory Committee on Describe the efficacy, contraindications and precautions, adverse Immunization Practices (ACIP) for the use of shingles vaccinations. reactions and administration of Zostavax. Introduction Herpes zoster, commonly known as shingles, affects approximately one Shingles causes a characteristic rash typically localized in one area of out of every three Americans in their lifetime, resulting in an estimated 1 the body. Serious complications can arise, which often depends on the million cases in the United States each year. It is caused by the varicella rash location, such as pain that persists after the rash has cleared and zoster virus, the same virus that causes chicken pox. Shingles affects even vision or hearing loss. Treatment typically focuses on antiviral anyone who has had chicken pox, and it can affect any age group, even therapy and symptom control. Shingles can be prevented through children, though the risk of developing shingles increases significantly vaccination, which is typically recommended for adults over 50 since with age. The risk also increases for people with a weakened immune the immune system weakens with age. This course serves to review system, such as those with human immunodeficiency virus (HIV) or the disease process of shingles and the use of vaccinations to prevent cancer, or those taking immunosuppressive medications such as steroids. shingles (Centers for Disease Control and Prevention, 2017). Overview of shingles Initial infection with varicella zoster virus ●● Serious infection of neonates if mother has an infection with Varicella, also known as chicken pox, is a contagious viral infection varicella that begins five days before through two days after birth. caused by the varicella zoster virus. The virus is commonly acquired Healthy children with chicken pox generally do not require oral through the respiratory tract and direct contact with skin lesions, after medications, but topical treatments such as calamine lotion and oatmeal which the virus enters an incubation period of approximately two baths are often used to alleviate symptoms. Immunosuppressed children weeks, while it replicates in the body. and adults can be prescribed acyclovir within 24 hours of symptom Symptoms of primary infection with varicella zoster virus begin after onset to prevent severe chicken pox. After the resolution of chicken the initial incubation period. Adults may have a fever or malaise for pox, the varicella zoster virus remains in the body as a latent infection, one to two days before developing a rash, while children often present persisting in the nervous system (Centers for Disease Control and with a rash as their first symptom. The rash typically starts at the head Prevention, 2015; Papadopoulos, 2017). and spreads to the trunk and extremities; it consists of small, raised, Reactivation of varicella zoster virus: Shingles itchy lesions that contain clear fluid. Lesions can also occur on mucous People who have had chicken pox as a child continue to carry the latent membranes throughout the body. The fluid contained in lesions is varicella zoster virus in the nervous system, typically in the dorsal nerve infectious and contact can lead to infection in a person who had not root or cranial sensory ganglia. The latent virus can reactivate later in had chicken pox (Centers for Disease Control and Prevention, 2015; life to cause herpes zoster, or shingles. Reactivation commonly occurs Papadopoulos, 2017). in people with a weakened immune system, which can be caused by Adults and immunocompromised patients are at a higher risk of illness, old age, immunosuppressive medication use, or extreme stress. developing more severe chicken pox and complications than healthy Upon reactivation, the virus begins to multiply again and moves along children. Complications can include: the affected nerve until it reaches the skin. It continues multiplying in ●● Secondary bacterial infections of chicken pox lesions. the skin cells, causing inflammation and the characteristic shingles rash. ●● Pneumonia. Pain is typically related to the nerve inflammation (Centers for Disease ●● Central nervous system complications such as meningitis or Control and Prevention, 2015; Immunization Action Coalition, 2017; encephalitis. Institute for Quality and Efficiency in Health Care, 2017; Merck, 2017). ●● Reye syndrome, if aspirin is taken during acute illness. Symptoms ●● Rare hemorrhagic complications such as thrombocytopenia. Before the rash appears, patients with shingles often experience fatigue ●● Rare inflammation of organs, such as heart, kidney, eyes, gonads or a general “run-down” feeling. A low-grade fever and tingling and liver. sensations under the skin can also precede shingles rash. Two to three Page 105 Pharmacy.EliteCME.com days later, the common symptoms begin: Burning or stinging pain in chicken pox as a child can still develop shingles later in life, though the affected area, followed by red patches of skin with small bumps it considered less common than developing shingles after chicken that develop into blisters. The blisters may be associated with itchiness, pox disease. For people who have never had chicken pox, shingles is and pain is often described as moderate to severe. The blisters typically contagious. Chicken pox-naïve patients who come in contact with the dry up within two to 10 days, leaving behind scabs that are commonly fluid from shingles lesions are at risk for developing chicken pox, as yellow in color. Skin symptoms of shingles typically clear up within this is the initial infection caused by varicella zoster virus. two to four weeks. Shingles patients are considered contagious until all Since 99.5 percent of adults over the age of 40 have been infected with blisters have dried up and scabs have fallen off. varicella zoster virus, nearly all older adults in the United States are The rash is commonly located in one area on a single side of the body, at risk for developing shingles. Risk factors associated with varicella although it is possible to occur in multiple areas at once. Shingles most zoster virus reactivation include immunosuppression and aging. Risk commonly affects the torso or chest, though it is possible to develop just of herpes zoster increases significantly after the age of 50. (Centers for about anywhere on the body, including arms, face, head, and even ears Disease Control and Prevention, 2015; Centers for Disease Control and or eyes. A small percentage of patients present with only pain and skin Prevention, 2017; Immunization Action Coalition, 2017; Institute for sensations with no rash. Approximately 12 percent of patients report flu- Quality and Efficiency in Health Care, 2017; Merck, 2017). like symptoms during acute herpes zoster infections, and helplessness Diagnosis and depression have also been reported (Centers for Disease Control Many people who develop shingles initially think they have a non- and Prevention, 2015; Immunization Action Coalition, 2017; Institute contagious skin infection, such as eczema. This can delay diagnosis and for Quality and Efficiency in Health Care, 2017; Merck, 2017). treatment if they believe they do not need to see a doctor. Diagnosis Complications during the early stages of shingles development can be difficult because Patients with compromised immune systems are more likely to the characteristic rash typically develops after pain starts. Depending experience complications as well as a more severe, longer-lasting on the affected area, other causes may be initially suspected, such as shingles rash. Pain and skin sensations associated with the shingles appendicitis, hernia or myocardial infarction. rash can persist for a variable amount of time, from several weeks Diagnosis is often based on the characteristic rash that develops on to a year or longer after the rash has been resolved. This is the most one side of the body, as well as the accompanying pain and sensations common complication of herpes zoster infection, referred to as post- related to nerve inflammation. If the diagnosis is unclear, fluid from herpetic neuralgia. Post-herpetic neuralgia can affect between 10 and 20 blisters can be tested to determine whether it contains varicella zoster percent of shingles patients. Risk of developing post-herpetic neuralgia virus. Blood tests to detect antibodies to varicella zoster virus can also increases with age, and older adults are at a higher risk of experiencing be helpful in the diagnostic phase (Centers for Disease Control and more severe and longer-lasting pain. Post-herpetic neuralgia occurs Prevention, 2015; Immunization Action Coalition, 2017; Institute for rarely in patients under the age of 40. Quality and Efficiency in Health Care, 2017; Merck, 2017). Scratching shingles blisters can cause a bacterial skin infection or lead to Treatment scarring. Changes in skin pigmentation can occur in the involved skin area Pain associated with shingles can often be treated with medications such after the infection, causing lighter or darker pigmentation than surrounding as acetaminophen or non-steroidal anti-inflammatory agents. Stronger skin. In rare cases, blisters can spread to neighboring skin areas and, medications may be necessary in some patients; opiates and drugs used even more rarely, spread over the whole body. This is often related to to treat neuropathic pain, such as gabapentin, can be used. a significantly weakened immune system, such as in cancer or AIDS patients. Under these rare situations, shingles can be life threatening. Antiviral medications, such as acyclovir, famciclovir and valacyclovir, can treat herpes zoster and decrease both the length of illness and Other complications are related to the site of zoster infection. its severity. These antivirals are particularly useful in patients who Involvement near the eye can lead to herpes zoster ophthalmicus, are over 50, have a weakened immune system, have severe shingles, causing conjunctivitis, ulcers on the cornea, and even blindness. have shingles affecting the head or neck, and those with a high risk Ramsey-Hunt syndrome occurs when the varicella zoster virus affects of complications. Antivirals help to shorten the clinical course as well the nerves that serve the ear; this syndrome can lead to ear pain, facial as prevent progression of complications. Antiviral therapy should nerve palsies, shingles rash in the ear canal, balance issues, and hearing be initiated as soon as possible after the rash appears to maximize loss. Nerve palsies can also affect other areas of the body depending on effectiveness – ideally within 72 hours. Antivirals are most beneficial the affected nerve. if initiated while new lesions are actively forming (Centers for Disease Patients with a significantly weakened immune system appear more Control and Prevention, 2015; Centers for Disease Control and likely to develop serious complications, including pneumonia, Prevention, 2017; Immunization Action Coalition, 2017; Institute for meningoencephalitis or liver inflammation (Centers for Disease Control Quality and Efficiency in Health Care, 2017; Merck, 2017). and Prevention, 2015; Centers for Disease Control and Prevention, Acyclovir is the prototype antiviral medication, available for both 2017; Immunization Action Coalition, 2017; Institute for Quality and oral and intravenous administration. It is less bioavailable than other Efficiency in Health Care, 2017; Merck, 2017). antiviral options, and its frequent administration requirements make it Prevalence less favorable for treating shingles. It is commonly administered at a Estimates show that approximately one out of every three people in dose of 800mg five times daily for seven to 10 days. Intravenous use is the United States will develop shingles in their lifetime. The majority typically reserved only for patients with severely compromised immune of shingles patients are over the age of 50. Approximately 1 million systems who are unable to take oral medications. Acyclovir is a generic cases per year occur in the United States. The risk of shingles is known medication, associated with the brand name Zovirax (Stankus, 2000). to increase with age, because immune systems weaken with age. Valacyclovir is a prodrug of acyclovir, meaning it is converted into Approximately 5 cases occur per 1000 people aged 50 to 59 years, acyclovir in the body after ingestion. Valacyclovir is more bioavailable while people over the age of 80 experience approximately 11 cases than acyclovir, with oral dosing producing antiviral blood levels per 1000 people. Post-herpetic neuralgia (PHN) is the most common similar to intravenous acyclovir. For treating shingles, it is commonly complication of herpes zoster; PHN occurs at a rate between 10 to administered in a dose of 1000mg three times daily for seven days. 13 percent in people over the age of 50 and the risk of developing When compared with acyclovir, valacyclovir shows slightly higher PHN increases with age (Centers for Disease Control and Prevention, effectiveness in decreasing pain severity of the shingles rash, as well 2015; Centers for Disease Control and Prevention, 2017; Dooling, as the duration of post-herpetic neuralgia. Valacyclovir is a generic 2018; Immunization Action Coalition, 2017; Institute for Quality and medication, associated with the brand name Valtrex (Stankus, 2000). Efficiency in Health Care, 2017; Merck, 2017). Famciclovir is another antiviral in the same drug class as acyclovir and Risk factors valacyclovir. It has the best bioavailability of all three agents and has a Anyone who has had chicken pox or vaccination against chicken longer half-life when compared with acyclovir. In treating shingles, it is pox can develop herpes zoster. Those who were vaccinated against commonly administered at a dose of 500mg three times daily for seven

Pharmacy.EliteCME.com Page 106 days. Famciclovir is a generic medication associated with the brand limited to patients over the age of 50, since these patients are at a name Famvir (Stankus, 2000). higher risk of developing post-herpetic neuralgia. Patient-specific Choice of antiviral agent should be individualized based on patient- factors should also be considered to determine if a patient is a specific factors. Dosing schedule and cost are often considered in the candidate for corticosteroid treatment (Stankus, 2000). selection process. All three antiviral medications are typically well- Adequate skin care is recommended in shingles patients. Lotions, tolerated, with the most common adverse reactions being nausea, such as calamine, as well as wet compresses and colloidal oatmeal vomiting, headache, dizziness and abdominal pain (Stankus, 2000). baths can often relieve itching. Opened blisters that are showing signs Despite variable results from clinical trials, prescribers may consider of bacterial infection may require topical or oral antibiotics. Patients using oral corticosteroids to treat pain associated with shingles. should be advised against scratching blisters if possible, since the Corticosteroids, such as prednisone, are thought to reduce nerve fluid in blisters is contagious and scratching creates wounds that could inflammation in shingles which leads to pain, and potentially reduce become infected or leave scars. Shingles patients should also avoid residual damage to the nerves involved. When used in conjunction direct contact with others who have unknown immunity to chicken pox, with antivirals, prednisone has been shown to reduce shingles- particularly immunosuppressed patients and pregnant women (Centers associated pain and some studies have shown reductions in post- for Disease Control and Prevention, 2015; Centers for Disease Control herpetic neuralgia. Since steroids can induce immunosuppression, and Prevention, 2017; Immunization Action Coalition, 2017; Institute which can lead to the development of shingles, their use should be for Quality and Efficiency in Health Care, 2017; Merck, 2017). VACCINATIONS TO PREVENT SHINGLES Two vaccinations are now available in the United States to prevent use in patients 60 and older; five years later, it was approved for those reactivation of latent varicella zoster virus that leads to shingles. In 50 and older; in October 2017, the FDA approved Shingrix for use in 2006, the Food and Drug Administration (FDA) approved Zostavax for patients 50 and older (GlaxoSmithKline, 2017; Merck, 2017). Zostavax In 2006, the FDA approved Zostavax for administration in people age therapy that has been discontinued for one month are still 60 and older, to reduce the risk of reactivating varicella zoster virus eligible for varicella vaccination. and developing shingles. In 2011, the FDA approved a label change ●● Moderate to severe HIV or AIDS. extending the use of Zostavax to people ages 50 to 59. A single dose is ●● Women who are pregnant or trying to become pregnant. recommended in this age group, regardless of prior history of shingles ○○ Pregnancy should be avoided for one month following varicella episodes. Zostavax contains about 14 times as much varicella zoster vaccination. virus than Varivax, the children’s chicken pox vaccine (Centers for ○○ Women who inadvertently receive varicella vaccinations Disease Control and Prevention, 2015). during pregnancy should be reported to the CDC’s Varicella Efficacy Vaccination in Pregnancy registry to monitor outcomes by The primary clinical trial for Zostavax, titled “Shingles Prevention calling 1-800-986-8999. Study (SPS) in Subjects 60 Years of Age and Older,” evaluated over ●● People with moderate to severe illness should wait until their 38,000 adults between 60 and 80 years old, who had no prior history of condition has improved before receiving live vaccines such as shingles. Trial participants received a single dose of Zostavax and were Zostavax. followed for 3.1 years after vaccination. When compared to a placebo ○○ Minor illness, such as ear infections, upper respiratory group, the group of vaccinated participants experienced 51 percent infections, concurrent antibiotic therapy, as well as recovery fewer episodes of shingles. The trial found efficacy was highest in the from mild illness, are not contraindications to receiving group of participants ages 60 to 69, with this group experiencing 64 varicella vaccine. percent efficacy. Efficacy declined with increasing age; participants 80 ●● Concurrent use of antiviral medications for herpes viruses, such as and older experienced 18 percent efficacy. acyclovir, famciclovir and valacyclovir, is considered a precaution to vaccination with Zostavax. Participants in this study who received the vaccination and subsequently ○○ If possible, discontinue medication at least 24 hours before developed shingles generally experienced less severe disease. Vaccine administration of Zostavax, and do not take again for at least 14 recipients who developed shingles experienced a 66 percent reduction days after receiving the vaccine. in the risk of developing post-herpetic neuralgia. ●● Zostavax should be initiated prior to starting treatment with immune A subsequent clinical trial evaluated the use of Zostavax in patients modulating medications, such as infliximab and adalimumab, or under 60, titled “Zostavax Efficacy and Safety Trial (ZEST) in Subjects deferred until at least one month after discontinuation. 50 to 59 Years of Age.” In this age group, the risk of developing ●● A randomized clinical trial showed reduced efficacy of Zostavax in shingles was reduced by 69.8 percent. Researchers noted that the patients who received Zostavax and Pneumovax 23 simultaneously duration of this risk reduction is not known (Centers for Disease Control when compared with patients who received these two products and Prevention, 2015). four weeks apart from one another. Clinicians should consider Models have shown the effectiveness of Zostavax to wane to zero within administering these two vaccinations four weeks apart from one four to 12 years after vaccination. This waning phenomenon is dependent another to maximize efficacy. on the patient’s age at the time of Zostavax vaccination (Dooling, 2018). Adverse reactions Contraindications and precautions The primary study on Zostavax noted several adverse reactions Since varicella zoster virus vaccinations are live vaccines, there are associated with vaccine administration. Local reactions such as several contraindications that must be considered. Contraindications injection site swelling, redness, pain and tenderness were among the to vaccination with Zostavax include (Centers for Disease Control and most common reactions, reported by 34 percent of vaccine recipients, as Prevention, 2015; Immunization Action Coalition, 2017; Merck, 2017): compared to 6 percent in the placebo group. Fevers of 101°F or higher ●● History of severe allergic reactions to vaccine components or prior were reported at a similar frequency in both groups, with the vaccine doses of vaccine. group experiencing fevers a rate of 0.8 percent, and the placebo group ●● Immunosuppression due to cancer, immune diseases or reporting 0.9 percent. The primary trial did not identify any clinically immunosuppressive medication therapy, including high-dose steroid significant serious adverse reactions (Centers for Disease Control and treatment. Prevention, 2015). Subsequent reports have noted cases of anaphylaxis ○○ Patients taking less than 20mg per day of prednisone for less to Zostavax (Merck, 2017). than two weeks; those on alternate-day therapy, topical or Vaccine administration inhaled corticosteroid therapies; or those on corticosteroid Zostavax is administered as a single dose of 0.65mL, injected subcutaneously in the deltoid region of the upper arm. Zostavax should

Page 107 Pharmacy.EliteCME.com be reconstituted with sterile water immediately upon removal from Vaccine components and storage the freezer. When reconstituting, the sterile water should be added to Zostavax is a live vaccine and therefore must be stored properly to the vaccine-containing vial slowly to avoid excessive foaming. Once ensure viability of its virus component. It must be stored under freezing combined, gently agitate the vaccine vial to thoroughly mix the vaccine temperatures, between -58°F and +5°F (-50°C and -15°C). Zostavax components while avoiding excess foaming, resulting in a semi-hazy does not contain preservatives and must be reconstituted with sterile off-white to pale-yellow liquid. It should be administered within 30 water prior to administration. The sterile water component should not be minutes of reconstitution to minimize loss of potency; if it is not given stored in the freezer, as it will be frozen and unable to be drawn out of within this timeframe, the reconstituted vaccine should be discarded the vial at the time of reconstitution. It contains gelatin and neomycin, (Merck, 2017). so patients should be screened for allergies prior to administration (Centers for Disease Control and Prevention, 2015). Shingrix Recently approved in October 2017, Shingrix is now available for It is unknown if Shingrix is excreted in breast milk, and no data is prevention of shingles caused by varicella zoster virus reactivation. available to assess any effects of Shingrix on milk production or the Shingrix is a recombinant, adjuvanted vaccine for intramuscular breastfed infant. The manufacturer recommends weighing the benefits injection and is FDA-approved for use in patients 50 and older of breastfeeding and the mother’s clinical need for Shingrix against any (GlaxoSmithKline, 2017). potential effects on the breastfed infant and the mother’s underlying Unlike Zostavax, Shingrix is not a live vaccine. Shingrix contains condition (GlaxoSmithKline, 2017). varicella zoster virus antigen to trigger a targeted immune response and Adverse reactions is combined with an adjuvant in order to enhance the immune response The most common adverse reactions reported in the initial studies on (GlaxoSmithKline, 2017). Adjuvanted vaccines are thought to trigger a Shingrix were injection-site reactions lasting for a median duration of more robust immune response, creating a stronger immune protection two to three days. Pain was reported in 88 percent of Shingrix recipients (Centers for Disease Control and Prevention, 2016). ages 50 to 59, as compared to 14 percent of placebo recipients in the Efficacy same age group. Redness and swelling also occurred at higher rates with The manufacturer of Shingrix, GlaxoSmithKline, conducted two Shingrix when compared to placebo. studies to assess its efficacy prior to FDA approval. The first study Other clinically significant adverse reactions reported in the initial was an age-stratified, randomized, placebo-controlled study of over studies include myalgia, fatigue, headache, shivering, fever, and GI 14,000 subjects that assessed vaccine efficacy in subjects ages 50 and side effects such as diarrhea, nausea, vomiting and abdominal pain. older. The study excluded those who were immunocompromised, had Systemic reactions were reported more frequently after the second a previous history of shingles, those who were vaccinated against dose of Shingrix as compared with the first. Rare serious adverse shingles or varicella, and those with significant comorbid conditions reactions that were found to potentially have a causal relationship with with an expected survival of less than four years. After following Shingrix included one case of lymphadenitis, one case of fever over subjects for an average of three years, the study found that two doses of 102.2°F, and three cases of optic ischemic neuropathy (Dooling, 2018; Shingrix resulted in a significant reduction – 97.2 percent – in the risk GlaxoSmithKline, 2017). of developing shingles when compared with a placebo. The study also Prior to vaccination, clinicians should discuss potential local and found a significant reduction in post-herpetic neuralgia with Shingrix, as systemic adverse reactions with vaccine recipients. Since adverse no cases developed in the vaccinated group as compared with 18 cases reactions to the first dose of Shingrix did not strongly predict adverse in the placebo group (GlaxoSmithKline, 2017). reactions to the second dose, patients should be encouraged to complete The second pre-approval study was a randomized placebo-controlled both doses even if they experienced a mild to moderate reaction to the study of over 13,000 subjects that assessed vaccine efficacy in patients first dose (Dooling, 2018). ages 70 and older. After an average follow-up of 3.9 years, vaccine Vaccine administration efficacy was noted to be approximately 85 percent in the fourth year after Prior to administration, Shingrix must be reconstituted. The product vaccination in this older patient population. Shingrix was also associated contains two vials; the first has a blue-green cap and contains the with lower rates of post-herpetic neuralgia in this age group when AS01B adjuvant suspension component. The second vial has a brown compared with placebo, with four cases reported in the vaccine group and cap and contains the lyophilized varicella zoster virus glycoprotein E 28 cases reported in the placebo group (GlaxoSmithKline, 2017). (gE) antigen component. The adjuvant suspension should be slowly When data were pooled between the two studies for patients ages 70 added to the antigen-containing vial, then gently mixed until the powder and older, researchers found a 91.3 percent reduction in the risk of is dissolved completely. The mixed product should be an opalescent, developing shingles in those who have received two doses of Shingrix colorless to pale-brown liquid, creating a single dose of 0.5mL. (GlaxoSmithKline, 2017). After reconstitution, the vaccine should be administered Since data are not currently available to evaluate the long-term efficacy intramuscularly, with the preferred site being the deltoid region of Shingrix vaccination, modeled data based on the first four years of the upper arm. If not used immediately after reconstitution, the of clinical trial data, as well as expert opinion, was used to assess reconstituted vaccine can be stored under refrigeration between 36° long-term efficacy. Modeled data show that in adults over the age of and 46°F and used within six hours. If not used within six hours, the 50, efficacy would wane to zero 19 years after vaccination, assuming reconstituted vaccine should be discarded. vaccinated patients received two doses of Shingrix at recommended Shingrix can be administered regardless of whether the recipient has dosing intervals (Dooling, 2018). received prior vaccination with varicella vaccine or Zostavax. It also Contraindications and precautions does not require screening for a history of infection with chicken pox Shingrix should not be administered to patients with a history of (Dooling, 2018). a severe allergic reaction to a previous dose of Shingrix or to any Shingrix requires two doses for maximal efficacy, regardless of prior component of the vaccine. Patients who have a current episode of immunization with Zostavax. The second dose should be administered herpes zoster or post-herpetic neuralgia should not receive Shingrix between two and six months after the first. Initial approval studies during their acute episode of herpes zoster (Dooling, 2018). compared dosing at zero and two months to dosing at zero and six Pregnancy and lactation months; both dosing schedules produced comparable antibody levels, Vaccine-associated risk with Shingrix in pregnant human patients was resulting in the open recommendation for the timing of the second dose. not evaluated. Female rats who received Shingrix did not experience Immune response was also studied when Shingrix was administered at the any vaccine-related fetal malformations or variations. Due to the same time as the quadrivalent flu vaccine, and no interference in immune lack of information in human pregnancy, it may be prudent to avoid response to either product was observed (GlaxoSmithKline, 2017). administering Shingrix to pregnant women.

Pharmacy.EliteCME.com Page 108 Vaccine components and storage 36°F and 46°F (2°C and 8°C). Vials should be protected from light, and if Shingrix is supplied with two components: The antigen component in either vial becomes frozen, the frozen vial should be discarded. Shingrix a vial with a brown cap, and the adjuvant component in a vial with a is a preservative-free vaccine and does not contain any antibiotics. The blue-green cap. Both vials should be stored under refrigeration, between vial stoppers do not contain latex (GlaxoSmithKline, 2017). Which vaccine to use? In January 2018, the Advisory Committee on Immunization Practices determined that prior recipients of Zostavax will likely benefit from (ACIP) released its official recommendations for the use of herpes immunization with Shingrix (Dooling, 2018). zoster vaccines. The committee recommends using the recombinant The ACIP voted on preference of Shingrix versus Zostavax and zoster vaccine Shingrix in immunocompetent adults ages 50 and older. determined that Shingrix is preferred over Zostavax by a narrow This recommendation was based on high efficacy rates of Shingrix, as margin, with eight votes for Shingrix, and seven votes for Zostavax. well as slow rates of waning protection, when studied for four years This recommendation was based on higher estimates of efficacy against post vaccination. The committee noted that beginning vaccination at both herpes zoster and post-herpetic neuralgia with Shingrix when age 50 will help reduce the incidence of herpes zoster in midlife and compared to Zostavax, as well as the substantial waning of efficacy over will likely provide significant protection against disease development as time with Zostavax. As a result, Shingrix is estimated to prevent more vaccine recipients get older (Dooling, 2018). cases of herpes zoster than Zostavax. The ACIP notes that post-licensure The ACIP also recommends Shingrix in people who have previously performance measures of Shingrix will continue to be monitored, received a dose of Zostavax. This recommendation is based on studies including duration of protection, rare adverse events, adherence to the that have shown that Shingrix has demonstrated higher efficacy than two-dose requirement, and effectiveness and protection duration of a Zostavax in all age categories, particularly in patients over the age of single dose of Shingrix. The vote was noted to be narrow because some 70, as well as the substantial waning efficacy of Zostavax over time. ACIP members preferred to recommend no vaccine preference until Since Shingrix has demonstrated similar safety and immunogenicity post-marketing data, such as head-to-head studies comparing the two regardless of prior immunization with Zostavax, the committee vaccines, could be evaluated (Dooling, 2018). Other considerations Timing of Shingrix in patients previously vaccinated with Zostavax administered simultaneously with other adult vaccinations if given at Clinicians should consider the patient’s age and the time since their different anatomic sites. Research on the administration of the quadrivalent Zostavax vaccination when determining when to administer Shingrix. flu vaccine with Shingrix did not indicate any concerns regarding safety or Studies only evaluated immunogenicity and safety of Shingrix when immune response to either vaccine. The concomitant administration of two administered more than five years after Zostavax; shorter intervals adjuvanted vaccines has not been evaluated (Dooling, 2018). have not been evaluated to date. The ACIP notes that there are not any Missed or early doses of Shingrix theoretical concerns or data indicating that Shingrix would be less effective If more than six months have passed since the initial dose of Shingrix, or less safe if given within a shorter interval. In addition, since Zostavax the vaccine series does not need to be restarted. However, the ACIP demonstrated reduced efficacy in adults over the age of 70, a shorter notes that the safety and efficacy of alternate dosing regimens has not interval for administering Shingrix may be considered to reduce the risk of been studied, and patients may remain at risk of developing herpes developing herpes zoster. Overall, the ACIP notes that Shingrix should not zoster if longer-than-recommended intervals between the first and be administered less than two months after Zostavax (Dooling, 2018). second doses are utilized. If the second dose of Shingrix is administered Co-administration with other vaccinations less than four weeks after the first dose, the ACIP recommends As per the Centers for Disease Control Best Practice Guidelines repeating the second dose (Dooling, 2018). for Immunization, adjuvanted and recombinant vaccinations can be Special populations History of herpes zoster additional data becomes available, the committee is expected to further Due to the potentially recurrent nature of herpes zoster, adults who have discuss this topic (Dooling, 2018). previously developed shingles should receive Shingrix. If the patient Patients with chronic medical conditions is currently experiencing a shingles episode, immunization should be Shingrix is recommended in patients with chronic medical conditions delayed until the acute phase has passed and symptoms have resolved such as diabetes, chronic obstructive pulmonary disease, chronic renal (Dooling, 2018). failure and rheumatoid arthritis (Dooling, 2018). Patients who are immunocompromised Patients known to be varicella zoster virus negative The ACIP recommends using Shingrix in patients taking low- It is not recommended to screen for a history of chicken pox prior to dose immunosuppressive medications, such as less than 20mg administration of Shingrix. However, in patients who have no prior per day of prednisone, as well as patients expecting to begin history of chicken pox or vaccination against chicken pox, the ACIP immunosuppressive therapy and those who have recently recovered recommends following guidelines for the administration of the varicella from an immunosuppressive illness. Since patients taking moderate- to vaccination. This is because Shingrix is not indicated for the prevention high-dose immunosuppressive therapy and those who are currently of chicken pox and has not been evaluated in patients who are immunocompromised were excluded from efficacy studies, the confirmed to be sero-negative for varicella zoster virus (Dooling, 2018). ACIP has not recommended the use of Shingrix in these patients. As Patient counseling Patients with shingles should be reminded about the contagious nature Patients are often concerned about their ability to return to work after of the fluid contained in shingles blisters. They should be reminded to developing shingles. Return to work often depends on where the patient cover the rash and avoid scratching or touching blisters. Washing hands works and where the rash is located. If the blisters are located in an area thoroughly after contact with lesions is recommended to prevent spreading that can be covered with bandages or clothing, patients can typically varicella zoster virus. Patients with shingles should be counseled to avoid return to work when they are feeling well. Patients with blisters located contact with immunocompromised people, such as pregnant women, on the face or an area that cannot be covered should not return to work premature infants, and those with weak immune systems such as people until the blisters have crusted over, which commonly takes seven to on immunosuppressive medications like chemotherapy or corticosteroids 10 days. Patients who work in childcare or healthcare settings should and those with conditions weakening the immune system such as HIV or consult their employer to determine when it is safe to return to work organ-transplant recipients. Contact should be avoided until the rash is no (Albrecht, 2017). longer producing new blisters and crusts or scabs have developed (Centers for Disease Control and Prevention, 2017).

Page 109 Pharmacy.EliteCME.com Conclusion Since shingles has the potential to affect over 30 percent of Americans, Advisory Committee on Immunization Practices to release new it is important to be aware of the disease process, treatment and recommendations for shingles vaccination. Being aware of these prevention of this common disease state. The recently approved updates allows pharmacy professionals to better serve and protect Shingrix vaccine has demonstrated significant efficacy in preventing patients against this potentially harmful disease. shingles outbreaks, and its high efficacy rates have prompted the References Albrecht, M. Patient Education: Shingles (Beyond the Basics). UpToDate. December 2017. Accessed GlaxoSmithKline. Shingrix Package Insert. October 2017. Accessed January 26, 2018, at www.fda. January 31, 2018, at www.uptodate.com/contents/shingles-beyond-the-basics gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM581605.pdf Anderson, W. Varicella-Zoster Virus. October 31, 2017. Accessed January 18, 2018, at http:// Immunization Action Coalition. Ask the Experts: Diseases and Vaccines: Zoster (shingles). December emedicine.medscape.com/article/231927-overview#showall 15, 2017. Accessed January 18, 2018, at www.immunize.org/askexperts/experts_zos.asp Centers for Disease Control and Prevention. About Shingles. October 17, 2017. Accessed January 31, Institute for Quality and Efficiency in Health Care. Shingles: Overview. April 6, 2017. Accessed 2018, at www.cdc.gov/shingles/about/index.html January 19, 2018, at www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072808/ Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Merck. Zostavax Package Insert. September 2017. Accessed January 26, 2018, at www.merck.com/ Diseases, Chapter 22: Varicella. April 2015. Accessed January 18, 2018, at www.cdc.gov/vaccines/ product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf pubs/pinkbook/downloads/varicella.pdf Papadopoulos, A. Chicken Pox Treatment and Management. April 14, 2017. Accessed January 18, Centers for Disease Control and Prevention. Vaccine Adjuvants. September 12, 2016. Accessed 2018, at http://emedicine.medscape.com/article/1131785-treatment#showall January 26, 2018, at www.cdc.gov/vaccinesafety/concerns/adjuvants.html Stankus, S., et al. Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia. American Dooling, K., et al. Recommendations of the Advisory Committee on Immunization Practices for Use Family Physician. April 15, 2000. Accessed January 31, 2018, at www.aafp.org/afp/2000/0415/p2437. of Herpes Zoster Vaccines. Morbidity and Mortality Weekly Report. January 26, 2018. Accessed html January 27, 2018, at www.cdc.gov/mmwr/volumes/67/wr/mm6703a5.htm SHINGLES DISEASE PROCESS AND VACCINATION FOR PHARMACISTS AND PHARMACY TECHNICIANS Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com 1. Herpes zoster, commonly known as shingles, affects approximately 7. The Shingrix pre-approval study that assessed vaccine efficacy in one out of every _____ Americans in their lifetime. subjects ages 50 and older found that two doses of Shingrix resulted a. Three. in a significant reduction in the risk of developing shingles by b. Two. ______when compared with placebo. c. Five. a. 51 percent. d. 10. b. 97.2 percent. 2. The most common complication of shingles is: c. 89 percent. a. Ramsey-Hunt syndrome. d. 62 percent. b. Post-herpetic neuralgia. 8. If not used immediately after reconstitution, Shingrix can be c. Bacterial skin infections. stored under refrigeration between 36° and 46°F and used within d. Blindness. ______. 3. The primary clinical trial for Zostavax, titled “Shingles Prevention a. 60 minutes. Study (SPS) in Subjects 60 Years of Age and Older,” found that b. 30 minutes. patients age 60 to 80 years old who received Zostavax experienced c. 12 hours. ____ fewer episodes of shingles when compared with placebo. d. Six hours. a. 51 percent. 9. The ACIP voted on preference of Shingrix versus Zostavax and b. 30 percent. determined that ______is preferred. c. 80 percent. a. Zostavax. d. 91 percent. b. Shingrix. 4. Zostavax should be given within ______of reconstitution c. Both are equally recommended. to minimize loss of potency, and if it is not given within this d. They stated no preference for either agent. timeframe, the reconstituted vaccine should be discarded. 10. If the second dose of Shingrix is administered less than four weeks a. 60 minutes. after the first dose, the ACIP recommends: b. 30 minutes. a. No further action. c. 6 hours. b. Restarting the series. d. 12 hours. c. Repeating the second dose. 5. Zostavax is a live vaccine and therefore must be stored properly to d. Drawing a titer to assess efficacy. ensure viability of the virus component of the vaccine. It must be stored between: a. -58°F and +5°F. b. 36°F and 46°F. c. 0°F and 25°F. d. 30°F and 50°F. 6. Shingrix is a recombinant, adjuvanted vaccine for intramuscular injection and is FDA approved for use in patients ___ years of age and older. a. 40. b. 60. c. 55. d. 50.

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Pharmacy.EliteCME.com Page 110 Chapter 12: Sterile Drug Preparation 1 Contact Hour

By: Katie Blair, PharmD, RPh Questions regarding statements of credit and other customer service Author Disclosure: Katie Blair and Elite Professional Education, LLC issues should be directed to 1-888-666-9053. This lesson is $4.00. do not have any actual or potential conflicts of interest in relation to this Educational Review Systems is accredited by the lesson. Accreditation Council of Pharmacy Education (ACPE) as a Universal Activity Number UAN: 0761-9999-18-194-H07-P provider of continuing pharmaceutical education. This Activity Type: Knowledge-based program is approved for 1 hours (0.1 CEU) of continuing Initial Release Date: April 30, 2018 pharmacy education credit. Proof of participation will be Expiration Date: April 30, 2020 posted to your NABP CPE profile within 4 to 6 weeks to Target Audience: Pharmacy Technicians in a community-based setting. participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course To Obtain Credit: A minimum test score of 70 percent is needed to evaluation to receive continuing pharmacy education credit. obtain a credit. Please submit your answers either by mail, fax, or online at Pharmacy.EliteCME.com Learning objectives Discuss the responsibilities of professionals involved in Describe the five risk levels for microbial contamination of compounding sterile products. compounded sterile products. Introduction Sterile compounding of pharmaceutical products is a fundamental products can be found in USP Chapter <797>. This course reviews practice of pharmacy that is highly regulated due to the potential for the standards of sterile compounding as discussed in USP Chapter harm to patients. The U.S. Pharmacopoeia (USP), a non-governmental <797>. Compliance with these standards is critical to remain compliant non-profit organization, is responsible for the development of standards with state and federal compounding regulations (United States to prevent harm to patients through improperly compounded sterile Pharmacopieal Convention, 2008; American Journal of Health-System products. The standards used to guide the compounding of sterile Pharmacy, 2014). Responsibilities of compounding professionals The USP <797> guidelines outline the responsibilities of personnel ●● All ingredients used in sterile compounding are of adequate quality involved in creating compounded sterile products (CSPs). The guidelines and purity, and correctly labeled. state that “compounding personnel are responsible for ensuring that ●● Containers that have been opened must be appropriately stored. CSPs are accurately identified, measured, diluted, and mixed, and are ●● Non-sterile compounded products containing water must be correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, sterilized within 6 hours. and distributed” (United States Pharmacopieal Convention, 2008). To ●● Appropriate sterilization techniques must be used to ensure sterility ensure these duties are performed appropriately, staff involved in sterile while maintaining the labeled strength of active product ingredients product compounding and dispensing should be supervised by a licensed and packaging integrity. health care professional to ensure that the 14 main objectives are followed ●● All components of CSPs must be clean, measured accurately, and (United States Pharmacopieal Convention, 2008). effective. ●● Employees responsible for compounding sterile products must ●● Prior to dispensing CSPs, potential harm from additives must be be appropriately educated, trained, and skilled to execute and assessed. document the following activities: ●● Packaging that maintains sterility and stability must be used. ○○ Perform appropriate hand cleaning and disinfect non-sterile ●● The environment used to compound sterile products must maintain compounding surfaces. the sterility of the final product, as well as of its ingredients. ○○ Don protective garments appropriately. ●● Appropriate labeling must be completed for all CSPs. ○○ Ensure CSPs are compounded in a sterile environment in ISO ●● Beyond-use dates must be appropriate to the CSP and based on Class 5, and protect sterile environments from contamination. scientific data. ○○ Identify, measure, and weigh ingredients. ●● Correct procedures must be followed when compounding CSPs. ○○ Alter sterile products in an aseptic fashion, sterile high-risk ●● Imperfections in compounding CSPs must be identified and CSPs, and appropriately label and inspect CSPs for quality. corrected quickly. ●● Quality evaluations must be conducted separately from compounding. Environmental quality control for compounded sterile products The International Organization for Standardization (ISO) has adequate lighting and a comfortable working temperature for personnel established a classification system for the cleanliness of the air in to perform sterile compounding comfortably. compounding environments. The cleanest area of the compounding The PEC should be contained by a physically separated buffer area, environment is the area where the actual compounding takes place. as well as by an ante-area, to serve as secondary engineering controls Sterile compounding is performed in a primary engineering control and to prevent contamination of the PEC and CSPs. The buffer area (PEC), which is a machine or room that ensures the environment for containing the PEC shall be an ISO Class 7 environment, or an compounding sterile products remains at an ISO Class 5 level. ISO environment containing not more than 352,000 particles 0.5 micron or Class 5 environments contain not more than 3520 particles 0.5 micron larger per cubic meter of air. The buffer area should provide sufficient or larger per cubic meter of air. The PEC uses HEPA filters to clean space around the PEC. It can contain a small number of devices and the air and provide unidirectional air flow to move particles away from objects such as computers and carts to stage products for compounding; the compounding space. The area containing the PEC should provide the choice of devices and objects for the ante area is dictated by their effect on environmental quality. The buffer area’s environment is

Page 111 Pharmacy.EliteCME.com maintained with an adequate, steady supply of HEPA-filtered air and and shelving should be cleaned monthly (United States Pharmacopieal room pressurization. Convention, 2008; American Journal of Health-System Pharmacy, 2014). The ante-area serves as a space to segregate the buffer area from the rest Environmental monitoring of the facility, as well as providing a place for garbing, decontaminating Monitoring the clean room environment is essential to prevent compounding materials, and housing sinks for hand washing. It must contamination of compounded sterile products. Airborne particle testing meet ISO Class 8 standards, providing air containing not more than should occur at least every 6 months to test for viable particles (living 3,520,000 particles of 0.5 micron or larger per cubic meter of air. organisms such as bacteria or fungi) and non-viable particles (non- Storage of compounding products and equipment should be outside of living particles such as dust). Testing should also occur any time the the buffer and ante-areas (United States Pharmacopieal Convention, PEC is moved or serviced; buffer and ante-areas must be tested every 2008; American Journal of Health-System Pharmacy, 2014). 6 months as well. Airborne particle testing should be performed by Surfaces qualified personnel who comply with the Certification Guide for Sterile Compounding surfaces must be smooth, with no cracks or seams that Compounding Facilities. could trap impurities. All surfaces in the PEC, buffer area, and anteroom Surfaces should be assessed periodically, at least every 6 months must be non-shedding, including walls, ceiling tiles, lighting, flooring, and after any major changes in compounding procedures or cleaning and paint. Stainless steel counters and work surfaces are preferred as occurs. Flat surfaces should be sampled with a nutrient agar contact they are easy to sanitize; if other types of surfaces are chosen they must plate, and non-flat surfaces such as equipment should be sampled be non-porous and easy to sanitize. Flooring should be single sheeting with swabs. Periodic surface sampling allows facilities to determine that is rolled up onto the wall. the effectiveness of cleaning and disinfection procedures, as well as Surfaces should be cleaned with water and a germicidal cleanser to maintaining sterility when compounding sterile products. remove visible contaminants before disinfection. After cleaning, all Controlled temperature areas for the storage or compounding of sterile room surfaces should be disinfected with isopropyl alcohol to remove products should be monitored at least once a day, with results recorded any potential microbial contamination. Personnel performing cleansing in a temperature log. Continuous temperature recording devices may be techniques should exercise caution when cleansing the PEC because the used as long as they are monitored at least once daily to make sure they HEPA filters must not get wet. The ISO Class 5 PEC should be cleaned are working properly. Frozen products should be stored at −25 °C to before each shift, before each batch of compounding, every 30 minutes −10 °C (–13 °F to 14 °F), and refrigerated products should be stored at during long compounding sessions, after any spills, and at any time that 2 °C to 8 °C (36 °F to 46 °F). Room temperature should be maintained contamination is suspected or known. Counters, work surfaces, and in all compounding areas, at 20 °C to 25 °C (68 °F to 77 °F) (United floors in the buffer area should be cleaned daily, and walls, ceilings, States Pharmacopieal Convention, 2008; American Journal of Health- System Pharmacy, 2014) . Beyond-use dating The beyond-use date (BUD) for sterile products is the date and time opening and may not be stored (United States Pharmacopieal Convention, after which the product can no longer be administered to a patient. It is 2008; American Journal of Health-System Pharmacy, 2014). determined based on the time and date the CSP is created, the chemical Multiple-dose containers stability of the product, and the sterility limits. Beyond-use dating can Multi-dose vials can be reused until the BUD recommended by the also be assigned to the products used in compounding, and should product’s manufacturer if they are not opened in a direct patient care be followed carefully to ensure the sterility of compounded products area, and if facility guidelines allow this practice. If the manufacturer (United States Pharmacopieal Convention, 2008; American Journal of does not recommend a BUD, multi-dose vials can be used for up to Health-System Pharmacy, 2014). 28 days after the initial needle puncture, or less if dictated by facility Single-dose containers guidelines. The employee who first opens a multi-dose vial must label Beyond-use dating of products used in the compounding of CSPs can the product with the BUD; multi-dose vials that have not been properly vary based on the design of the packaging. Single-dose vials are designed labeled should not be reused (United States Pharmacopieal Convention, for one time use, and cannot be stored regardless of the environment 2008; American Journal of Health-System Pharmacy, 2014). it was opened in. Similarly, ampules must be used immediately after Risk levels for microbial contamination of CSPs Traditionally, there have been three major risk levels used to describe ●● Less than 3 commercially prepared sterile non-hazardous the risk of microbial contamination of CSPs: low risk, medium risk, and medications in the manufacturer’s original containers are used for high risk. The 2008 revision of USP <797> added two additional risk compounding, and no more than two entries may be made into any levels: immediate use and low risk with 12-hour beyond-use dating. one container. The risk levels are used to determine the type of controls necessary for ●● The compounding process is continuous and occurs over the span of compounding specific types of sterile products, based on their risk of less than 1 hour. contamination, to ensure quality sterile products are delivered to the ●● Aseptic technique is used for compounding and the product is patient (United States Pharmacopieal Convention, 2008; American continuously observed to minimize the risk of contamination. Journal of Health-System Pharmacy, 2014) . ●● The product must be administered to the patient no more than 60 Immediate-use CSPs minutes after the preparation of the product begins. These controls are used for items prepared for emergency use, or ●● The product is labeled appropriately with patient identification, for products that would be delayed in delivery to the patient when names and quantities of all ingredients, and the exact 1-hour BUD compounded under tighter restrictions, potentially harming the patient. and time. The immediate-use risk level is only used for compounded products that ●● If not administered within 1 hour, the product must be discarded. would otherwise be classified as low-risk CSPs; products that would be Low-risk CSPs medium- or high-risk are not appropriate for immediate-use classification. This risk level is used to describe CSPs that are made from When compounding products under the immediate-use risk level, batch commercially available sterile drug products. All compounding of low- compounding and compounding for storage cannot be done. risk CSPs must occur in an ISO Class 5 clean room. The ISO Class 5 CSPs can be classified as immediate use and are exempt from the low- area must be contained within an ISO Class 7 buffer area within an ISO risk level guidelines if all of the following requirements are met (United Class 8 ante area. Employees must follow garbing procedures before States Pharmacopieal Convention, 2008; American Journal of Health- entering the clean room area when compounding low-risk CSPs, and all System Pharmacy, 2014): quality assurance and visual inspection procedures must be followed. ●● Hand hygiene is followed according to Centers for Disease Control The compounding of low-risk CSPs should be simple aseptic transfers recommendations. of products within a closed system; it cannot involve the transfer,

Pharmacy.EliteCME.com Page 112 mixing, or measuring of more than three sterile products, and each detachments and attachments of nutrient source products, as well sterile container cannot be accessed more than twice. Beyond-use dating as filling reservoirs of infusion devices with more than three sterile for low-risk CSPs should be 48 hours or less for products stored at products (United States Pharmacopieal Convention, 2008; American room temperature, 14 days or less for refrigerated products, and 45 days Journal of Health-System Pharmacy, 2014). or less for frozen products (United States Pharmacopieal Convention, High-risk CSPs 2008; American Journal of Health-System Pharmacy, 2014). This classification is reserved for sterile products that are contaminated Low-risk CSPs to be used within 12 hours or are at a high risk of becoming contaminated. This can occur when This classification is used for sterile products compounded in an ISO CSPs are compounded from sterile products that have been exposed to Class 5 clean room that is not located within an ISO Class 7 buffer environments less than ISO Class 5 for longer than an hour, putting their area, such as a satellite pharmacy’s compounding PEC. Since there sterility at risk. Water-containing preparations that are not sterilized is a greater risk of contamination when a buffer area is not used, within 6 hours of compounding are also considered high-risk CSPs, as the beyond-use dating must be shortened to 12 hours, regardless of well as CSPs that are created by employees not wearing proper garb and storage at room temperature or under refrigeration. The sterile product gloves and compounds made from non-sterile ingredients or devices. preparation area must be separated from other operations, and located These products comprise the highest risk level because their purity and away from high traffic areas, unsealed windows, food service areas, strength are not verified through documentation or direct methods of sinks, and construction sites to reduce the risk of contamination. determining their quality. Employees involved in the compounding of sterile products at this risk CSPs in this category must be sterilized prior to administration to a level must follow all garbing, aseptic technique, quality assurance, patient using terminal sterilization. The Food and Drug Administration competency, and environmental testing requirements (United States defines terminal sterilization as applying a lethal process such as Pharmacopieal Convention, 2008; American Journal of Health-System autoclaving or steam under pressure to a sealed container to achieve Pharmacy, 2014). a sterility assurance level of one nonsterile unit per million sterilized Medium-risk CSPs units. If the product cannot be processed with heat due to product heat Medium-risk CSPs involve the use of multiple bulk commercial sterile lability issues, a sterilizing grade filter must be used to filter out any products to create products for more than one patient or several products impurities. Since filtration only ensures a sterility assurance level of one for one patient. They generally involve more complicated aseptic nonsterile unit per thousand sterile units, filtration should be reserved compounding procedures, or those that take a prolonged period of time only for products that cannot be heat processed. to make. Beyond-use dating for high-risk CSPs should be 24 hours or less for Beyond-use dating for medium-risk CSPs should be 30 hours or less products stored at room temperature, 3 days or less for refrigerated for products stored at room temperature, 9 days or less for refrigerated products, and 45 days or less for frozen products. The quality assurance products, and 45 days or less for frozen products. The same quality procedures followed for high-risk CSPs are the same as those used for assurance and environmental conditions as seen with low-risk CSPs apply low-risk products, but employee evaluation is more rigorous. Media- to the medium-risk level, though compounding employees must complete fill evaluation must be completed semi-annually, replicating the most more challenging media-fill evaluations on an annual basis to ensure challenging compounding situations and each high-risk sterilization proper compounding techniques are used for these higher risk products. process with dry non-sterile media verification (United States Pharmacopieal Convention, 2008; American Journal of Health-System Examples of medium-risk CSPs include compounding of total Pharmacy, 2014). parenteral nutrition (TPN) which requires multiple injections, Hazardous products The safety of employees involved in the preparation and storage of ●● Anterooms adjacent to the negative pressure buffer area must be hazardous CSPs is paramount. The National Institute for Safety and positive pressure ISO Class 7, to provide inward air flow to contain Health published guidelines to prevent injuries related to accidental any airborne drug. exposure to hazardous pharmaceutical products, and these guidelines Employees responsible for compounding hazardous products must are closely aligned with USP <797>. These guidelines include (United receive ongoing training that includes (United States Pharmacopieal States Pharmacopieal Convention, 2008; American Journal of Health- Convention, 2008; American Journal of Health-System Pharmacy, 2014): System Pharmacy, 2014): ●● Negative pressure techniques for compounding. ●● Chemotherapy gloves must be worn when receiving, distributing, ●● Aseptic technique. stocking, inventorying, preparing, and disposing of hazardous ●● Training on correct use of biological safety cabinets or medications. compounding aseptic containment isolators. ●● The preparation of hazardous products must occur in an ●● Appropriate use of closed system transfer devices. environment with an ISO Class 5 environment. ●● Procedures for containing, cleaning, and disposing of spills and ●● Biological safety cabinets or compounding aseptic containment breakages of hazardous materials, according to state and federal isolators must be used with an ISO Class 5 environment to ensure regulations. the safety of the compounder. ●● Guidelines to treat employees who have been exposed to hazardous ●● Biological safety cabinets or compounding aseptic containment medications through contact or inhalation. isolators should be completely vented to outside air through HEPA filters. Training and evaluating aseptic technique Personnel involved in compounding sterile products are responsible cosmetics, and artificial nails. Cell phones, MP3 players, and other for accurate measurement, mixing, and dilution of CSPs, as well as personal electronic devices should be removed prior to hand washing ensuring CSPs are properly sterilized, purified, packaged, labeled, and garbing, and should not be brought into the compounding area. stored, dispensed, and distributed. Quality standards must be maintained Food, drinks, gum, and paper products are prohibited in the ante-, to control the compounding processes and environments. Quality buffer, and compounding areas. standards must also be established to assess the knowledge and skills of Hand hygiene must occur before and after gowning. Hands, wrists, arms compounding personnel. (up to the elbow), and fingernails should be washed for 30 seconds with Cleaning and garbing a cleansing agent approved by the facility before drying with a non- Employees involved in compounding sterile products must comply shedding towel or electric hand dryer. After washing, hands should be with hand hygiene and garbing procedures to minimize the risk of sanitized with an alcohol-based hand rub. contaminating compounding areas. Employees must remove personal outer garments, jewelry on visible body parts such as hands and wrists,

Page 113 Pharmacy.EliteCME.com Garbing, or putting on clothing to maintain the sterility of the before placing in the PEC and the overwrap should be discarded compounding area, should be done before entering the buffer area immediately (United States Pharmacopieal Convention, 2008; American or anteroom. Personal protective equipment should be put on in the Journal of Health-System Pharmacy, 2014). following order: Competency testing ●● Shoe covers. Employees involved in the compounding of sterile products are required ●● Hair covers for head and facial hair. to pass a written examination at the end of their training. Competency ●● Eye shields and/or face masks. in aseptic technique must be demonstrated, as well as appropriate ●● Perform hand washing. use of products and devices used to create CSPs. Maintenance of the ●● Non-shedding gown. compounding environment should also be assessed, including garbing, Once the employee has entered the buffer area or anteroom, he or she cleaning, and disinfection techniques used to maintain the various ISO must: Class conditions. ●● Put on sterile, powder-free gloves. Compounding employees must also be evaluated through skills tests. ●● Sanitize gloves with 70% isopropyl alcohol and allow them to dry. Hand washing techniques should be observed and evaluated, and gloved Employees with infections such as conjunctivitis, weeping wounds, fingertip sampling shall be conducted during employee assessment to rashes, or infections of the respiratory system may not compound sterile ensure compounding personnel minimize the risk of contamination of products until the infection is resolved. Facilities should establish CSPs. policies for ensuring compounding personnel meet set thresholds for Media-fill testing, which requires the compounding employee health status (United States Pharmacopieal Convention, 2008; American to prepare a test product that will be incubated and assessed for Journal of Health-System Pharmacy, 2014). possible contamination, must be performed to objectively evaluate an Compounding areas employee’s CSP. Media-fill testing must occur at least annually for Before entering compounding areas, employees must remove cardboard employees involved in low- to medium-risk compounding, and semi- packaging from products used in compounding, and products that are annually for high-risk compounders (United States Pharmacopieal not overwrapped should be decontaminated with a facility-approved Convention, 2008; American Journal of Health-System Pharmacy, disinfectant. Products in plastic or foil overwrap should remain wrapped 2014). until they are introduced to the PEC, and should be opened immediately Labeling and final verification All CSPs must be checked by a pharmacist prior to dispensing to ●● Active ingredients. ensure the compound was prepared accurately. A visual inspection ●● Concentrations of active ingredients. should be performed to check for any visible errors, such as rubber ●● Beyond use date and time. cores, unwanted particles in suspension, and discolorations. Checking ●● Any requirements for storage. procedures should follow facility protocol, and can be done by checking ●● Identification of the person responsible for preparing the compound. the supplies used in compounding, cameras, or video recordings. In addition, CSPs prepared in batches must include the lot number, Sterility and endotoxin testing may be required for large batches of precautions and auxiliary labeling, and any necessary device-specific high-risk CSPs. Accuracy should be checked by someone other than the instructions (United States Pharmacopieal Convention, 2008; American compounder to minimize the risk of error. Journal of Health-System Pharmacy, 2014). CSPs should be accurately labeled to ensure patient safety. Labels must include: References American Journal of Health-System Pharmacy. (2014). ASHP Guidelines on Compounding Sterile The United States Pharmacopeial Convention. (2008). Pharmaceutical Compounding – Sterile Preparations. 71 (2) 145-166. Retrieved from https://www.ashp.org/-/media/assets/policy-guidelines/ Preparations. Retrieved from https://www.sefh.es/fichadjuntos/USP797GC.pdf docs/guidelines/compounding-sterile-preparations.ashx

Pharmacy.EliteCME.com Page 114 STERILE DRUG PREPARATION Final Examination Questions Choose the best answer for questions 1 through 10 and mark your answers online at Pharmacy.EliteCME.com

1. Sterile compounding is performed in a PEC, which is a machine 7. ______must be worn when receiving, distributing, or room that ensures the environment for compounding sterile stocking, inventorying, preparing, and disposing of hazardous products remains at the following level: medications. a. ISO Class 5 level. a. Face masks. b. ISO Class 4 level. b. Gown. c. ISO Class 7 level. c. Chemotherapy gloves. d. ISO Class 8 level. d. Shoe covers. 2. ______counters and work surfaces are preferred in 8. Which of the following items is allowed in compounding areas? compounding areas as they are easy to sanitize. a. Food. a. Plastic. b. Drinks. b. Granite. c. Paper products. c. Stainless steel. d. Face masks. d. Wood. 9. Which of the following is NOT a required piece of personal 3. When monitoring the clean room environment, airborne particle protective equipment required when compounding sterile products? testing for viable and non-viable particles should occur at least a. Ear covers. every ______months. b. Shoe covers. a. 12. c. Hair covers for head and facial hair. b. 6. d. Eye shields and/or face masks. c. 3. d. 24. 10. Which of the following is NOT required on a label for a compounded sterile product? 4. Refrigerated compounded sterile products should be stored a. Active ingredients. between: b. Inactive ingredients. a. −25 °C to −10 °C. c. Beyond use date and time. b. 2 °C to 8 °C. d. Identification of the person responsible for preparing the c. 8 °C to 16 °C. compound. d. 20 °C to 25 °C. 5. If the manufacturer does not recommend a BUD, multi-dose vials can be used for up to ____ days after the initial needle puncture, or less if dictated by facility guidelines. a. 28. b. 14. c. 10. d. 30. 6. Beyond use dating for low-risk CSPs should be _____ hours or less for products stored at room temperature. a. 24. b. 48. c. 72. d. 96.

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Each licensee sets up a NABP profile and is assigned a NABP e-profile number. The licensee registers with CPE Monitor using their e-profile ID number. Licensees are required to give their e-Profile ID and their date of birth to providers in order to receive credit for an ACPE accredited course.

For more information on CPE Monitor: www.CPEmonitor.net

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Customer Information All 30 Hrs ONLY $99 Three Easy Steps to Completing Your License Renewal Step 1: Complete your Elite continuing education courses: 99 Read the course materials and answer the test questions. 99 Submit your final exams along with your payment to Elite online. 99 Complete the course evaluation. What if I Still Have Step 2: Receive your certificate of completion: Questions? 99 Go to Pharmacy.EliteCME.com and follow the prompts. No problem, we have several You will be able to print your certificate immediately upon options for you to choose from! completion of the course. Online at Pharmacy.EliteCME. com you will see our robust FAQ Step 3: Once you have received your certificate of completion you section that answers many of can renew your license online at https://pharmacy.az.gov/ your questions, simply click FAQ node/5126, or mail in your renewal. in the upper right hand corner or e-mail us at office@elitecme. Board Contact Information: com or call us toll free at 1-888- Arizona State Board of Pharmacy 666-9053, Monday - Friday 9:00 Mailing Address: am - 6:00 pm, EST. P.O. Box 18520 Phoenix, AZ 85005 Physical Address: 1616 W. Adams St., Suite 120 Phoenix, AZ 85007 Phone: (602) 771-2727 | Fax: (602) 771-2749 Website: https://pharmacy.az.gov/

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