Louisiana Society of Health-System Pharmacists 2016 Midyear Meeting

October 1, 2016

Program Book LOUISIANA SOCIETY OF HEALTH‐SYSTEM PHARMACISTS BOARD OF DIRECTORS AND COMMITTEE CHAIRS

Jennifer Smith—President Shawn Manor—Immediate Past President Joseph Gary Leblanc—President Elect Kisha Gant—Secretary Tommy Mannino—Treasurer Monica Morgan—Director at Large —Director at Large Scott Dantonio—Director at Large Roxie Stewart—Director at Large Jason Chou—Director‐elect Jessica Brady—Director‐elect

Ashley Sadowy—NLSHP President Vacant—NELSHP President Alexis Horace—SCLSHP President Christopher Gillard—SELSHP President Shane Domingue—SWLSHP President Joseph Gary LeBlanc—CLSHP President

Jessica Brady‐University of Louisiana at Monroe Faculty Liaison Iman Borghol‐Xavier University Student Faculty Liaison

Committee Chairs Jamie Terrell—Education & Workforce Development Mike Loftin & Scott Dantonio– Pharmacy Management William Kirchain & Jeff Evans– Public Policy Vacant– Programming & Practitioner Education Dana Jamero– Publications Lisa Ross—Membership & Marketing Tammy Belleau– Pharmacy Practice Helen Calmes– Organizational Affairs & Documents Anne LaVance– Technician Activities Katie Ducote—New Practitioners Committee Elizabeth Laitte & Katie Astle—Midyear Meeting Coordinators

Table of Contents

General Information & Activities 1

Midyear Meeting Program 3

Sponsors & Exhibitors 5

Syllabus (listed chronologically)

More Than Black and White? What Pharmacists Need to Know about contrast Media 6 Kathryn Astle, PharmD, BCPS

Medication Reconciliation: A Tale of Two Hospitals 16 Monica Morgan, PharmD & Catherine Oliver, PharmD, BCPS

Biosimilars: Are They Similar Enough? 28 Morgan Corbin, PharmD

Updates in Sepsis Management 41 Katherine Jennings, PharmD

Essential Oils: The Essentials of Their Safety and Eficacy 52 Stephanie Hatten, PharmD

Pharmacy Legislative and Administrative Update 64 Jeff Evans, PharmD

Can’t Stop Bleeding, A Journey through Anticoagulation Reversal 71 Jill Comeau, PharmD, BCOP

Would You Like Fries With That? Intro to Parenteral and Enteral Nutrition for Pharmacists 82 Katie Weigartz, PharmD

Review of Current Treatment for Acute Coronary Syndromes 93 Olivia Antosz, PharmD

Antifuntal Therapies for Systemic Infections 108 Ashley Trojcak, PharmD

Appropriate Use of Antipsychotics in the Inpatient Setting 121 Alyssa Simpson, PharmD

General Information & Activities Registration The Midyear Meeting Registration and Information Desk will be open from 7:00 a.m.-5:00 p.m.

Badges Badges must be worn at all times. Badges are required for admittance to all Midyear Meeting functions. Registrants, staff, guests and speakers have white badges. Exhibitors have blue badges.

Meeting Locations All meeting sessions and exhibits will be held on the 2nd level of the Shreveport Convention Center. Please consult the program-at-a-glance or the schedule in this program book for specific meeting room locations.

Continental Breakfast There will be a continental breakfast from 7:00-7:45 a.m. in the Pre-Function Area on the 2nd floor.

Exhibit Program The exhibit program is located in Ballroom C&D on the 2nd level of the Shreveport Convention Center from 11:00 a.m. to 12:00 p.m. Our exhibitors then join us for lunch at noon. Please take time to visit our exhibitors and express your thanks for their participation. Additionally, please thank your local representative whom you see regularly at your practice site.

Lunch Lunch is provided for all paid registrants and exhibitors. Lunch will be served in the Exhibit Area of Ballroom C&D at 12:00 p.m.; lunch will not be served prior to 12:00. Please remember bring the lunch ticket found in your packet with you; lunch is only served to those with a ticket. Spouses/ guests are invited to attend lunch for $25 per ticket.

Continuing Education Credit The Louisiana Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. A total of 11 contact hours (1.10 CEUs) are scheduled for Saturday’s program, of which a maximum of 7 hours (0.7 CEUs) may be earned by an individual participant.

Evaluations Activity evaluations are extremely important in the development of educational needs assessment for future programs. Please take a moment to evaluate each CE activity you attend; we appreciate and value your input. A booklet of evaluations was included in your registration packet. Please personally turn in your evaluation packet at the end of the meeting, or after attending your last CE activity. We must collect this evaluation packet for you to receive CE credit for the activities at this meeting. Also, a separate general meeting evaluation form is in your packet. Please complete it and turn it in at the registration desk.

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General Information & Activities, continued

Certification of Continuing Education Hours/ How to Receive Credit: To receive credit for continuing education activities at the Midyear Meeting registrants must: 1. Register and pay all applicable fees. 2. Attend the activity. 3. Complete the Continuing Education Credit Report packet that you received at registration. 4. Initial next to each activity that you attend. PARTIAL CREDIT WILL NOT BE GIVEN FOR ANY ACTIVITY. (For example, if you attended only 1 hour of a 2 hour activity, then you will not get any credit for it.) 5. Complete and sign the form and submit to the registration desk at the end of the conference or after attending your last activity. Include on the form your month of birth in “MM” format (for example, January is “01”) and day of birth in “DD” format (for example, the 3rd of the month is “03”). Also include your NABP e-Profile ID.

Due to ACPE credit recordation requirements, LSHP no longer issues statements of credit. Your CE credit will be recorded by the LSHP office electronically via CPE Monitor (see details below) within 60 days after the meeting.

CPE Monitor is a national, collaborative effort by ACPE and the National Association of Boards of Pharmacy (NABP) to provide an electronic system for pharmacists and pharmacy technicians to track their completed continuing pharmacy education (CPE) credits. All pharmacists and pharmacy technicians must obtain their NABP e-Profile ID by going to www.nabp.net. Your NABP e-Profile ID is required to receive credit for the LSHP Midyear Meeting. After the Midyear Meeting, LSHP will send to NABP and ACPE (via the CPE Monitor) the amount of credit you received (using your e-Profile ID) at the Midyear Meeting. Once this information is received by NABP, pharmacists and pharmacy technicians will be able to log in to access information about their completed CPE.

To receive credit, registrants must attend activities designated for their credential. Activities acceptable for pharmacists are indicated by a “P” suffix in the activity number. Programs acceptable for pharmacy technicians are indicated by a “T” suffix in the activity number.

A total of 11 contact hours (1.10 CEUs) are scheduled for Saturday’s program, of which a maximum of 7 hours (0.7 CEUs) may be earned by an individual participant.

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Program Saturday, October 1, 2016

Registration 7:00 A.M.—5:00 P.M.

Continental Breakfast 7:00—7:45 A.M. Pre-function Area - Level 2

Welcome & Announcements

Joint Session 8:00—9:00 A.M.

More Than Black and White? What Pharmacists Need to Know About Contrast Media Kathryn Astle, PharmD, BCPS 0179-0000-16-024-L01-P/ 0179-0000-16-024-L01-T Meeting Rooms 202/203

Concurrent Sessions 9:00—10:00 A.M.

9:00 - 10:00 a.m. 9:00—10:00 a.m. Medication Reconciliation: A Tale of Two Biosimilars: Are They Similar Enough? Hospitals Morgan Corbin, PharmD Monica Morgan, PharmD 0179-0000-16-026-L01-P/ Catherine Oliver, PharmD, BCPS 0179-0000-16-026-L01-T 0179-0000-16-025-L04-P/ Meeting Room 204 0179-0000-16-025-L04-T Meeting Rooms 202/203 Concurrent Sessions 10:00—11:00 A.M.

10:00—11:00 a.m. 10:00—11:00 a.m. Updates in Sepsis Management Essential Oils: The Essentials of Their Safety Katherine Jennings, PharmD and Efficacy 0179-0000-16-027-L01-P/ Stephanie Hatten, PharmD 0179-0000-16-027-L01-T 0179-0000-16-028-L01-P/ Meeting Room 202/203 0179-0000-16-028-L01-T Meeting Room 204

Exhibits 11:00 A.M.—12:00 P.M Ballroom C&D

Lunch 12:00—1:00 P.M. Ballroom C&D

Program continued on next page. 3

Program (continued)

Joint Session 1:00—2:00 P.M.

Pharmacy Legislative and Administrative Update Jeff Evans, PharmD 0179-0000-16-035-L03-P/ 0179-0000-16-035-L03-T Meeting Rooms 202/203

Concurrent Sessions 2:00—3:00 P.M. Can’t Stop Bleeding, A Journey through Would You Like Fries With That? An Intro to Anticoagulation Reversal Parenteral and Enteral Nutrition for Pharmacists Jill Comeau, PharmD, BCOP Katie Weigartz, PharmD 0179-0000-16-030-L01-P/ 0179-0000-16-029-L01-P/ 0179-0000-16-030-L01-T 0179-0000-16-029-L01-T Meeting Rooms 202/203 Meeting Room 204

Concurrent Sessions 3:00—4:00 P.M.

Review of Current Treatment for Acute Coronary Antifungal Therapies for Systemic Infections Syndromes Ashley Trojcak, PharmD Olivia Antosz, PharmD 0179-0000-16-032-L01-P/ 0179-0000-16-031-L01-P/ 0179-0000-16-032-L01-T 0179-0000-16-031-L01-T Meeting Room 204 Meeting Rooms 202/203

Joint Session 4:00—5:00 P.M. Appropriate Use of Antipsychotics in the Inpatient Setting Alyssa Simpson, PharmD 0179-0000-16-033-L01-P/ 0179-0000-16-033-L01-T Meeting Rooms 202/203

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Sponsors The success of LSHP’s Midyear Meeting depends, in large part, on the participation and support of pharmaceutical and related interests. LSHP is very appreciative of the companies listed below that have generously supported the 2016 Midyear Meeting by educational or event sponsorship.

Meeting Sponsor Exhibitors Below are the companies who are exhibiting this year. Please be sure to visit their exhibit table and thank them for supporting LSHP.

Abbvie American Regent, Inc. Chiesi USA, Inc. CSL Behring Intelliguard RFID Solutions Ipsen McKesson Pharmaceutical Morris & Dickson Co. Octapharma Omnicell PharMEDium Services, LLC Prodigy Health Sunovion Pharmaceuticals TEVA Oncology

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Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

8:00—9:00 a.m. More Than Black and White? What Pharmacists Need to Know About Contrast Media

Kathryn Astle, PharmD, BCPS Emergency Medicine/Inpatient Pharmacist University Health-Shreveport Shreveport, LA

0179-0000-16-024-L01-P/ 0179-0000-16-024-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacist Technician 1. Review currently available contrast media 1. Recognize agents that are classified as agents and the safety profile of each. contrast media. 2. Describe routes of administration for 2. Distinguish iodine-based contrast agents currently available contrast media. from gadolinium-based contrast agents. 3. Explain how to recognize and manage patients at risk for adverse effects from contrast media.

Dr. Astle has disclosed that she has no relevant financial relationships.

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DISCLOSURES

 I have nothing financial to disclose 

MORE THAN BLACK AND  I intend for you to learn a lot during this presentation! Katie Astle, WHITE? WHAT Pharm.D., BCPS PHARMACISTS NEED TO KNOW ABOUT CONTRAST MEDIA

PHARMACIST OBJECTIVES TECHNICIAN OBJECTIVES

 Review the currently available contrast media and the safety  Recognize agents that are classified as contrast media profile of each  Distinguish iodine‐based contrast agents from gadolinium‐based  Describe routes of administration for currently available contrast contrast agents media  Explain how to recognize and manage patients at risk for adverse effects of contrast media

OVERVIEW CT VS. MRI

 Contrast agents have changed the game on modern‐day radiologic imaging studies CT MRI  Uses X‐rays  Magnetic  According the CDC, the number of patients who receive   computed tomography (CT) or magnetic resonance imaging (MRI) Radiation exposure Time consuming in the emergency department has nearly tripled since 2001  Often used in the ER due  Expensive . 6% in 2001 vs. 17% in 2010 to its ability to be done  May cause more quickly claustrophobia for  There has been some interest in recent years in getting more patients oversight of the practices of the radiology department . Currently, although contrast media are medications, the Joint Commission does not require pharmacist verification prior to administration

CDC. National Hospital Ambulatory Medical Care Survey. Available at http://www.cdc.gov/nchs/ahcd/ahcd_questionnaires.htm.

7 CLASSIFICATION

 Classified based on structure (monomer vs. dimer), ionization, and osmolality  Structure based on modifications of the 2, 4, 6 tri‐iodinated benzene ring structure

IODINE‐BASED CONTRAST High‐Osmolality MEDIA

Low‐Osmolality

Iodinated Contrast Media: Classification and Use IODINE‐BASED CONTRAST MEDIA ‐

Ionic High‐Osmolality Contrast Media (HOCM) ‐ > 1000 mOsm/kg OSMOLALITY Use: Oral or GI1, Intrauterine, Bladder Ionic Monomers  Oral/GI: diatrizoate sodium/diatrizoate meglumine (Gastrografin®, Higher Osmolality is a measure of the number of dissolved Gastroview®), diatrizoate sodium (Hypaque®) Osmolality particles per kilogram of water Intrauterine: iodipamide meglumine/diatrizoate meglumine (Sinografin®) . Osmolarity is per liter Bladder: iothalamate meglumine (Conray®, CystoConray®), diatrizoate meglumine (Cystografin®) . Normal human plasma: 270 – 300 mOsm/kg Use: Arteriography ONLY! . Normal CSF: 280 – 300 mOsm/kg Ionic Dimer Ioxaglate (Hexabrix®) – Withdrawn from market September 2015  Osmolality depends on concentration and ionicity  Osmolality has a threshold phenomenon for causing pain Non‐Ionic Low‐Osmolality Contrast Media (LOCM) < 900 mOsm/kg and ultimately, tissue damage Use: IV, IT2, Intrauterine, Bladder, Oral/Rectal1 Non‐ionic Monomers . Peripheral vein: < 600 mOsm/kg = no injection site pain Iohexol (Omnipaque®), Iopamidol (Isovue®), Iopromide (Ultravist®), Ioversol > 900 mOsm/kg = injection site burning and pain (Optiray®) Non‐ionic Dimers (iso‐osmolar contrast) Lower Iodixanol (Visipaque®) Osmolality

1Oral/Rectal: Iohexol only FDA‐approved, others off‐label use 2Intrathecal: Iohexol, Iopamidol only FDA‐approved, 180‐300 mg/mL concentrations only, 10‐20 mL max

HIGH‐OSMOLALITY IODINE‐BASED LOW‐OSMOLALITY IODINE‐BASED CONTRAST MEDIA CONTRAST MEDIA

 Greater than 1000 mOsm/kg  Broad Use: Intravascularly, intra‐arterially, oral, rectal, GI, bladder, intrauterine, intra‐articularly . 5‐8X normal plasma osmolality  General Properties  100% ionic . Osmolality ranges 290 – 844 mOsm/kg . Two generic names: anion + cation . Normally used concentration: 200 – 370 mgI/mL (300 mgI/mL most often used)  NOT routinely given intravascularly due to adverse physiological . Cost is ~ 10X higher than HOCM effects . Associated with lower incidence of adverse drug events than HOCM  Restricted to GI tract, bladder, gallbladder, uterus, and fallopian  Further subcategorized by iconicity tubes . Ionic dimer (no longer available in U.S.)  Should be stored SEPARATELY from IV formulations of contrast . Non‐ionic monomer . Non‐ionic dimer (i.e., iso‐osmolar contrast)

mgI/mL = milligrams of Iodine per milliliter

8 WARMING IODINE‐BASED CONTRAST VISCOSITY MEDIA

 High viscosity = lower miscibility (mixing with blood)  Effects: Warming from room temperature to body temperature . As molecular size, shape, weight, and iodine concentration increases, reduces viscosity by ~50% viscosity increases  When to warm? . High rate IV LOCM power injectors (>5 ml/sec)  Normal Plasma Viscosity = 1.4 –1.8 cP at 37°C . Injections of viscous LOCM with concentrations > 300 mgI/mL . Direct arterial injections through small‐bore catheters (5 Fr or less)  Higher viscosity agents = higher injection pressures to initiate . IV injected arterial studies in which timing and peak enhancement are and maintain iodine delivery rates = increased risk of catheter critical damage/vascular trauma

CHOOSING YOUR AGENT CONCENTRATION AND VOLUME

 GI Tract Imaging  FDA‐approved range for adult low‐osmolar contrast media . If previous allergic reaction to barium, use HOCM or LOCM iodine‐based enhanced CT head and body exams: 30 –60 grams iodine agents  Factors that determine how much contrast the patient may . If barium unavailable, generally use HOCM, unless LOCM clinically receive: preferred or less expensive . Scanner technology (strength & speed) and radiologist’s preference . Injectable LOCM is generally preferred over barium and HOCM if: . Patient’s clinical condition and the procedures being performed . Suspected bowel perforation (trauma)  Concentration influences image quality – depends on location or . Unable to swallow/risk for aspiration (neonates) depth of the area of interest . Surface features (veins) –lower concentrations used (200 – 250 mgI/mL)  Drug shortages/price changes of HOCM have resulted in more off‐label use of LOCM orally or rectally . Deep features (arteries, coronary angiogram) –higher concentrations necessary (300 – 370 mgI/mL) . All LOCM CAN be administered orally or rectally – diluted or full strength  Volume . Depends on the number and size of the vessels or cavity imaged

INTRA‐ARTERIAL DOSES IV DOSES

Procedure (ICM Injection site Adult Dose Max Dose Procedure (ICM Injection Site Adult Dose Maximum concentration) concentration) Dose Peripheral Venography Peripheral venography Minimum volume 250 mL (60 grams (240 – 250 mgI/ml) necessary to visualize iodine) Cerebral arteriography Carotid arteries 3 –12 mL 150 mL (45 Excretory Urography Excretory urography ~300 mgI/kg body 100 mL (30 grams (300 – 320 mgI/ml) Vertebral arteries 4 –12 mL grams iodine) (300 mgI/ml) weight iodine) Aortic arch injection (4 vessel 20 –50 mL Contrast CT (300 Head 50 – 200 mL 200 mL (60 grams study) mgI/ml) iodine) Peripheral Subclavian or Femoral artery 5 –40 mL 200 mL (60 Contrast CT (300 – 320 Body 200 mL (60 grams arteriography (300 Aortic bifurcation 25 – 50 mL grams iodine) mgI/ml) Bolus injection 50 – 200 mL iodine) mgI/ml) Rapid Infusion 100 – 200 mL Contrast CT (350 – 370 Head 41 – 162 mL 200 mL (60 grams Coronary arteriography Right coronary artery 3 –14 mL 200 mL (60 mgI/ml) iodine) and left Left coronary artery 3 –14 mL grams iodine) ventriculography (300 Left ventricle 30 –60mL Contrast CT (350 – 370 Body 200 mL (60 grams – 370 mgI/ml) mgI/ml) Bolus injection 41 – 162 mL iodine) Rapid infusion 81 – 162 mL

9 SAFETY CONSIDERATIONS ACUTE ADVERSE EVENTS: CLASSIFICATION

 Acute adverse reactions Symptoms Treatment . WITHIN 1 hour of injection  Allergic reactions Mild (self‐limiting) Nausea, mild vomiting Observation & Urticaria, itching reassurance  Delayed adverse reactions . AFTER 1 hour and up to 1 week post‐injection Moderate (potential Severe vomiting Symptomatic Marked urticarial treatment & close  Post‐contrast acute kidney injury and contrast‐induced to be severe) Bronchospasm monitoring nephropathy Facial/laryngeal edema  Special populations Vasovagal symptoms  Extravasation Severe (potential Hypotensive shock CPR/code cart morbidity/death) Respiratory arrest Hospitalization (initial Cardiovascular arrest & or prolonged) severe arrhythmias Convulsions

ACUTE ADVERSE REACTIONS: RISK FACTOR PHYSIOLOGIC REACTIONS SCREENING

 Product Specific  Vasovagal Reactions . High‐osmolality ionic contrast media: avoid or minimize intravascular . Relatively common, usually self‐limited, observation is the best use for all patients treatment . Hypotension + bradycardia  Patient Related  Cardiovascular Reactions . Previous history of ICM reaction: 7‐17% increased rate of mild reactions . Mild reactions not shown to increase rate of serious adverse events . Specifically in patients with underlying CV disease or those . Previous moderate or severe acute ICM reaction: 5X increased risk of undergoing cardiac imaging subsequent acute reactions . Increased risk of pulmonary edema in HF patients . Any severe allergic reaction to food or medication that required medical  Anxiety treatment . May be necessary to pre‐medicate patients . Hereditary predisposition (atopic syndrome): asthma, hay fever, allergic rhinitis, or dermatitis (eczema or psoriasis) . Can potentiate other adverse effects

RISK FACTORS FOR ACUTE ADVERSE ALLERGIC‐LIKE REACTIONS REACTIONS

 Manifest similarly to true allergic reactions, but because the  Prior allergic‐like reaction to contrast media is the most allergen‐antibody response cannot always be identified, these substantial risk factor for a recurrence reactions are called “anaphylactoid”, “allergic‐like”, or . Prior allergic‐like reaction does not mean the patient will experience a “idiosyncratic” recurrence . Literature suggests that these occur in 10‐35% of patients  Etiology: Not fully understood  Asthma . We do know that ICM causes histamine release from basophils and mast . More likely to experience bronchospasm cells  activation of the complement & kinin system  Underlying cardiovascular disease  patients more susceptible . NO cross‐reactivity between “iodine‐rich” foods and iodine‐based to hemodynamic changes contrast media  Test injections do NOT reduce the incidence of adverse . Reactions due to iodinated solutions or ointments (povidone iodine) are reactions, and are not recommended by ACR UNRELATED to iodine

 Treatment: Exactly the same as a true allergic reaction

10 ACUTE REACTIONS: PREVENTION DELAYED REACTIONS

 Consider alternate testing that does not require ICM  Most commonly cutaneous reactions occurring three hours to 2  Use a different ICM agent than before days post‐exposure  NO test dose –not useful . Incidence: 0.5% ‐ 14% .  Premedication More common in patients treated with IL‐2 therapy . Elective procedure  Symptoms . Oral prednisone > IV if there is at least 6 hours until imaging . Cutaneous: urticaria +/‐ persistent rash, pruritis, sometimes angioedema . H1 antihistamine oral or IV 1 hour prior (e.g., diphenhydramine 50 mg) . Allergic‐like . Emergency procedure . Also possible: nausea, vomiting, fever, headache, drowsiness . Methylprednisolone 40 mg IV or hydrocortisone 200 mg IV every 4 hours prior  Treatment: to ICM . Generally self‐limiting – minimal or no treatment . Diphenhydramine 50 mg IV 1 hour prior to ICM . Symptomatic relief with corticosteroids and/or antihistamines, . Note: May exclude steroids altogether and just administer H1 antagonist antipyretics, and antiemetics

POST‐CONTRAST ACUTE KIDNEY INJURY AND CONTRAST‐INDUCED NEPHROPATHY: DEFINITION PC‐AKI & CIN: PATHOGENESIS

 Post‐contrast acute kidney injury (PC‐AKI): General term for  PC‐AKI may be caused by any nephrotoxic event (including CIN) sudden deterioration in renal function that occurs WITHIN 48 which is coincident to the IV administration of contrast material HOURS following IV iodine‐based contrast . There is a normal daily fluctuation in serum creatinine (SCr) . May occur regardless of whether the contrast media was the cause . Patients with underlying kidney disease have greater variability in their  Contrast‐induced nephropathy (CIN): Specific term for sudden SCr than normal patients deterioration in renal function that is CAUSED BY IV administration of iodine‐based contrast  Pathogenesis of CIN not fully elucidated . CIN is a subgroup of PC‐AKI . Possibly due to renal vasoconstriction  CIN ≠ PC‐AKI, however in many studies, there is not a suitable . Osmotic and direct chemotoxic mechanisms control group to distinguish CIN from PC‐AKI so they are often . Possibly due to direct tubular toxicity reported together . Direct cytotoxic effect on tubular epithelial cells  As of today, ACR recognizes “…that CIN is a real, albeit rare, entity”

CIN: INCIDENCE & PATIENT HARM CIN: RISK FACTORS

 3rd leading cause of hospital‐acquired acute kidney injury  CKD is the most important risk factor for development of CIN . eGFR is more reliable than SCr in assessing CIN risk  Overall incidence of CIN ~6.5% among patients with risk factors  Diabetes mellitus  Acute kidney injury  Patient harm  Dehydration (any condition associated with hypovolemia) . Increased length of stay (LOS): average of 2 days  Large contrast volumes –proportional nephrotoxic effect . 0.4 to 1% require dialysis –increased LOS by 17 days  Cardiac angiography . Increased in‐hospital mortality  ICM repeated within the last week . 22% mortality during index hospitalization vs. 1.4% without CIN  Acute gout . Increased post‐discharge morbidity and mortality . 1 year mortality: 12.1% with CIN vs. 3.7% w/o CIN  Concurrent nephrotoxic medications . 5 year mortality: 44.6% with CIN vs. 14.5% w/o CIN . All have a much higher incidence of renal, cardiac, and neurological events

11 SCREENING GUIDELINES: WHO NEEDS A CIN RISK REDUCTION STRATEGIES BASELINE SCR?

 Determine eGFR prior to procedure  Baseline SCr should be obtained for all patients with CIN risk factors  Consider alternative imaging studies (ultrasound, non‐  Patients WITH the following risk factors SHOULD HAVE a baseline contrast MRI) SCr  Use the lowest effect dose (concentration & volume) of . Age > 60 years contrast media possible . History of renal disease (eGFR ≤ 60 ml/min/1.73m2)  Stop nephrotoxic drugs . History of hypertension requiring medical therapy . History of diabetes mellitus  Routine/emergency hydration protocols . Intra‐arterial ICM injection or CT angiography exam  Antioxidants  No maximum interval between baseline renal function assessment . Oral Acetylcysteine – insufficient evidence to recommend and ICM administration in at‐risk patients . Outpatients: Typically 30‐60 days (some, up to 6 months) . Inpatients: Typically within 1‐2 weeks . Shortened interval recommended for patients with a new risk factor or heightened risk of renal dysfunction (abdominal trauma)

METFORMIN & CONTRAST‐INDUCED EXTRAVASATION NEPHROPATHY

 Metformin does NOT increase the risk of CIN  Incidence ranges from 0.1% ‐ 0.9%  Patients who develop a PC‐AKI while taking metformin are . NOT related to injection flow rate susceptible to lactic acidosis  Symptoms:  Patient management is risk‐based . Frequently, patients will complain of burning and pain at the injection . Category I: Patients with no evidence of AKI and eGFR ≥ 30 site ml/min/1.73m2  there is NO need to discontinue metformin either . May be erythematous/edematous prior to or following contrast administration . Some may experience little or no discomfort . Also do NOT have to monitor patient’s renal function after the administration  Treatment . Category II: Patients with AKI, or moderate‐severe CKD (eGFR < 30), or . No clear guidelines undergoing arterial catheter studies that may result in emboli to the renal arteries, metformin should be temporarily discontinued at the . ACR recommends raising the affected extremity above the level of the time of the procedure, withheld for 48 hours, and reinstituted ONLY heart if possible after renal function has been found to be normal . Warm and cold compresses can be used . Available evidence does not support the aspiration of contrast media or local injection of other medications like corticosteroids or hyaluronidase

PATIENTS AT INCREASED RISK FOR ASSESSMENT QUESTION EXTRAVASATION

 Those who cannot communicate adequately  True or False: High osmolar contrast media are completely safe . Elderly, infants/children, altered consciousness for intravascular use.

 Severely ill or debilitated patients

 Patients with abnormal circulation to the limb being injected

. Raynaud’s, PVD, diabetic vascular disease, venous thrombosis or FALSE!! insufficiency

 Certain injection sites . Hand, wrist, foot – should be avoided if possible

 Use of an indwelling line that has been in place for > 24 hours

12 ASSESSMENT QUESTION

 JR is a 63 y/o patient with a PMH of DM, CKD, HTN, HLD, and CAD. He presents to the ED with a complaint of abdominal pain. He has had previous gastric emptying studies done which do not show gastroparesis. The ED MD wants to obtain an abdominal CT with contrast. Which of the following is correct regarding contrast administration GADOLINIUM‐BASED in JR? . A. There should be zero problems concerning contrast administration in JR CONTRAST AGENTS . B. We should recommend checking a SCr on JR . C. We should find out if JR takes metformin at home . D. JR should probably receive some IV hydration prior to his contrast study . E. B, C, and D E. B, C, and D

FACTORS AFFECTING THE SAFETY OF AVAILABLE AGENTS GADOLINIUM BASED CONTRAST AGENTS

 Stability . Ionicity  Gadopentetate dimeglumine (Magnevist®) Oldest (1988) . Linear vs. macrocyclic structure  Gadoteridol (ProHance®)  Osmolality  Gadodiamide (Omniscan®)  Viscosity  Gadoversetamide (Optimark®)  Gadobenate dimeglumine (MultiHance®)  Gadoxetate disodium (Eovist®/Primovist®)  Gadofosveset trisodium (Ablavar®)  Gadobutrol (Gadovist®)  Gadoterate meglumine (Dotarem®) Newest (2013)

IONICITY SAFETY CONCERNS

 Acute adverse events Ionic Agents Non‐Ionic Agents  Nephrogenic systemic fibrosis (NSF)  Gadopentetate  Gadodiamide (Omniscan®)  Gadolinium deposition dimeglumine (Magnevist®)  Gadoversetamide  Gadobenate dimeglumine (Optimark®) (MultiHance®)  Gadobutrol (Gadavist®)  Gadoxetate disodium  Gadoteridol (ProHance®) (Eovist®)  Gadofosveset trisodium (Ablavar®)  Gadoterate meglumine (Dotarem®)

13 ACUTE ADVERSE EVENTS PRETREATMENT REGIMENS

 Most are mild & self‐limiting  Planned procedure: . Injection site reactions, nausea +/‐ vomiting, headache, dizziness . Prednisone 50 mg PO 13, 7, and 1 hour prior to contrast administration  Severe reactions are RARE! . Diphenhydramine 50 mg PO 1 hour prior to contrast administration . ~0.03% of administrations  Risk Factors:  Emergency procedure: . Asthma . Methylprednisolone 40 mg IV q4h until contrast is administered . Allergies . Diphenhydramine 50 mg IV 1 hour before contrast administration . History of prior adverse reactions

NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

 Systemic fibrosing disorder with its most prominent effects in the skin . May also affect lungs, esophagus, heart, and skeletal muscles  Observed almost exclusively in patients with underlying renal disease  First described in 1997, but really became a hot topic around 2006

Initial symptoms may include thickening of the skin or pruritis

NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Signs and symptoms may develop and progress rapidly leaving some patients with contractures and joint immobility May be fatal in some patients!

14 NEPHROGENIC SYSTEMIC FIBROSIS (NSF) GADOLINIUM DEPOSITION

 Most commonly found in patients who had been exposed to: . Gadodiamide (Omniscan®) . Gadopentetate dimeglumine (Magnevist®) . Gadoversetamide (Optimark®)  Agents are classified into 3 categories based on likelihood of causing NSF Group 1Agents associated with greatest Omniscan® number of NSF cases Magnevist® Optimark® Group 2 Agents associated with few or MultiHance® no unconfounded cases of NSF ProHance® Gadavist® Dotarem® Group 3Agents new to market Ablavar® Eovist®

GADOLINIUM DEPOSITION ASSESSMENT QUESTION

 Recently, the FDA became aware that gadolinium deposition had  Which of the following is a safety concern with gadolinium‐based occurred in some patients with multiple exposures to GBCAs contrast agents? throughout their lifetime . A. Nephrogenic Systemic Fibrosis  Can occur even if blood‐brain barrier is intact and brain is . B. Acute Adverse Reactions healthy . C. Deposition into tissues  Can occur in patients regardless of renal function . D. All of the Above  As of now, the deposits do not appear to be harmful or neurotoxic, but more research is definitely needed to elucidate long‐term sequelae and causes of the deposition D. All of the Above

SUMMARY REFERENCES

 [Guideline] American College of Radiology. ACR Manual on Contrast Media v10.2. Available at  There are various types of contrast media with differing safety http://www.acr.org/quality‐safety/resources/contrast‐manual. profiles  Mruk B. Renal Safety of Iodinated Contrast Media Depending on Their Osmolarity ‐ Current Outlooks. Pol J Radiol. 2016. 81:157‐65. [Medline].  Using patient‐specific parameters, pharmacists can assist in  Bucher AM, De Cecco CN, Schoepf UJ, et al. Is Contrast Medium Osmolality a Causal Factor for Contrast‐Induced Nephropathy?. Biomed Research International. Available at mitigating the risk of adverse reactions http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988854/. 2014; Accessed: Aug. 18, 2016.  Pharmacists can also assist in clarifying potential contrast or  Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast iodine allergies with patients to make appropriate Media. Radiology. 1990;175(3):621‐8. recommendations to the team  Schabelman E, Witting M. The relationship of radiocontrast, iodine, and seafood allergies: a medical myth exposed. J Emerg Med. 2010;39(5):701‐7.  Gadolinium‐based contrast agents are very well tolerated  Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996;275(19):1489‐94.  They should generally be avoided in patients with eGFR < 30  Wang CL, Cohan RH, Ellis JH, Adusumilli S, Dunnick NR. Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology. mL/min to reduce the risk of nephrogenic systemic fibrosis 2007;243(1):80‐7.

15

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

9:00—10:00 a.m. Medication Reconciliation: A Tale of Two Hospitals

Catherine Oliver, PharmD, BCPS Assistant Director of Pharmacy Clinical Services Ochsner Medical Center New Orleans, LA

Monica Morgan, PharmD Clinical Pharmacy Coordinator Ochsner Medical Center Baton Rouge, LA

0179-0000-16-025-L04-P/ 0179-0000-16-025-L04-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Describe the role of the pharmacist in med 1. Describe the role of the technician in med rec. rec. 2. List key components of med reconciliation 2. Identify components of the best possible pilot program/design/implement pilot. medication history. 3. Identify key metrics of impact or success of 3. List ideal qualifications/qualities of med reconciliation. technicians involved in med history composition.

Drs. Oliver and Morgan have disclosed that they have no relevant financial relationships.

16

Disclosures Medication Reconciliation • Dr. Morgan A Tale of Two Hospitals – Nothing to disclose Monica Morgan, PharmD Clinical Coordinator • Ochsner Medical Center‐Baton Rouge Dr. Oliver – Nothing to disclose Catherine B. Oliver, PharmD, BCPS Assistant Director‐Clinical Services Ochsner Medical Center‐New Orleans

Learning Objectives Learning Objectives

• Pharmacist • Technician – Describe the role of the pharmacist in medication – Describe the role of the technician in medication reconciliation (med rec) reconciliation – List key components to design and implement a – Identify components of the best possible pilot program medication history – Identify key metrics to measure the impact of – List ideal qualifications and qualities of technicians pharmacist‐driven medication reconciliation involved in medication history composition

Definitions Implications of Incorrect Med Rec

• Medication reconciliation: • Preventable adverse drug events within a hospital setting adds approximately $8750 to the cost of the – the process of identifying the most accurate list of hospital stay. all medications that the patient is taking • At 400,000 events each year, the annual cost of – AND comparing the medical record to an external preventable adverse drug events amounts to $3.5 list of medications obtained from a patient, billion. hospital, or other provider • 66% of medication errors occur during a patient’s transition from one setting to another – Incorrect/incomplete medication reconciliation = ~ $2.3 billion annually American Society of Health System Pharmacy and American Pharmacists Association. Best Practices from the ASHP‐APhA Medication Management in Care Transitions Initiative. February 2013. https://www.cms.gov/Regulations‐and‐ National Transitions of Care Coalition (NTOCC). Improving transitions of care: Guidance/Legislation/EHRIncentivePrograms/downloads/7_Medication_Reconciliation.pdf Findings and considerations of the “Vision of the NTOCC”. Accessed August 19, 2016 Institute of Medicine Brief Report 2006. "Preventing Medication Errors."

17 National Patient Safety Goal 03.06.01 National Patient Safety Goal 03.06.01

• Maintain and communicate accurate patient • Obtain information on what the patient is medication information currently taking upon admission – Identify and resolve discrepancies • Compare list with medications ordered within – Address duplications, omissions, interactions and the hospital need to continue • Provide the patient with written information – A qualified individual, identified by the hospital, upon discharge from the hospital does the comparison

https://www.jointcommission.org/assets/1/6/2016_NPSG_HAP.pdf https://www.jointcommission.org/assets/1/6/2016_NPSG_HAP.pdf Accessed 8/20/2016 Accessed 8/20/2016

Who performs medication Pharmacist’s Role reconciliation?

A. Physicians Farley 2014 Phatak 2015 B. Nurses • Standard process vs. • Standard process vs. pharmacist d/c med rec and pharmacist interview and C. Pharmacists counseling + pharmacy care follow‐up calls after D. Pharmacy Technicians plan sent to PCP and discharge community pharmacy • Patients on >3 meds or high E. All or any of the above • Discrepancies at 30 days risk meds significantly reduced with • Reduced composite ED “enhanced” intervention visits and readmissions

Farley TM, et al. Int J Clin Pharm. 2014 Apr; 36(2): 430‐7. Phatak A. et al. UJ Hosp Med.U 2016 Jan; 11(1): 39‐44.

Pharmacist’s Role Pharmacy Technician’s Role

Zemaitis 2016 Mekonnen 2016 Buckley 2013 Cooper 2014 • Med history and • In‐hospital med rec process • Med rec prior to discharge • Outlined standardized reconciliation at admit and by a pharmacist completed by technician method for technician‐ education by pharmacy staff • Meta‐analysis; high risk per protocol or at MD obtained history at prior to discharge populations included COPD request admission • Used technicians, pharmacy and HF • Recent admission, AMI, HF, • Improved prescriber residents, and pharmacists • Reduced all‐cause warfarin use, ASA or compliance with • Reduction in all‐cause readmissions, ED visits, and clopidogrel use, multiple reconciliation, time metrics, readmission at 30 days ADE‐related hospital visits comorbidities and core measure but NS composite outcome • 59.6% of discrepancies adherence originated at admit history

Zemaitis CT, et al. Hosp Pharm. 2016 June; 51 (6): 468‐73 Buckley MS, et al. Ann Pharmacother. 2013; 47: 1599‐1610 Mekonnen AB, et al. J Clin Pharm Ther. 2016; 41: 128‐144. Cooper JB, et. Am J Health‐Syst Pharm. 2014; 71: 1567‐74.

18 What are some ideal qualities of pharmacy technicians to be involved with medication reconciliation? Pharmacy Technician’s Role

A. Three years of retail pharmacy experience • Experienced pharmacy technician B. USP 797 Sterile Compounding Certification • Retail background C. Strong interpersonal skills • Strong interpersonal skills D. A and C • Strong oral and written communication skills

Outcomes of Pharmacy Driven Med Pharmacist Driven Med Rec Program at Little Rec Programs Company of Mary Hospital in IL

• Little Company of Mary Hospital – Evergreen Park, Before initiative: After initiative: Illinois • 32.3% accuracy of admit • 94.2% accuracy of admit – Pharmacists completed admission med rec September med list med list 2012‐March 2013 • Average # of errors at • Average # of errors: 0.07 – Admission and discharge medication lists were assessed admission: 2.94 per patient per patient • 25% accuracy of discharge for errors before the intervention in August 2011 and in • 16.7% accuracy of discharge September 2012 and March 2013 med list (*Note: med lists pharmacists did not conduct – Analyzed admission and discharge medication lists after • Average # of errors at discharge med rec for this implementation of pharmacy driven med rec program discharge: 4.2 per patient project) • Average # of errors at discharge: 2.92 per patient

Simone, Aimee. Pharmacists Key to Improving Medication Reconciliation. Pharmacy Times. February 2014. Accessed at: http://www.pharmacytimes.com/news/pharmacists‐key‐to‐improving‐ Simone, Aimee. Pharmacists Key to Improving Medication Reconciliation. Pharmacy Times. February 2014. Accessed at: medication‐reconciliation. http://www.pharmacytimes.com/news/pharmacists‐key‐to‐improving‐medication‐reconciliation.

Outcomes of Pharmacy Driven Med Pharmacy Driven Med Rec Progam at Rec Programs Florida A&M • Florida A&M University Hospital –Pensacola, • 27.8% discrepancies between nurses’ med list and FL pharmacy students’ med list (p=0.02) – 1045 home meds reviewed, 290 discrepancies identified – Hospital Corporation of America healthcare system – 143 interventions made st – Observational prospective cohort study from June 1 , 2014 • Most frequent interventions: to August 31st, 2014 – Dose optimization – Student pharmacists collected and evaluated med histories – Added therapy utilizing patient interviews and outpatient pharmacies – after nursing completed the initial med rec Discontinued therapy – Discrepancies were identified and reported • Estimated annual gross savings of preventable adverse drug events: ~$205 million

Smith L, Mosley J, Lott S, et. Al. Impact of pharmacy‐led medication reconciliation on medication errors during Smith L, Mosley J, Lott S, et. Al. Impact of pharmacy‐led medication reconciliation on medication errors transition in the hospital setting. Pharmacy Practice. 2015; Oct‐Dec: 13(4): 634. doi: during transition in the hospital setting. Pharmacy Practice. 2015; Oct‐Dec: 13(4): 634. doi: 10.18549/PharmPract.2015.04.634. 10.18549/PharmPract.2015.04.634.

19 Pharmacy‐Led Medication Ochsner Medical Center‐New Orleans Reconciliation • Med histories completed by pharmacy technicians + Med reconciliation completed by pharmacists = IMPROVED PATIENT OUTCOMES and COST SAVINGS!

Ochsner Medical Center‐New Orleans Admission Medication Reconciliation

Notification of Compare List Med List in • 550‐bed academic medical center Patient to Inpatient EMR • 1 director, 4 managers, 4 supervisors Admission Orders • 140 pharmacist and technician FTEs Collect – 31 clinical pharmacy specialists Review of Pharmacist Supplemental • Transplant, Internal Medicine, Critical Care, Oncology, Source Data Note in EMR Infectious Disease, Pediatrics, Emergency Medicine, Info PRN Cardiology, Surgery, Drug Information, Medication Safety – 7 PGY1, 1 IM PGY2, 1 Transplant PGY2 Residents Patient Patient Notify – 2 Medication History Technicians Assistance Interview Prescriber PRN – 120 P4 student pharmacists annually Referral PRN

Admission Medication Reconciliation Admission Medication Reconciliation

• Notification of Patient Admission • Patient interview • Review of Source Data – Standardized format – EMR, list or bottles from home, pharmacy, – Verify allergies insurance, prior facility – Scheduled and PRNs – Claims data software – Indications – Include OTC, herbals, topicals, eye/ear drops, inhalers, injections – Last dose taken

20 Admission Medication Reconciliation Admission Medication Reconciliation

• Patient Interview • Pharmacist Medication Reconciliation Note – Adherence assessment – Standardized format – Affordability assessment – Omissions, duplications, other discrepancies – Medication‐related problem list – Other questions or problems – Recommendations – Preferred pharmacy • Contact prescriber for critical discrepancies • Patient Assistance Referral – Antiarrhythmics, benzodiazapines, • Bedside Delivery offering anticonvulsants, antiretrovirals, anticoagulants, immunosuppressants, chronic opioids

Step 1 : Medication History Collection Step 1 : Medication History Collection

1. Incomplete medication list 2. Begin interview by confirming name and date of birth – Print out Rx Medication Reconciliation at Admission form from EPIC and MedMined source document 3. Introduction and brief description of events to take place – Hello Mr./Mrs. __. My name is __. I am a pharmacist/pharmacy – As needed basis sources technician/pharmacy resident/pharmacy student • Physician provider – I would like to review the medications you take at home so we have an • Caregivers up‐to‐date list and make sure you are on the right medications while in the hospital. • Family member – (if others are present) Is it all right if I speak to you about your • Long‐term care facility or nursing home medications in front of your guests?

Step 1 : Medication History Collection Step 1 : Medication History Collection

4. Do you have any allergies? If so, with what drugs and what 6. Ask patient to display containers for all prescription was the reaction? medications, OTC products, herbal products, and nutritional products (if available, go through each 5. Does anyone normally help you remember to take your item and question). medicines? – If item(s) not available, ask patient to display a list of – If yes, who? (allow that person to assist with answering the questions) medication(s). – If no, then patient must answer all questions without assistance. – If patient cannot provide, have patient verbalize list of medications

21 Step 1 : Medication History Collection Step 1 : Medication History Collection

7. Medicines patient is taking at the moment 8. Any patches, creams/ointments, eye drops, inhalers, shots, (brand/generic)? (allowed to use med rec eye or ear drops? administration form as guide) 9. Herbals, vitamins, minerals, or anything over the counter? – Name 10. Any questions or concerns about your medications? – Indication 11. What vaccinations have you recently received? – Dosage 12. Do you ever forget to take your medicine? – Frequency 13. Do you have problems affording your medication? – Route 14. Which pharmacy do you prefer to use? – Last dose taken 15. Thank patient for their time.

Audience Participation Tips for Conducting Medication Interview

OTC/herbal products should be included in the • Incorporate “probing questions” med history list. • Use open and closed‐ended questions • True • Ask about routes of administration • False • Ask patient to match medication to medical condition • Ask description of medication (color, size, shape) • Ask about when medication is taken (time of day, week, month, as needed)

Admission Medication Reconciliation Admission Medication Reconciliation

• Supplemental Information • Technician hand‐off to pharmacist – Family or caregivers • Compare List to Inpatient Orders – Call prescriber, pharmacy, insurance company, – Omissions, duplications, other discrepancies prior facility – Rationale for not continuing at admission • Enter medication list into EMR – Formulary interchanges to address prior to – Note as “taking” or “not taking” discharge

22 Identify and Clarify Discrepancies Identify and Clarify Discrepancies

Requires Physician Requires Physician Category Definition Example Followup? Category Definition Example Followup? (Yes/No) (Yes/No) “One‐to‐One" Medications ordered Patient takes furosemide 40 No Intended Discrepancies exist but are Antibiotics started for No Match for the patient during mg by mouth twice daily at Discrepancy (i.e., appropriate based on the patient's infection. purposeful) plan of care (e.g., based on the episode of care or home, which is ordered upon "As needed" medications information gathered on rounds, upon discharge match admission. ordered for pain/fever. based on a review of the what the patient was Patient's pre‐admission dose physician's history and physical and Pre‐admission doses of taking prior to of simvastatin by mouth progress notes, based on patient's blood pressure admission. communication/ handoffs in medications were changed every evening is continued preparation for discharge, etc.). due to hypotensive during the hospital stay and episodes. at discharge. Warfarin and aspirin held for a procedure.

Formulary substitution.

Identify and Clarify Discrepancies Ochsner Medical Center‐Baton Rouge

Requires Physician Category Definition Example Followup? (Yes/No) Unintended Discrepancies exist and The patient takes her blood pressure Yes—physician should be Discrepancy require clarification of medication twice daily at home but consulted for resolution intent because there is it's ordered only once daily in the and resulting changes no supporting hospital. No indication for frequency and/or clarifications documentation of change and patient's current blood documented. explanation based on the pressure slightly elevated. patient's current clinical Patient's simvastatin was omitted condition or care plan. from their discharge instructions without any clear indication for why.

Ochsner Medical Center‐Baton Rouge Discharge Medication Reconciliation

• Notification of Patient Educate Patient on 150 bed acute care hospital Pharmacist Note In EMR – MSICU Discharge Discharge Medications – Telemetry – Medical/Surgical – L&D Call Patient’s Pharmacy to Discontinue – Mother‐Baby Review EMR/claims Complete Discharge Med Medications Not database software Rec in EMR – Level III NICU Continued After Discharge • 8 full‐time pharmacists, 1 part‐time pharmacist, 4 PRN pharmacists Reconcile Home Meds, Review Report from • 8 full‐time technicians, 2 PRN technicians Claims Database Inpatient Meds and Patient Assistance Indicating New – 1 purchaser technician Notify Prescriber of Referral PRN Discrepancies Prescriptions Not Picked • 1 clinical coordinator, 1 operations coordinator, 1 director Up and Call Patient of pharmacy

23 Discharge Medication Reconciliation Discharge Medication Reconciliation

• Notification of patient discharge • Reconcile home meds, inpatient meds – Estimated date of discharge column in EMR allows – Notify prescriber of any discrepancies and prioritization recommend alternatives if necessary • Review EMR and Claims Database Software • Patient assistance referral – For patients unable to afford their medications, refer – Review home medications, inpatient medications, and to case management and outpatient pharmacy medications ordered for discharge assistance program • Duplications, omissions, interactions, allergies, dose – Retail pharmacy to deliver several doses if patient – Claims data software needs a bridge until assistance available • Prescription fill history, pharmacy and prescriber information • Bedside delivery of new or refill medications • Assists in gathering most accurate medication history

Discharge Medication Reconciliation Discharge Medication Reconciliation

• Complete discharge med rec in EMR • Pharmacist Medication Reconciliation Note – Enter new medications, delete duplications, – Standardized format ensure correct dose – Omissions, duplications, other discrepancies – Pend list in EMR for prescriber to “e‐sign” – Medication‐related problem list • Educate patient on discharge medications – Recommendations – ALWAYS utilize teach‐back method • Call patient’s pharmacy to discontinue – Indication, dose, frequency, side effects refill unnecessary medications to ensure it is not status accidentally filled

Other Considerations in Completing Discharge Medication Reconciliation Discharge Med Rec • Claims database will generate a report of • Review medication administration records to assess when next doses are due and if PRN medications are discharged patients who have not picked up necessary for discharge (MAR, Med/Surg report). new prescriptions. • No one report provides a good overview of therapy • Pharmacy tech will call patients on list to changes throughout admission; use the pharmacist add/edit/comments fields of the patient profile or the inquire as to why the prescription was not sticky notes to communicate changes throughout the obtained. admission to aid in discharge medication reconciliation. • Review notes to ensure that recommendations from consult services were considered / implemented.

24 Other Considerations in Completing Pharmacist Med Rec Note Discharge Med Rec • Assess appropriateness of discharge medications by reviewing monitoring parameters relevant to each • Source of list medication. – Patient, family, claims database • Assess appropriateness of medications for patients > 65 years old by utilizing the Beers Criteria. • Medication‐related problems • High priority/alert medications: – Risk of non‐adherence using Morisky scale • Antibiotics  appropriateness of agent and duration/quantity based on cultures • • Anticoagulation dose, duration/quantity, access, teaching, f/u with Recommendations an anticoagulation clinic • Insulin restart of home oral anti‐diabetics or appropriate dosing of insulin for outpatient care • Anti‐arrhythmics drug interactions, QTc • Opioids  doses, prn use, review for inappropriate duplicate therapy

Which method should be used to educate patients about their medications? Key Metrics A. Question and answer • # Discrepancies noted B. Teach‐back – Omission, commission, wrong drug, route, frequency • Potential severity of discrepancy C. Teach‐to – High alert medications D. Demonstration – Narrow therapeutic index drugs • Readmission rate – 72 hour – 30 day

Key Metrics Challenges

• HCAHPS • Limited resources to review all patients – Communication about meds • Health literacy of patients – Side effects • Financial impact of non‐formulary to formulary • Obtaining an accurate list of medications changes in regards to the patient’s third party payer • Communication to physicians or other medical staff • Notification of admit/discharge

25 Audience Feedback Solutions

• What barriers can you identify to performing • Target high‐risk patients an admit and/or discharge med rec at your – LACE+ score – Patients on high‐alert, error‐prone medications institution? • Anticoagulants, anticonvulsants, HIV medications • What metrics will you measure for your – Patients on a target number of medications – Specific disease states: HF, COPD, DM program? • Utilize available technology – EMR – Claims Data Software – Drug information resources (ex. Drug cards) • Centralized order verification

LACE+ Score LACE+ Score

Walraven 2012 • Length of stay (L) • Number of elective admissions • Acuity of admission (A) in previous year • Scoring tool for risk assessment of 30‐day death or • Comorbidity (C) • Case‐mix group score urgent readmission • Emergency department • Number of days on alternative • Can be calculated from administrative data utilization in the 6 months level of care status (ALC) • Interaction terms • Improved ability to predict risk before admission (E) • Age – Age x Charlson score • Final index ranges from ‐15 to 114 • Sex – Age x number of urgent • Higher LACE+ score, greater probability of 30‐day • Teaching status of discharge admissions in previous year death or urgent readmission institution – Charlson score x number of urgent admission in previous year

Van Walraven C, et al. Open Med. 2012 Jul; 6(3): e90‐e100. Van Walraven C, et al. Open Med. 2012 Jul; 6(3): e90‐e100.

LACE+ Score Pearls

• When educating patients, utilize the teach back method. • No “one‐size fits all” program • In the first stages, identify need –admit or discharge med rec, targeted populations

Van Walraven C, et al. Open Med. 2012 Jul; 6(3): e90‐e100.

26 References

1. Becerra‐Camargo J, Martinez‐Martinez F, Garcia‐Jimenez E. A multicentre, double‐blind, randomised, controlled, parallel‐group study of the effectiveness of a pharmacist‐acquired medication history in an emergency department. BMC Health Services Research BMC Health Serv Res. 2013;13(1):1‐12. 2. Chan C, Woo R, Seto W, Pong S, Gilhooly T, Russell J. Medication Reconciliation in Pediatric Questions? Cardiology Performed by a Pharmacy Technician: A Prospective Cohort Comparison Study. The Canadian Journal of Hospital Pharmacy. 2015;68(1):8‐15. 3. Fabre‐LaCoste N. Pharmacy Medication Reconciliation Program and Education Module. 2016. 4. Lancaster JW, Grgurich PE. Impact of Students Pharmacists on the Medication Reconciliation Process in High‐Risk Hospitalized General Medicine Patients. American Journal of Pharmaceutical Education. 2014;78(2):34. 5. Van Walraven C, Wong J, Forster AJ. LACE+ index: extension of a validated index to predict early death or urgent readmission after hospital discharge using administrative data. Open Medicine. 2012;6(3):e80‐e90.

References

6. American Society of Health System Pharmacy and American Pharmacists Association. Best Practices from the ASHP‐APhA Medication Management in Care Transitions Initiative. February 2013. Available at http://www.ashp.org/DocLibrary/Policy/Transitions‐of‐ Care/ASHP‐APhA‐Report.pdf. Accessed August 25, 2015. 7. National Transitions of Care Coalition (NTOCC). Improving transitions of care: Findings and considerations of the “Vision of the NTOCC”. Available at: http://www.ntocc.org/portals/0/pdf/resources/ntoccissuebriefs.pdf. 8. Institute of Medicine Brief Report 2006. "Preventing Medication Errors." Available at: https://iom.nationalacademies.org/~/media/Files/Report%20Files/2006/Preventing‐ Medication‐Errors‐Quality‐Chasm‐Series/medicationerrorsnew.pdf. 9. Simone, Aimee. Pharmacists Key to Improving Medication Reconciliation. Pharmacy Times. February 2014. Accessed at: http://www.pharmacytimes.com/news/pharmacists‐key‐to‐ improving‐medication‐reconciliation. 10. Smith L, Mosley J, Lott S, et. Al. Impact of pharmacy‐led medication reconciliation on medication errors during transition in the hospital setting. Pharmacy Practice. 2015; Oct‐ Dec: 13(4): 634. doi: 10.18549/PharmPract.2015.04.634.

27

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

9:00—10:00 a.m. Biosimilars: Are They Similar Enough?

Morgan Corbin, PharmD Pharmacy Intern University Health– Shreveport Shreveport, LA

0179-0000-16-026-L01-P/ 0179-0000-16-026-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacist Technician 1. Recognize common terminology for 1. Define what a biosimilar product is vs. a biosimilar products. biological product. 2. Explain the FDA approval process for 2. Recognize common terminology for biosimilars and interchangeables. biosimilar products. 3. Recognize legal issues concerning 3. Select the benefits of biosimilar products. biosimilars. 4. Identify potential medication errors with 4. Identify potential medication errors with biosimilars. biosimilars. 5. Recommend an approach for adding biosimilars to formulary.

Dr. Corbin has disclosed that she has no relevant financial relationships.

28

Pharmacist Objectives:

X Recognize common terminology for biosimilar products X Explain the FDA approval process for biosimilars Biosimilars: Are They Similar Enough? and “interchangeables” X Recognize legal issues concerning biosimilars Morgan Corbin, Pharm.D. X Identify potential medication errors with PGY1 Pharmacy Resident biosimilars University Health Shreveport X Recommend an approach for adding biosimilars to formulary

2

Technician Objectives: “The difference between the almost X Define what a biosimilar product is vs. a right word and the right word is biological product really a large matter – it is the X Recognize common terminology for biosimilar difference between the lightning products bug and the lightning. ” X Select the benefits of biosimilar products X Identify potential medication errors with Mark Twain biosimilars

3 4

Morrow, T. Defining the Difference: What Makes Biologics Unique. Biotechnology Healthcare. 2004: 25-29.

Biologics Biologic Sources

X Biological Product X Virus, therapeutic serum, toxin, antitoxin, or analogous product

X Made from a variety of natural sources X Sugars, proteins, nucleic acids, cells, tissues, or a combination

6 5 http://www.signalsblog.ca/cell-lines-patient-samples-and-cultures-oh-my/ http://www.bb666c.com/news/health-34392522 http://www.bbc.com/news/science-environment-23244768 Chhina MN. Overview of Biological Products. FDA Basics Webinar. June 2013. http://www.nature.com/news/2009/091211/full/news.2009.1140.html http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM356666.pdf. Accessed August 1, 2016. http://www.edvotek.com/908

29 Biologics - Examples Biologics & Biosimilars – a new fad?

X Not new! X Examples: X Botox® – neurologic and dermatologic uses X First biologic – recombinant human insulin introduced in X Herceptin® – breast cancer 1982! X Enbrel® – RA and psoriasis X With new emphasis on genomics we have a new subset of X Insulin targets

X Increasing knowledge Æ increasing potential for new drugs (biologics)

7 8 http://money.cnn.com/2014/11/17/investing/allergan-actavis-merger-boom/ http://www.herceptin.com/ Morrow, T. Defining the Difference: What Makes Biologics Unique. Biotechnology Healthcare. 2004: 25-29. http://www.medscape.com/viewarticle/865154 Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: Primer for the Health-System Pharmacist. American journal of health-system pharmacy : AJHP : official journal of the http://www.whatisbiotechnology.org/science/mabs American Society of Health-System Pharmacists. 2013;70(22):2004-2017.

Top 10 Drugs by 2016 Worldwide Sales What does this mean?? 18 15.7 16 14 12 11.6 10 Humira Rituxan Avastin 8 7.3 7 6.9 6.8 6.7 6.1 5.8 6 5 4 2016 WW Sales ($bn) 2016 2 0 Herceptin Remicade Lantus

9 10

Urquhart L, Gardner J, Elmhirst E. EP Vantage 2016 Preview. Evaluate Ltd. December 2015. Urquhart L, Gardner J, Elmhirst E. EP Vantage 2016 Preview. Evaluate Ltd. December 2015.

Top 10 Drugs by 2016 Worldwide Sales 18 Humira 15.7 16 14 12 11.6 10 8 7.3 7 6.9 6.8 6.7 % of 2015 6.1 5.8 Product Company 2015 Sales ($bn) 6 5 Company Sales 4 2016 WW Sales ($bn) 2016 2 Humira AbbVie 14,090 62% 0

11 12

Urquhart L, Gardner J, Elmhirst E. EP Vantage 2016 Preview. Evaluate Ltd. December 2015. Urquhart L, Gardner J, Elmhirst E. EP Vantage 2016 Preview. Evaluate Ltd. December 2015.

30 What is a Biosimilar? Generics vs. Biosimilars

X Biosimilar X Generic X Highly similar to an FDA-approved reference biological product X A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. X No clinically meaningful differences in safety and efficacy X A generic drug product must contain the identical amounts of the X Minor differences in clinically inactive components allowed same active ingredient(s) as the brand name product. X CANNOT be automatically substituted X Able to be substituted by pharmacists (Orange book)

X Reference product X Biosimilar X Single biological product against which a biological product is evaluated in an application submitted X A biosimilar must be highly similar and produce the same results and be just as safe as its reference product when given multiple times

13 14 A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. United States Food and Drug Administration. Information on Biosimilars. May 2016. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApproApprovalApplica/ http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016. TherapeuticBiologicApplications/Biosimilars/. Accessed August 19, 2016. Chhina MN. Overview of Biological Products. FDA Basics Webinar. June 2013. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM356666.pdf. Accessed August 1, 2016.

Question #1 Small vs. Large Molecule Drugs

X A single biological product against which a Characteristic Small-molecule Drugs Biopharmaceuticals Structure Simple Complex biological product is evaluated in an application Size Small Large submitted is known as: Ease of Readily defined Difficult to fully characterization characterize a) Biosimilar Manufacturing Straightforward, predictable, Complex, involving living b) Biologic process controlled, organic chemistry systems reactions using known c) Reference product chemicals and reagents d) Interchangeable Purity and stability High purity and stability Heterogeneous product with impurities, vulnerable to environmental factors and improper handling Immunogenicity Low High

16 15 A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016. Chhina MN. Overview of Biological Products. FDA Basics Webinar. June 2013. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM356666.pdf. Accessed August 1, 2016.

Pharmaceutical Manufacturing

Raw Measured and Mixing materials weighed

Finished Filling Packing products storage

Quality Assurance

18 17 http://www.slideshare.net/boreddysunilkumarreddy/pilot-plant-scaleup-techniques-used-in- http://www.chemtech-online.com/P&B/Ramniwas_april13.html pharmaceutical-manufacturing

31 Size and Complexity Each Biosimilar is Unique

Aspirin 180 Da Monoclonal Antibody ~150,000 Da

19 20

Chhina MN. Overview of Biological Products. FDA Basics Webinar. June 2013. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM356666.pdf. Accessed August 1, 2016. https://www.amgen.ca/english/science/how_biosimilars_differ.html

Question #2 When can pharmacists substitute?

X What is the difference between a biologic and X The product must be “Interchangeable” biosimilar? X Must be a biosimilar a) A biosimilar is the exact same as a biologic and may be substituted by pharmacists X Meets additional standards for interchangeability b) A biologic is FDA approved for certain indications, X May then be substituted for the reference product without while a biosimilar is comparable and may be approved intervention by prescribing provider for those same indications as the biologic X Label of biosimilar must state whether deemed c) A biologic is better than a biosimilar interchangeable d) A biosimilar works faster than a biologic

21 22

Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: Primer for the Health-System Pharmacist. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2013;70(22):2004-2017.

Does interchangeability matter? Question #3

X What extra requirements must an interchangeable X Formulary concerns biosimilar meet? X Biologics and biosimilars on formulary a) The biosimilar is expected to produce the same clinical result as the reference product in any given patient

b) The risk in terms of safety or diminished efficacy of alternating or X Pharmacists autonomy switching between the use of the product and its reference product is not greater than the risk of using the reference product X Ease of substitution without such alternation or switch

c) The biosimilar must be exactly the same as it’s reference product X Insurance coverage in every way d) A & B

23 24

A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016

32 The Purple Book Purple Book

X Lists all biologics and currently approved biosimilars and Reference interchangeables Product Date of Product Proprietary Date of Interchangeable BLA STN (Proper first Exclusivity Withdrawn name Licensure (I)/Biosimilar (B) name) Licensure Expiry Date X Used to determine what products pharmacist can substitute, etc. 103749 Daclizumab Zenapex 12/10/97 NA NA Yes Filgrastim- 125553 Zarxio 03/06/15 B sndz Tbo- 125294 Granix 08/29/12 08/29/12 08/29/24 filgrastim

BLA STN - Biologic License Application Submission Tracking Number

26 25 Center for Drug Evaluation and Research. Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Center for Drug Evaluation and Research. Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. July 2016. Evaluations. July 2016. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprHowD/ApprovalApplications/TherapeuticBiologicApplications/Bi http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprHowD/ApprovalApplications/TherapeuticBiologicApplications/Bi osimilars/UCM439049.pdf. Accessed August 19, 2016. osimilars/UCM439049.pdf. Accessed August 19, 2016.

How do Products become biosimilars? How Does a Biosimilar Become Approved

X Biologics Price Competition and Innovation Act of X A 351(k) application including the following information: 2009 (BCPI Act) X Biosimilarity to the reference product X Same mechanism of action for the proposed condition(s) of use X Condition(s) of use have been previously approved for the X Allows an abbreviated licensure pathway for reference product biological products X Same route of administration, dosage form, and strength as the reference product; and X If highly similar to an FDA-licensed biological product may rely on publicly-available information X Comparability not therapeutic equivalence

27 28 Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016.

What information is required in a 351(k) Stepwise Approach to Demonstrating application? Biosimilarity

X Analytical studies X Totality of evidence approach in evaluating X Animal studies biosimilarity X Clinical study or studies X Not one “pivotal” study that demonstrates biosimilarity

X FDA may determine that an element is not necessary for X FDA evaluates the applicant’s integration of the application various types of information to provide an overall assessment

29 30 Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016.

33 Totality of Evidence Question #4 X What is necessary in the application for a

Additional biosimilar to become approved? Clinical Studies a) Biosimilarity to the reference product Clin Pharm b) Same mechanism of action for the proposed condition(s) of use c) Condition(s) of use have been previously approved for Nonclinical the reference product d) Same route of administration, dosage form, and Analytical strength as the reference product e) All of the above

31 Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. 32 http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016.

State Legislation on Biosimilars

X Differs by State X Features include: X Prescribers preventing substitution X Notification to prescribers of substitution X Patient notification and consent X Substitution records Total of 21 states and Puerto Rico X As of July 1, 2016 there were bills or resolutions filed in a total of 36 states related to biologics and/or biosimilars

33 34

Cauchi, R. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures. 2016. Cauchi, R. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures. 2016. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed July 15, 2016. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed July 15, 2016.

State Legislation Features LA Legislation on Biosimilars (HB No. 319)

X Typical features include: X Effective August 1, 2015 X Biosimilar in order to be substituted must be approved as X A pharmacist may substitute a biosimilar for a prescribed interchangeable biologic if: X Prescribers are able to prevent substitution X 1. The biosimilar is FDA approved as interchangeable; X Prescribers must be notified of a substitution X 2. The prescriber has not prohibited substitution; and X Patient must be notified of a substitution/consent must be had X 3. The patient has consented X Records must be retained by the pharmacist/physician X X Immunity for pharmacists The pharmacist (or designee) must notify the prescriber: X State maintenance of list of permissible interchangeable products X 1. Of the dispensed product’s name and manufacturer; X 2. Within 5 days via any means X Not required if a refill with no change from previous product

35 36

Cauchi, R. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures. 2016. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed July 15, 2016. Simon, S. House Bill No. 319. Louisiana State Legislature. 2015. https://www.legis.la.gov/Legis/BillInfo.aspx?i=226919. Accessed August 11, 2016.

34 Question #5 Europe as a Model

X What is required in Louisiana for a pharmacist to be X European Union regulatory pathway established 2005 allowed to substitute a biosimilar for a biologic? X First biosimilar (HGH) approved 2006 a) The biosimilar must be FDA approved as an interchangeable

b) The prescriber must not have prohibited the substitution X 22 biosimilars approved, 20 still in use

c) The patient must give consent X Human growth hormone, G-CSFs, ESAs, insulin, FSH, TNF- inhibitors d) The prescriber must be notified of substitution including name and manufacturer of the product within 5 days X Two have been withdrawn e) All of the above X 1 for filgrastim April 2011 X 1 for somatropin May 2012 X Overall 30% price reduction

37 38

GaBI Online - Generic and Biosimilars Initiative. Biosimilars approved in Europe. May 2016. http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Accessed August 15, 2016.

What’s in a Name? Example Names

X WHO Draft guidance X International nonproprietary name (INN) + 4-letter, randomly assigned suffix Zarxio Inflectra Erelzi

X FDA proposed naming (Aug 2015) X No separate identifier Filgrastim- Infliximab- Etanercept- sndz dyyb szzs X Nonproprietary name of originator + suffix of 4 random consonants

39 40 WHO Executive Summary. 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances Geneva, 16–18 October 2012. INN Working Center for Drug Evaluation and Research. Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Doc. 13.329. February 2013. Interchangeability Evaluations. July 2016. FDA. Nonproprietary Naming of Biological Products Guidance for Industry. US Department of Health and Human Services. August 2015. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprHowD/ApprovalApplications/TherapeuticBiologicApplicati http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459984.pdf. Accessed July 20, 2016. ons/Biosimilars/UCM439049.pdf. Accessed August 19, 2016.

Naming – What’s the fuss Question #6 X Which of the following examples shows the Pros Cons correct proposed FDA naming of biosimilars? X Distinguishes medicines without X Suffix devoid of meaning a) Filgrastim-ssz superiority b) Filgrastim-sndz X Increased likelihood of error c) Filgrastim-a X Pulls all medicines in same class together in computer d) Filgrastim-1 X Impedes pharmacovigilance

X Promotes equality and substitution X Education needed

41 WHO Executive Summary. 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances Geneva, 16–18 October 2012. INN Working 42 Doc. 13.329. February 2013. FDA. Nonproprietary Naming of Biological Products Guidance for Industry. US Department of Health and Human Services. August 2015. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459984.pdf. Accessed July 20, 2016.

35 Pharmacists’ Perceptions on Naming Confidence in Dispensing an Interchangeable Biosimilar Based X Cross-sectional survey of 781 members of the Academy of Managed Care on Naming Conventions 64.00% Pharmacy and the Hematology/Oncology Pharmacy Association 62.90%

62.00%

60.00%

58.00% 57.40%

56.00%

PERCENTAGE 53.80% 54.00% 53.70%

52.00%

50.00%

48.00% Nonproprietary base w/ Nonproprietary base Nonproprietary base Unique brand name suffix alone w/prefix NAMING STYLE 4343 44

Tomaszewski, D. Biosimilar Naming Conventions: Pharmacist Perceptions and Impact on Confidence in Dispensing Biologics. Tomaszewski, D. Biosimilar Naming Conventions: Pharmacist Perceptions and Impact on Confidence in Dispensing Biologics. Journal of Managed Care & Specialty Pharmacy. 2016; 22(8): 919-926. Journal of Managed Care & Specialty Pharmacy. 2016; 22(8): 919-926.

First US Biosimilar Approved

X Zarxio Zarxio Neupogen X FDA Approved March 2015 Indications: same Indications: same X FDA Indications ADE: similar ADE: similar X Patients with cancer who are on Dosing: same Dosing: same myelosuppressive chemotherapy

X AML who are on induction or consolidation Supply & Costs Supply & Costs chemotherapy • Prefilled syringe • Solution for injection • 300 mcg/mL - $ 367.15 X Patients who are having a bone marrow • 300 mcg/0.5 mL - $330.79 • 480 mcg/1.6mL - $584.64 transplant • 480 mcg/0.8 mL - $526.78 • Prefilled syringe X Autologous peripheral blood progenitor cell • 300 mcg/0.6 mL - $389.16 collection therapy • 480 mcg/0.8 mL - $619.74

X Severe chronic neutropenia 45 46 www.zarxio.com United States Food and Drug Administration. FDA News Release: FDA Approves first biosimilar product Zarxio. March 6 2015. Zarxio® [package insert]. Princeton, NJ: Sandoz; 2015. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm436648.htm. Accessed. August 20, 2016. Neupogen® [package insert]. Thousand Oaks, CA: Amgen; 2015.

PIONEER Study Study Design

X Zarxio vs. Neupogen Zarxio Neupogen X Randomized, double-blind, comparative study in breast (n=109) (n=109) cancer patients n=54 n=55 n=55 n=54 X 24 weeks duration

X 4 arms total

47 48

Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016. Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016.

36 PIONEER Methods Results: Primary Endpoint X 6 cycles (3 weeks per cycle) X TAC (docetaxel, doxorubicin, cyclophosphamide) on D1 of each cycle X On D2 of each cycle Zarxio or Neupogen was administered Zarxio (n = 101) Neupogen (n=103) daily until ANC recovered to 10 x 109/L after the NADIR or up to a max of 14 days Cycle 1 Mean DSN (SD) 1.17 days (1.11) 1.20 days (1.02)

X Primary Endpoint DSN Difference (90% CI) 0.04 days (-0.21, 0.28) X Comparative equivalency assessment of mean duration of severe neutropenia between Zarxio and Neupogen in DSN – duration of severe neutropenia Cycle 1 DSN difference – neupogen minus zarxio

49 50

Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016. Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016.

Results: Secondary Endpoints Results: Adverse Drug Events X >10% in cycle one

Zarxio N=101 Neupogen N=103 X Similar between groups Incidence of febrile X Overall safety profile was similar across all 6 cycles with continuous treatment 4 (4.0%) 2 (1.9%) neutropenia (FN) (n[%]) Treatment emergent Zarxio N=107 n(%) Neupogen N=107 n(%) Time to ANC recovery adverse event 1.8 + 0.97 1.7 + 0.81 (days) (mean + SD) Alopecia 62 (57.9) 63 (58.9) Depth of ANC nadir (x109) 0.734 ± 1.1388 0.757 ± 1.3131 (mean ± SD) Nausea 39 (36.4) 43 (40.2) Number of days of fever 0 (0-2) 0 (0-2) Asthenia 30 (28.0) 42 (39.3) (days) (median, range) Bone pain 19 (17.8) 23 (21.5) Frequency of infections 2 (2.0%) 2 (1.9%) (n[%]) Fatigue 17 (15.9) 12 (11.2) Incidence of Cardinal Adverse Events hospitalizations due to FN 11 (n) Musculoskeletal pain 27 (25%) 31 (29%)

51 Injection site reaction 2 (2%) 1 (1%)

52 Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016. Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016.

Inflectra (infliximab-dyyb) Erelzi (etanercept-szzs)

X Biosimilar to Enbrel proposed as a treatment for Rheumatoid arthritis, X Approved April 5, 2016 polyarticular juvenile idiopathic arthritis in patients aged 2 years and older, psoriatic arthritis, anklylosing spondylitis, and adults with plaque psoriasis X FDA Indications X FDA Arthritis Advisory Committee unanimously voted to recommend X Crohns licensure for GP2015 in July 2016 X Ulcerative Colitis X APPROVED August 30, 2016 for all indications X Rheumatoid Arthritis X Additional autoimmune conditions X May take years to reach market X NOT Pediatric Ulcerative Colitis X Lawsuits claiming Amgen is wrongly profiting from research on etanercept

53 54 United States Food and Drug Administration. FDA News Release: FDA approves Erelzi, a biosimilar to Enbrel. August 30, 2016. http://www.fda.gov. Accessed August 30, Brown, T. Biosimilar to Enbrel Unanimously Recommended by FDA Panel. Medscape Medical News. July 14, 2016. 2016 Sandoz Biosimilar Etanercept Recommended by FDA Advisory Committee for Approval to Treat Multiple Inflammatory Diseases. Sandoz. July 13, 2016. http://www.medscape.com/viewarticle/866154. Accessed August 17, 2016. www.sandoz.com. Accessed August 15, 2016.

37 Granix (tbo-filgrastim) Formulary Selection

X Approved in 2012 Manufacturer Product Hospital/Patient Efficacy/Safety Considerations considerations factors X NOT a biosimilar • Clinical data • Supply reliability • Packaging and • Economics X Approved under the biologics pathway, prior to abbreviated • Indications • Drug shortages labeling • Transitions of care biosimilar pathway • Therapeutic •Patient • Bar coding • IT system changes Interchange assistance • Compatibility • Educational X Slight structural differences between Neupogen and Granix • Other agents on programs with robots, etc. opportunities formulary • Reimbursement • Preparation and X PK, safety, and efficacy do not differ significantly •Post-marketing support administration surveillance •Storage X FDA approved ONLY for decreasing the incidence of infection requirements associated with severe neutropenia in patients receiving myelosuppressive therapy for nonmyeloid malignancies

56

55 Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. Granix® [package insert]. North Wales, PA: Teva Pharmaceutical Industries Ltd; 2014. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016.

P&T Pharmacovigilance

X Health system pharmacists can play a vital role to detect, X Many considerations go into the decision to add assess, and prevent adverse events and problems from biosimilars and biologics to formulary biopharmaceuticals X Formulary or step therapy approach to drive X Prospective patients registries prescribers to preferred agents X Data mining of billing claims, databases, and EHRs X Therapeutic interchange – Our secret weapon X Documentation of lot numbers at time of administration X “Grandfathering” reference brands? X System for linking adverse events to specific biologicals X Pharmacist should take leadership on biosimilars

58

57 Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: Primer for the Health-System Pharmacist. American journal of health-system pharmacy : AJHP : A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. ASHP Advantage. 2012. official journal of the American Society of Health-System Pharmacists. 2013;70(22):2004-2017. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016.

Question #7 Latest in the News

X A pharmacist is presenting a new biosimilar to P&T X Lantus committee for inclusion in the hospitals formulary. What considerations should the P&T committee take into X Humira consideration when adding a biosimilar to formulary? a) Cost X Pegfilgrastim biosimilar recently denied approval b) Interchangeable status

c) Indications of the biosimilar X Epogen biosimilar rejected

d) A

e) A & B

f) A, B, & C

59 60

38 Remember Lantus… Humira (adalimumab)

X FDA advisers unanimously voted in July that biosimilar ABP-501 should be X New “biosimilar” on the way approved for 7 chronic inflammatory conditions July 2016 X Basaglar (insulin glargine) X 1st ever “biosimilar” insulin approved in US December X “highly similar” 2015 X Lantus follow on X Litigation may prevent coming to market until 2018 X AbbVie claims patents protect Humira from competition until 2022 X Not a biosimilar or generic but a new chemical entity X Amino acid sequence identical to Lantus X Launch December 15, 2016 X Already launched in other countries at a 15-20% discount

61 62 www.basaglar.com Levy, J. FDA Approves Lily/Boehringer Lantus biosimilar. Pharmafile. December 12, 2015. www.pharmafile.com. Accessed August 5, 2016. Edney, A. Amgen Moves Closer to Selling Competitor for AbbVie’s Humira. Bloomberg. http://www.bloomberg.com/news/articles/2016-07-12/amgen- DiaTribe. FDA Approves New Insulin Glargine Basaglar – The First “Biosimilar” Insulin in the US. DiaTribe. January 11, 2016. www.diatribe.org. Accessed August 16, 2016. moves-closer-to-selling-competitor-for-abbvie-s-humira. Accessed August 17, 2016.

Rejections Final Thoughts

X EPO biosimilar X Biosimilars are here to stay X Rejected in October 2015 X No interchangeable biosimilars on the market X More complex, made with genetically engineered mammalian cells as opposed to bacteria X Pharmacists cannot substitute at this time

X Has been approved in Europe (Retacrit) since 2007 X Naming is still up in the air

X Lots of biosimilars in the pipeline – be on the lookout X Neulasta biosimilar X Pharmacists should take ownership of biosimilars X Rejected July 2016 X No news as to why X For more information:

X Working with FDA to clear up issues X www.biosimilarsresourcecenter.org

63 64 Cohen A, Royzman I. FDA Rejects Hospira’s EPO Biosimilar Application. Biologics Blog. November 5, 2015. www.biologicsblog.com Accessed August 15, 2016. Dangi-Garimella, S. FDA Rejects Novartis’ Biosimilar Application for Pegfilgrastim, Seeks Additional Information. American Journal of Managed Care. July 20, 2016. www.ajmc.com. Accessed August 15, 2016.

Question #8 Questions? X What is the benefit of biosimilars coming to market? a) They work better than their reference biologic b) They are less expensive than their reference biologics and create competition in the market providing patients with different options c) There is no benefit d) They require smaller doses to have the same impact as their reference biologic

65 66

39 References References

X A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical X DiaTribe. FDA Approves New Insulin Glargine Basaglar – The First “Biosimilar” Insulin in the US. DiaTribe. Considerations. ASHP Advantage. 2012. January 11, 2016. www.diatribe.org. Accessed August 16, 2016. http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf. Accessed July 15, 2016. X Edney, A. Amgen Moves Closer to Selling Competitor for AbbVie’s Humira. Bloomberg. X Brown, T. Biosimilar to Enbrel Unanimously Recommended by FDA Panel. Medscape Medical News. http://www.bloomberg.com/news/articles/2016-07-12/amgen-moves-closer-to-selling-competitor-for-abbvie- July 14, 2016. http://www.medscape.com/viewarticle/866154. Accessed August 17, 2016. s-humira. Accessed August 17, 2016. X Cauchi, R. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. X FDA. Nonproprietary Naming of Biological Products Guidance for Industry. US Department of Health and Human National Conference of State Legislatures. 2016. http://www.ncsl.org/research/health/state-laws- Services. August 2015. and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed July http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459984.pdf. 15, 2016. Accessed July 20, 2016. X GaBI Online - Generic and Biosimilars Initiative. Biosimilars approved in Europe. May 2016. X Center for Drug Evaluation and Research. Purple Book: Lists of Licensed Biological Products with http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Accessed August 15, 2016. Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. July 2016. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApp X Granix® [package insert]. North Wales, PA: Teva Pharmaceutical Industries Ltd; 2014. rHowD/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM439049.pdf. X Levy, J. FDA Approves Lily/Boehringer Lantus biosimilar. Pharmafile. December 12, 2015. Accessed August 19, 2016. www.pharmafile.com. Accessed August 5, 2016. X Chhina MN. Overview of Biological Products. FDA Basics Webinar. June 2013. X Li EC, Stevenson JG. BIOSIMILARS: What Every Pharmacist Needs to Know. APhA Presentation. 2016. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM356666.pdf. Accessed August 1, http://aphameeting.pharmacist.com/sites/default/files/slides/Biosimilars_handout.pdf. Accessed July 20, 2016. 2016. X Cohen A, Royzman I. FDA Rejects Hospira’s EPO Biosimilar Application. Biologics Blog. November 5, X Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: Primer for the Health-System Pharmacist. American journal 2015. www.biologicsblog.com Accessed August 15, 2016. of health-system pharmacy:AJHP:official journal of the American Society of Health-System Pharmacists. 2013;70(22):2004-2017. X Dangi-Garimella, S. FDA Rejects Novartis’ Biosimilar Application for Pegfilgrastim, Seeks Additional X Neupogen® [package insert]. Thousand Oaks, CA: Amgen; 2015. Information. American Journal of Managed Care. July 20, 2016. www.ajmc.com. Accessed August 15, X 2016. Sandoz Biosimilar Etanercept Recommended by FDA Advisory Committee for Approval to Treat Multiple 68 Inflammatory Diseases. 67

References Image References

X Sandoz. July 13, 2016. www.sandoz.com. Accessed August 15, 2016. X http://www.pharmacytechnicianhq.com/quesitons-and-feedback/ X Simon, S. House Bill No. 319. Louisiana State Legislature. 2015. https://www.legis.la.gov/Legis/BillInfo.aspx?i=226919. Accessed August 11, 2016. X https://www.amgen.ca/english/science/how_biosimilars_differ.html X Tomaszewski, D. Biosimilar Naming Conventions: Pharmacist Perceptions and Impact on Confidence in Dispensing Biologics. Journal of Managed Care & Specialty Pharmacy. 2016; 22(8): 919-926. X http://www.signalsblog.ca/cell-lines-patient-samples-and-cultures-oh-my/ X United States Food and Drug Administration. FDA News Release: FDA approves Erelzi, a biosimilar to X http://www.bbc.com/news/health-34392522 Enbrel. August 30, 2016. http://www.fda.gov. Accessed August 30, 2016. X United States Food and Drug Administration. FDA News Release: FDA Approves first biosimilar X http://www.bbc.com/news/science-environment-23244768 product Zarxio. March 6 2015. http://www.fda.gov. Accessed August 20, 2016. X http://www.nature.com/news/2009/091211/full/news.2009.1140.html X United States Food and Drug Administration. Information on Biosimilars. May 2016. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Appr X http://www.edvotek.com/908 oApprovalApplica/TherapeuticBiologicApplications/Biosimilars/. Accessed August 19, 2016. X X Urquhart L, Gardner J, Elmhirst E. EP Vantage 2016 Preview. Evaluate Ltd. December 2015. http://money.cnn.com/2014/11/17/investing/allergan-actavis-merger-boom/ X WHO Executive Summary. 55th Consultation on International Nonproprietary Names for X http://www.herceptin.com/ Pharmaceutical Substances Geneva, 16–18 October 2012. INN Working Doc. 13.329. February 2013. X http://www.medscape.com/viewarticle/865154 X Zarxio® [package insert]. Princeton, NJ: Sandoz; 2015. X Zarxio clinical data. 2016. www.zarxio.com/info/hcp/pioneer.jsp. Accessed August 2016. X http://www.whatisbiotechnology.org/science/mabs X http://www.slideshare.net/boreddysunilkumarreddy/pilot-plant-scaleup- techniques-used-in-pharmaceutical-manufacturing

69 70

Morgan Corbin, Pharm.D. PGY-1 Pharmacy Resident University Health Shreveport [email protected]

40 Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

10:00—11:00 a.m. Updates in Sepsis Management

Katherine Jennings, PharmD Clinical Pharmacist Medical/Surgical Critical Care Ochsner Medical Center New Orleans, LA

0179-0000-16-027-L01-P/0179-0000-16-027-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Explain the pathophysiology of sepsis. 1. Identify medications used in the treatment 2. Describe the new definitions of sepsis and of sepsis. septic shock. 2. Describe the new definitions of sepsis and 3. Develop therapeutic care plans for the septic shock. management of sepsis and septic shock. 3. List the time-sensitive treatment goals for sepsis and septic shock.

Dr. Jennings have disclosed that they have no relevant financial relationships.

41

Pharmacist Objectives

1. Explain the pathophysiology of sepsis 2. Describe the new definitions of sepsis and Updates in Sepsis Management septic shock 3. Develop therapeutic care plans for the Katherine Jennings, PharmD management of sepsis and septic shock Clinical Specialist –Critical Care Ochsner Medical Center

Pharmacy Technician Objectives Sepsis Overview

1. Identify medications used in the treatment of • Incidence increasing: > 750,000 per year in U.S. sepsis – Aging population 2. Describe the new definitions of sepsis and – Increased awareness septic shock – Greater recognition 3. List the time‐sensitive treatment goals for • Costs sepsis and septic shock – 5.2% of total U.S. hospital costs in 2011 • Decrease in mortality

Singer M. JAMA. 2016;315(8):801‐810

Pathophysiology Pathophysiology

Tissue Immune •Pro‐inflammatory  tissue damage Hypoperfusion Dsyregulation •Anti‐inflammatory  immunosuppression Immune Coagulation Dsyregulation Abnormalities • Endothelial injury  increased vascular Tissue permeability  decreased preload •Increased nitric oxide synthesis  vasodilation Hypoperfusion • Mitochondrial damage  impaired oxygen use Host Response •Causative pathogen •Virulence •Bacterial load Infection • ↑ Procoagulants and ↓ ancoagulants •Host characteristics Coagulation •Fibrin deposition  microvascular thrombi •Age Abnormalities •Genetics • Disseminated intravascular coagulation •Co‐morbidites Finfer S. N Engl J Med 2013;369:840‐51 Finfer S. N Engl J Med 2013;369:840‐51

42 Overview: Sepsis Management

• Early identification • Treat the infection – Broad‐spectrum antibiotics New Sepsis Definitions – Source control • Treat the shock – Fluid resuscitation – Vasopressors • Re‐evaluate

Previous Sepsis Definitions Sepsis 3: New Definitions

Sepsis Sepsis = SIRS + infection • Definition: life‐threatening organ dysfunction due to a dysregulated host response to infection Severe sepsis = sepsis + organ dysfunction • Clinical Criteria: Suspected or documented Septic shock = severe sepsis + infection and an acute increase of ≥ 2 SOFA hypotension or elevated lactate points refractory to fluid resuscitation

SOFA = Sequential (Sepsis‐related) Organ Failure Assessment Levy M. et al. Crit Care Med 2003; 31:1250 –1256 Singer M. JAMA. 2016;315(8):801‐810

Sepsis 3: New Definitions SOFA Score

Septic shock Organ System Clinical Criteria Neurologic Glasgow coma scale

• Definition: Sepsis with circulatory and Respiration PaO2:FiO2 ratio cellular/metabolic abnormalities profound Cardiovascular MAP, vasopressor use enough to substantially increase mortality Renal SCr, urine output Coagulation Thrombocytopenia Liver Serum bilirubin • Clinical Criteria: Sepsis + vasopressor therapy • Mortality prediction score required for MAP ≥ 65 mmg Hg and lactate > 2 • Calculate on admission and every 24 hours using the worst values mmol/L after adequate fluid resuscitation • Score: 0 (normal) to +4 (maximum degree of dysfunction or failure) • Issue: need many labs, labor intensive

Singer M. JAMA. 2016;315(8):801‐810 Vincent JL et al. Crit Care Med.1998 Nov;26(11):1793‐800

43 qSOFA

Identifying Sepsis Patients with

Hypotension Altered mental status the New Definitions SBP ≤ 100 mmHg (GCS < 15)

Tachypnea (RR ≥ 22)

Screening tool to identify patients at high risk of poor outcome Score of ≥ 2 = increased mortality and ICU stay qSOFA = quick sepsis‐related organ failure assessment Singer M. JAMA. 2016;315(8):801‐810

Patient with suspected infection Sepsis

No No Sepsis still Monitor and qSOFA ≥ 2? suspected? re‐evaluate No Despite adequate fluid Yes resuscitation, 1. Vasopressors required to Yes Assess for evidence of maintain MAP ≥ 65 mmHg organ dysfunction 2. Serum lactate level > 2 mmol/L?

Yes No Monitor and SOFA ≥ 2 re‐evaluate Septic shock

Yes Singer M. JAMA. 2016;315(8):801‐810 Singer M. JAMA. 2016;315(8):801‐810

Patient Case #1 Patient Case #1 A 76‐year old woman arrives to the Emergency Department with community‐acquired After 30 mL/kg of 0.9% sodium chloride, your pneumonia. Her family states she has become patient’s blood pressure is 87/46 mmHg (MAP increasingly lethargic and confused over the last 2 60) and lactate level is 3.5 mmol/L. How days. Her baseline vitals signs are: HR: 115 RR: 26 BP: 83/44 mmHg Temp: 38.9° would you classify her sepsis?

What is her qSOFA score? A. Sepsis A. 0 B. Severe sepsis B. 1 C. 2 C. Septic shock D. 3 D. None of the above

44 Overview: Sepsis Management Antibiotic Therapy

• Early identification • Initiate as soon as possible • Treat the infection – Goal = within 1 hour – Broad‐spectrum antibiotics • Broad‐spectrum – Direct at suspected site/pathogens – Source control – Local resistance patterns • Treat the shock – Patient‐specific factors – Fluid resuscitation • Previous exposure to antibiotics – Vasopressors • Prior cultures • Re‐evaluate • Severity of illness • De‐escalate when appropriate

Dellinger R, et al. Crit Care Med2013; 41:580–637

Time to Antibiotics Decreasing Time to Antibiotics

• Load broad‐spectrum agents (ie. cefepime) into automated dispensing cabinets • Sepsis protocols – ensure medications built as STAT • ED auto‐verification • “Code Sepsis” carts • Educate all pharmacy staff on importance of antibiotic timing in sepsis Each hour delay = ↑ Mortality 7.6%

Kumar et al. Crit Care Med. 2006;34:1589–1596

Procalcitonin Procalcitonin in Sepsis

• Procalcitonin (PCT) = precursor of calcitonin • Guide duration of antibiotic therapy – Calcitonin synthesis inhibited by cytokines and • Do NOT use as guide to start antibiotics in endotoxins  increased PCT levels in bacterial unstable patients infections • If initially elevated (ie. > 0.25 ng/mL), trend levels – Usually undetectable in absence of bacterial – Consider discontinuation of antibiotics if level falls infection below 0.25 ng/mL or > 80% of peak • Limitations • Meta‐analysis – Localized infections – PCT‐guided treatment led to shorter duration of – Can be elevated in certain non‐infectious states antibiotics – Lacking data in immunocompromised patients – No difference in mortality or length of stay

Prkno et al. Critical Care 2013, 17:R291 Boudama L, et al. Lancet 2010; 375: 463‐74 Dellinger R, et al. Crit Care Med 2013; 41:580–637

45 Source Control Patient Case #2

• Examples: abscess drainage, necrotic tissue • A 62‐year old man presents to the Emergency Department with septic shock from a debridement, resection of ischemic bowel suspected intra‐abdominal infection. Which of • Intervention within first 12 hours if possible the following statements regarding his treatment plan is FALSE? • Prefer less invasive procedure – Percutaneous drain vs. surgery A. Initiate broad‐spectrum antibiotics ASAP • Remove IV access device if potential source B. Wait for the PCT level to start antibiotics C. Consult surgery for source control D. Review the chart for previous cultures and antibiotic exposure

Dellinger R, et al. Crit Care Med2013; 41:580–637

Surviving Sepsis Campaign Guideline Overview: Sepsis Management Recommendations (2014) • Early identification • Protocolized, quantitative resuscitation of • Treat the infection patients with sepsis‐induced tissue hypoperfusion. During the first 6 hours, the – Broad‐spectrum antibiotics goals should include the following: – Source control – CVP 8 –12 mmHg • Treat the shock – MAP ≥ 65 mmHg – Fluid resuscitation – Urine output ≥ 0.5 mL/kg/hr

– Vasopressors – ScVO2 goal 70%; SVO2 goal 65% • Re‐evaluate • Target resuscitation to normalize lactate in patients with elevated lactate

Dellinger R, et al. Crit Care Med2013; 41:580–637

Early Goal Directed Therapy EGDT Algorithm

CVP CVP < 8 mmHg Crystalloid 1° outcome: Colloid •In‐hospital mortality 130 patients 2° outcomes: CVP 8‐12 mmHg 263 patients EGDT •28‐day and 60‐day Severe sepsis or mortality MAP MAP < 65 mmHg septic shock •Resuscitation Vasopressor endpoints •Organ dysfunction MAP 60 –90 mmHg scores 133 patients •Administered RBC Standard care treatments •Prospective, randomized, single‐ ScVO2 < 70% transfusion center trial until Hct ≥ 30% •Emergency Department •Central access ≥ 70% < 70% ≥ 70% •EGDT group: continuous ScVO2 monitoring Goal? Inotropic ≥ 70% agent Rivers et al. N Engl J Med. Rivers et al. N Engl J Med. 2001;345:1368‐77 2001;345:1368‐77

46 EGDT Criticisms of EGDT

• EGDT: Decreased in‐hospital mortality • Single‐center trial in the Emergency – 30.5% vs. 46.5% (P = 0.009) Department • In the first 6 hours, EGDT patients received • Unblinded: “Rivers Effect” more fluids, blood, and inotropes. • All or nothing: unclear which interventions are • Conclusion: early identification and goal‐ the most important directed therapy led to significant benefits in • Barriers to implementation severe sepsis and septic shock. – Staff requirements – Central venous catheter insertion

Rivers et al. N Engl J Med. 2001;345:1368‐77 Calbron D. et al. Crit Care Med 2007; 35:2525–2532

Criticisms of EGDT

• TRICC trial – No mortality benefit for liberal transfusion threshold (10 g/dL vs. 7 g/dL) – More adverse effects with liberal strategy The End of EGDT? • Lactate clearance as less invasive resuscitative endpoint than ScVO 2 ProCESS, ARISE, ProMISE • Dobutamine not shown to improve microvascular perfusion • Lack of large, randomized controlled trials to confirm results Hebert P et al. N Engl J Med 1999; 340:409‐417 Jones A et al. JAMA 2010 February 24; 303(8): 739–746 Hernandez G. Intensive Care Med. 2013 Aug;39(8):1435‐43

ProCESS •≥ 2/4 SIRS criteria ProCESS Randomized, multicenter •Refractory hypotension trial in 31 US hospitals (SBP < 90 or required Intervention EGDT Standard Protocol Usual Care P‐value 1341 septic shock vasopressor after ≥ 1000 Pre‐randomization patients mL IVF) OR hypoperfusion (lactate > 4 mmol/L) IV fluids (mL) 2254 ± 1472 2226 ± 1369 2083 ± 1405 0.15 Antibiotics (%) 75.6 76.9 76.1 0.91 Randomization to 6 hours 446 patients 439 patients 456 patients Protocol‐based IV fluids (mL) 2805 ± 1957 3285 ± 1743 2279 ± 1881 <0.0001 EGDT Usual care standard therapy Central line (%) 93.6 56.5 57.9 <0.0001 Vasopressor (%) 54.9 52.2 44.1 0.03 Dobutamine (%) 8 1.1 0.9 <0.0001 Protocol‐based standard therapy •Less aggressive 6‐hour approach Blood 14.4 8.3 7.5 0.001 •Does not require central line transfusion (%)

•Fluids and vasopressors to meet SBP and shock index goals ScVO2 93.6 4.0 3.5 <0.001 •PRBC only if Hgb < 7.5 mg/dL monitoring (%) •Clinical reassessment Antibiotics (%) 97.5 97.1 96.9 0.90

N Engl J Med 2014; 370:1683‐1693 N Engl J Med 2014; 370:1683‐1693

47 ProCESS ProCESS: Conclusion

Outcome EDGT Standard Protocol Usual Care P‐value Death (%) 21 18.2 18.9 0.83 Benefit No Benefit In‐hospital by 60 days * Death by 90 31.9 30.8 33.7 0.66 •Early identification • Mandatory central days (%) •Early antibiotics line *= primary outcome • Fluid resuscitation •CVP monitoring No difference in: • 1‐ year mortality • ScVO2 monitoring •Acute cardiovascular failure • Dobutamine •Acute respiratory failure •Duration of organ support •Liberal blood •ICU length of stay transfusion threshold •More EGDT patients admitted to ICU •Hospital length of stay •Discharge status at 60 days N Engl J Med 2014; 370:1683‐1693

ARISE ARISE

Early recognition: • No difference in 90‐day mortality 796 patients Randomized within EGDT 2 hours – EGDT: 18.6% vs. usual care: 18.8% (P = 0.90) Early antibiotics: 1600 septic shock st patients Received 1 dose • No difference in other outcomes antibiotic prior to randomization • First 6 hours, EGDT received more fluids, 804 patients Usual care vasopressors, blood, and inotropes •Suspected or Primary Outcome: confirmed infection 90‐day mortality – Patients in both groups received about 2.5 liters •≥ 2 SIRS criteria •Refractory prior to randomization hypotension or • No benefit of EGDT compared to usual care hypoperfusion (SBP < 90 or MAP < 65 – Usual care = early identification, early antibiotics, despite ≥ 1000 mL IVF OR lactate > 4 and fluid resuscitation mmol/L) N Engl J Med 2014; 371:1496‐1506 N Engl J Med 2014; 371:1496‐1506

ProMISE ProMISE • No difference in 90‐day mortality Early recognition: – EGDT: 29.5% vs. usual care: 29.2% (P = 0.90) 630 patients Randomized within EGDT 2 hours • Secondary outcomes 1260 septic shock Early antibiotics: patients – EGDT: more ICU days, cardiovascular support Received 1st dose antibiotic prior to – No difference in other outcomes including costs and randomization quality of life 630 patients •Suspected or Usual Care • First 6 hours, EGDT received more fluids, confirmed infection Primary Outcome: vasopressors, blood, and inotropes •≥ 2 SIRS criteria 90‐day mortality •Refractory – Patients in both groups received about 2 liters prior to hypotension or randomization hypoperfusion (SBP < 90 or MAP < 65 • No benefit of EGDT compared to usual care despite ≥ 1000 mL IVF – OR lactate > 4 Usual care = early identification, early antibiotics, and mmol/L) fluid resuscitation Mouncey P. N Engl J Med 2015; 372:1301‐1311 Mouncey P. N Engl J Med 2015; 372:1301‐1311

48 Conclusion: EGDT Has Retired Vasopressors

• “Usual care” has greatly advanced since EGDT • First line: Norepinephrine (NE) published in 2001. • Second line: Epinephrine • Add vasopressin (0.03 units/min) to NE • EGDT increased early recognition, fluid – No mortality benefit resuscitation, and frequent re‐assessment. – Used to ↑ MAP or ↓ NE dose • Protocols do not improve survival but can be – Not recommended as sole agent used as a checklist to ensure all components • Alternative: Dopamine – Patients with low risk for tachyarryhthmias of care are implemented. – Bradycardia • Phenylephrine not typically recommended

Dellinger R, et al. Crit Care Med 2013; 41:580–637

Sepsis Bundles

TO BE COMPLETED WITHIN 3 HOURS Sepsis in 2016 1. Measure lactate level 2. Obtain blood cultures prior to antibiotics Sepsis Bundles + New Definitions 3. Administer broad‐spectrum antibiotics CMS Core Measures 4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L

http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.pdf

Sepsis Bundles

TO BE COMPLETED WITHIN 6 HOURS Step 1: Screen and Manage Infection 1. Vasopressors (for hypotension that does not respond to fluids) to maintain MAP ≥ 65 mmHg 2. If persistent hypotension (MAP < 65) or initial • Identify infection lactate ≥ 4, re‐assess volume status and • Obtain appropriate cultures tissue perfusion • Administer antibiotics 3. Re‐measure lactate if initially elevated • Labs to evaluate for infection‐related organ dysfunction

http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.pdf

49 Step 2: Screen and Manage Step 3: Identify and Organ Dysfunction Manage Initial Hypotension

• Use same criteria including lactate • Infection + hypotension OR lactate ≥ 4 mmol/L  • qSOFA screen to identify patients at risk of clinical 30 mL/kg crystalloid deterioration • 6‐hour bundle components • If identified, ensure 3‐hour bundle components are – Vasopressors implemented – Re‐assess volume status/tissue perfusion – Lactate, cultures, antibiotics, and fluids – Repeat lactate level if initial > 2 mmol/L

Sepsis CMS Core Measures (SEP‐1) Meeting Core Measures

• Created before new definitions • Multidisciplinary committee – Severe sepsis: lactate >2 mmol/L or organ • Utilize the electronic medical record dysfunction – – Septic shock: severe sepsis + hypoperfusion despite Screening adequate fluid resuscitation OR lactate > 4 mmol/L • SIRS criteria • All or nothing: must meet ALL measures • qSOFA? – Data extraction • 3‐ and 6‐hour bundles – Septic shock patients MUST have reassessment of • Dedicated personnel volume assessment/tissue perfusion • Hospital‐wide education • Excluded: transfers, comfort care

https://www.jointcommission.org/topics/hai_sepsis.aspx http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.pdf

Patient Case #3 Patient Case #3

• A 65‐year old male in your Surgical ICU develops • Blood and respiratory cultures are obtained, antibiotics a suspected ventilator‐associated pneumonia. His are started, and your patient received 30 mL/kg of current vitals signs are: 0.9% NaCl. Thirty minutes after completion of the IV fluids, the BP is 88/48 mmHg (MAP 61 mmHg). The HR: 107 RR: 23 BP: 82/40 mmHg Temp: 38.8°C initial lactate level decreased from 3.2 to 2.4 mmol/L. What do you recommend next? What do you recommend? A. Send cultures A. Start norepinephrine B. Start piperacillin/tazobactam and vancomycin B. Start dobutamine C. Send labs including lactate C. Tissue perfusion assessment D. 30 mL/kg 0.9% sodium chloride D. Blood transfusion E. All of the above E. A and C

50 Updates in Sepsis Management

Katherine Jennings, PharmD Clinical Specialist –Critical Care Ochsner Medical Center

51

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

10:00—11:00 a.m. Essential Oils: The Essentials of Their Safety and Efficacy

Stephanie Hatten, PharmD Pharmacy Intern Brookshire’s Pharmacy Monroe, LA

0179-0000-16-028-L01-P/ 0179-0000-16-028-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Discuss the proven safety and efficacy, or 1. Describe the use of common essential oils. lack thereof, of select essential oils. 2. Recognize the potential risk and benefits of 2. Recognize the “indication” of discussed discussed essential oils. essential oils. 3. Formulate an educated view about the use of essential oils.

Dr. Hatten has disclosed that he has no relevant financial relationships. 52

Objectives  Pharmacists 1. Discuss the proven safety and efficacy, or lack thereof, of select essential oils 2. Recognize the “indication” of discussed essential oils Stephanie Hatten, Pharm.D. 3. Formulate an educated view about the use of essential oils University Health PGY-1 Resident Technicians 1. Describe the use of common essential oils 2. Recognize the potential risk and benefits of discussed essential oils

What is an essential oil? How do we obtain them?   Expression- cold pressing  Citrus essential oils, such as tangerine, lemon, bergamot, sweet “An essential oil is a product made by distillation with either orange, and lime. water or steam or by mechanical processing of citrus rinds or by dry distillation of natural materials. Following the distillation, Distillation-most common process the essential oil is physically separated from the water phase.”  Advantage: volatile components can be distilled at temperatures lower than the boiling points of their individual constituents  Easily separated from the condensed water.

Shutes J. The Quality of Essential Oils Journal. Available at: http://www.naha.org/assets/uploads/The_Quality_of_Essential_Oils_Journal. Accessed August 15, 2016. Available at https://www.naha.org/explore-aromatherapy/about-aromatherapy/how-are-essential-oils-extracted.Accessed August 12,2016.

Marketing Novel Idea?   Digoxin FDA regulates labeling for cosmetics and drugs  Foxglove Advertising claims are regulated by the Federal Trade Paclitaxel Commission.  Pacific Yew Tree No standardization Morphine  Poppy Not “Generally Recognized as Safe”

Available at: http://www.fda.gov/Cosmetics/ProductsIngredients/Products/ucm127054.htm. Accessed 8/3/2016. Veeresham C. Natural products derived from plants as a source of drugs. Journal of Advanced Pharmaceutical Technology & Research. 2012;3(4):200-201. doi:10.4103/2231- 4040.104709.

53 Aromatherapy  Routes  Topical  Inhalation  Enteral

Topical Inhalation   Contact dermatitis seen with most essential oils Most popular route Often used in massage therapy heavily diluted Diffusers No safety data in infants  Readily available Nebulizers?  No!

Available at https://www.cff.org/News/News-Archive/2014/CF-Foundation-Recommends-Against-Using-Peppermint-Oil-in-Nebulizer. Accessed 8/14/2016.

CYP Interaction Essential Oil

CYP2D6 Inhibition Chamomile, chamazulene, alpha-bisabolol, Enteral Farnesene, E-spiroether, Z-spiroether, Safrole

CYP3A4 Inhibition Chamomile, chamazulene, alpha-bisabolol,  Farnesene, E-spiroether, Z-spiroether, Peppermint, Few considered safe for ingestion Menthol, Menthyl acetate, Bergamottin, Bergaptol, Methoxsalen, Psoralen, Safrole High Seizure Risk  Camphor  Lavender CYP2C9 Inhibition Chamomile, alpha-Bisabolol, Chamazulene, Farnsene  Fennel Oil CYP2E1 Inhibition Tangerine oil, Bergamot oil, Mandarin oil, Petitgrain  Sage Oil oil, Lemon oil, Orange oil, Grapefruit oil, Lime oil, Neroli oil, Garlic oil, Diallyl sulfide, Safrole

CYP1A2 Induction Rosemary oil, Diallyl sulfide

Tisserand R, Young R. Essential Oil Safety, A Guide for Health Care Professionals. Churchill Livingstone; 2013.

54 Poison Control   webPOISONCONTROL® online tool for guidance  1-800-222-1222 Essential Oils  www.poison.org   Emergency Department

Available at: http://www.poison.org/articles/2014-jun/essential-oils. Accessed August 10,2016

Argan Oil Ginger

 Alleged benefits  Alleged benefits   Moisturize and help smooth rough skin, dry hair and brittle nails  Anxiety  Lexicomp  Used for dermatological and anti-hyperlipidemic effects  Nausea  Studies Lexicomp  Dermal  Used for aromatherapy for postoperative and chemotherapy-induced  Skin elasticity  Wound Care nausea and vomiting  Some studies suggesting validity in cholesterol lowering effects Studies  Unsupported claims  Research shows mixed results regarding effectiveness  Reduce blood pressure  Reduce hyperglycemia  Reduce insulin resistance Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016 Available at: Chemotherapy induced nausea and vomiting http://www.doctoroz.com/article/health-benefits-ginger. Accessed August 10, 2016. Berrougui H, Cloutier M, Isabelle M, Khalil A. Phenolic-extract from argan oil (Argania spinosa L.) inhibits human low-density lipoprotein (LDL) oxidation and enhances cholesterol efflux from human THP-1 macrophages. Atherosclerosis. 2006;184(2):389-96. Available at :https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750018. Accessed August 4, 2016. Boucetta KQ, Charrouf Z, Aguenaou H, Derouiche A, Bensouda Y. The effect of dietary and/or cosmetic argan oil on postmenopausal skin elasticity. Clin Interv Aging. 2015;10:339-49. Avsar U, Halici Z, Akpinar E, et al. The Effects of Argan Oil in Second-degree Burn Wound Healing in Rats. Ostomy Wound Manage. 2016;62(3):26-34.

Study Design  Effects of inhaled ginger aromatherapy  Single-blind, controlled, randomized cross-over study  60 female breast cancer patients on chemotherapy-induced nausea and  18 years or older  Normal sense of smell vomiting and health-related quality of  5 days of aromatherapy  Oil instilled in a necklace patients wore 24 hours/day life in women with breast cancer  Ginger essential oil  Ginger fragrance oil  Patients received same antiemetics before and after treatment  Used Visual Analog Scale (VAS) nausea score for quantification

PL, Salihah N, Mazlan N. Effects of inhaled ginger aromatherapy on chemotherapy-induced nausea and vomiting and health-related quality of life in women with breast cancer. Complement Ther Med. 2015;23(3):396-404

55 Results Lavender Oil    Alleged benefits  VAS nausea score  Restlessness, insomnia, anxiety  Significantly lower after ginger essential oil inhalation compared to placebo  Diabetes, GI distress during acute phase (P = 0.040) but not sustained for overall treatment effect  Dementia, depression  Lexicomp  No significant effect of aromatherapy on vomiting  CNS depressants and anticonvulsants may potentiate sedative effects  Statistically significant change from baseline for global health status  Increased bleeding risk with concomitant use of lavender and anticoagulants.  Contact dermatitis, photosensitization, nausea, vomiting and anorexia reported  Studies  GI  Depression

 Anxiety Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016. Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750228. Accessed August 7,2016.

Pre-pubertal Gynecomastia Lavender Oil

 4 year old boy    2-3 week history of gynecomastia  Dementia  Mother applied a “healing balm” compounded with lavender  Depression and Anxiety  Partial resolution was seen after 4 months of discontinuation of healing balm  10 year old boy  Silexan  5 month history of gynecomastia  applying a styling gel and using shampoo that contained lavender oil, as well as tea tree oil.  Reevaluation 9 months after discontinuation ,almost complete resolution of gynecomastia  7 year old boy  One month history of gradual gynecomastia  Lavender scented soap.  Completely resolved a few months after discontinuation

Kemper KJ, Romm AJ, Gardiner P. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med. 2007;356(24):2541-2.

Study Design  Efficacy of Silexan in mixed  Double-blind, randomized, placebo-controlled, parallel-group multicenter trial anxiety-depression- A randomized,  318 adult patients diagnosed with MADD placebo controlled trial  Been through a 3-7 day screening period  >= 18 points on Hamilton Anxiety Rating Scale  2 or more points on the MADRS Montgomery Asberg Depression Rating Scale (suicidal thoughts ) were excluded  Concomitant psychotropic medication and psychotherapy were not allowed during study participation

Woelk H, Schläfke S. A multi-center, double-blind, randomized study of the Lavender oil preparation Silexan in comparison to lorazepam for generalized anxiety disorder. Phytomedicine. 2010;17(2):94-99

56 Study Design Results

 MADRS total score  Given one 80 mg dose of Silexan daily or Placebo for 10 weeks  Silexan Masking  Baseline:22.0±6.4 points  Smell of the investigational treatments was matched by flavoring  End point:12.8±8.7 points the capsules containing placebo  Placebo  1/1000 of the amount of lavender oil contained in the Silexan capsules.  Baseline: 22.1±6.1 points Primary outcomes were measured as HAMA and MADRS total  End point:16.0±9.8 points score difference

Lemon oil Lemon Grass Oil

 Alleged benefits   Alleged benefits   Stress  Headache  Antibacterial effects  Fever  Lexicomp  “Kills germs”  Lexicomp  Some bacteriostatic activity  Antimicrobial effects  Studies  Gram positive, gram negative, fungi  No data supporting the calming effects of lemon oil  Studies  Bacteriostatic effect of lemon oil shown to be inferior to other essential  Tinea versicolor (Pityriasis versicolor) oils  Other claims unsubstantiated by research

Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750231#uses-nested. Accessed August 7,2016. Fisher K, Phillips CA. The effect of lemon, orange and bergamot essential oils and their components on the survival of Campylobacter jejuni, Escherichia coli O157, Listeria Available at:https://draxe.com/lemongrass-essential-oil/. Accessed August 20,2016. monocytogenes, Bacillus cereus and Staphylococcus aureus in vitro and in food systems. J Appl Microbiol. 2006;101(6):1232-40. Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750234. Accessed August 8,2016. Carmo ES, Pereira Fde O, Cavalcante NM, Gayoso CW, Lima Ede O. Treatment of pityriasis versicolor with topical application of essential oil of Cymbopogon citratus (DC) Stapf - therapeutic pilot study. An Bras Dermatol. 2013;88(3):381-5.

57 Manuka Oil Oil of Oregano

  Alleged Benefits   Alleged benefits:  Antimicrobial  Antifungal properties, promote wound healing of cuts and scrapes  Strengthen immune system  Lexicomp:  Lexicomp  Selective antibacterial activity against gram positive organisms, particularly s.  Gastrointestinal upset, allergic reactions. aureus  No clinical data exists  Potential synergistic effects: bacitracin, cefadroxil, meropenem  Studies  Antagonist effects: ofloxacin, enoxacin, sparfloxacin  Aspergillus ochraceus  Unsupported claims:  Immune system and antibacterial claims unsubstantiated by research  Activity against fungi and yeast .

Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750254. Accessed August 12, 2016. Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016. Harkenthal M, Reichling J, Geiss HK, Saller R. Comparative study on the in vitro antibacterial activity of Australian tea tree oil, cajuput oil, niaouli oil, manuka oil, Available at https://www.sciencebasedmedicine.org/oil-of-oregano/. Accessed August 10,2016 kanuka oil, and eucalyptus oil. Pharmazie. 1999;54:460-463 Basílico MZ, Basílico JC. Inhibitory effects of some spice essential oils on Aspergillus ochraceus NRRL 3174 growth and ochratoxin A production. Lett Appl Microbiol. 1999;29(4):238-41016 Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016.

Peppermint Oil

 Alleged Benefits  A novel delivery system of  Ease irritable bowel syndrome symptoms  Headache relief peppermint oil is an effective  Lexicomp  5-HT3 receptor therapy for irritable bowel  IBS dosing .1 to .24 ml,  May be up to 48% menthol which can be toxic when ingested  Seizures syndrome symptoms  More effective than placebo but not more effective than standard treatment  Studies  Headache  IBS

Cash BD, Epstein MS, Shah SM. A Novel Delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Symptoms. Borhani haghighi A, Motazedian S, Rezaii R, et al. Cutaneous application of menthol 10% solution as an abortive treatment of migraine without aura: a randomised, double-blind, placebo-controlled, crossed-over study. Int J Clin Pract. 2010;64(4):451-6. Dig Dis Sci. 2016;61(2):560-71 Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750296. Accessed August 22, 2016. Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016.

Study Design Results    4 week, randomized, double–blind, placebo controlled clinical trial  Reduction in IBS symptoms  72 patient pool  Peppermint oil:41.8%  Patients fulfilled Rome III criteria for IBS-M or IBS-D  Placebo: 22.1%  Randomized to peppermint oil or placebo three times daily  Reduction in mean symptom scores for pain or discomfort  Primary endpoint measured  Peppermint oil: 31.3%  Change from baseline in total IBS symptom score 4 weeks post start of  Placebo: 19.8% therapy

.

58 Rose Hip Oil Thyme Oil    Alleged Benefits  Alleged benefits  Full of vitamins E and A, rejuvenates and brightens skin, contains essential  Immune system fatty acids, which may improve dry skin conditions like eczema or psoriasis  Respiratory, digestive, and nervous system  Anti-inflammatory  Lexicomp  Anti-diabetic  Antimicrobial effect  Antimicrobial  Gram positive bacteria, Candida species, Aspergillus  Antioxidant effect claims  Gastrointestinal  Little clinical data  Lexicomp  Studies  Rich in Vitamin C, and contains A, B, K, and folate  Synergistic effects with antifungals  All Alleged benefits are unsubstantiated, or proven ineffective by studies  Other claims unsubstantiated by research

Available at: https://www.youngliving.com/en_EU/products/thyme-essential-oil.Accessed August 12,2016. Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016. Available at: http://online.lexi.com:Accessed Accessed August 8,2016 Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750330. Accessed August 14, 2016. Giordani R, Regli P, Kaloustian J, Mikaïl C, Abou L, Portugal H. Antifungal effect of various essential oils against Candida albicans. Potentiation of antifungal action of amphotericin B by essential oil from Thymus vulgaris. Phytother Res. 2004;18(12):990-5.

Essential Oil Combinations  Investigation of the effectiveness of  Clove oil Syzygium aromaticum, Lavandula  Eugenol, oleic acids and lipids  English Lavender angustifolia and Geranium robertianum  Robert Geranium essential oils (Lamigex) in the treatment  Claims of antibacterial activity of acute external otitis: a comparative trial with ciprofloxacin

Antimicrobial activity of essential oils and other plant extracts. Journal of Applied Microbiology. 86(6):985 Gruenwald, J., Brendler, T., and Jaenicke, C. PDR for herbal medicines. 3rd ed. Thomson, Montvale; 2004 (p. 204–8, 285–8) . Panahi Y, Akhavan A, Sahebkar A, et al. Investigation of the effectiveness of Syzygium aromaticum, Lavandula angustifolia and Geranium robertianum essential oils in the treatment of acute external otitis: a comparative trial with ciprofloxacin. J Microbiol Immunol Infect. 2014;47(3):211-6.

59 Study Design Study Design    Non-inferiority trial  Random Assignment  70 adult patients  ciprofloxacin 0.3%  Mean age of the patient  Lamigex  37.11 (ciprofloxacin)  37.29 (Lamigex)  3 drops to affected ear every 12 hours x 1 week  Interval between onset of symptoms and time to doctor visit was not  Examined for symptoms and ear discharge and cultured at baseline and different in each group at the end of the trial  Pain severity was also recorded

Results   Equally improved in both ciprofloxacin and Lamigex groups  Tenderness  Erythema  Edema  Itching  Discharge  Number of positive cultures for all tested microorganisms were reduced at the end of the trial in both groups

Cannabis Oil

  Cannabis exerts its pharmacologic action at two receptors  CB1  Expressed predominantly at presynaptic sites in GABAergic neurons  Neuronal terminals of the basal ganglia, cerebellum, hippocampus, neocortex, hypothalamus, and limbic cortex.  Agonistic activity of CB1  Decreases cAMP and calcium influx  Diminishes neuronal hyper-excitability  Ameliorates the spasticity and tremors of multiple sclerosis  CB2  Affect inflammation and immunosuppression.

Kolikonda MK, Srinivasan K, Enja M, Sagi V, Lippmann S. Medical Marijuana for Epilepsy? Innovations in Clinical Neuroscience. 2016;13(3-4):23-26.

60 Cannabis Oil for Multiple Sclerosis Cannabis Oil for Multiple Sclerosis    American Academy of Neurology  Sativex oromucosal spray is possibly ineffective for reducing MS-related  Cannabis extract tremor over 15 weeks (1 Class II26).  Spasticity and central neuropathic pain  Clinicians might offer Sativex oromucosal cannabinoid spray  Not good for short term, but possibly good for long term (nabiximols), where available, to reduce symptoms of spasticity, pain, or  Orally administered cannabinoids (cannabis extract, synthetic THC) urinary frequency, although it is probably ineffective for improving  Mucosally delivered cannabinoids (cannabis extract oral spray, nabiximols [trade name Sativex]) objective spasticity measures or number of urinary incontinence  Smoked cannabis episodes (Level B).  All been studied for therapeutic effects in MS.  Clinicians might choose not to offer Sativex oromucosal cannabinoid spray to reduce MS-related tremor (Level C).

Yadav V, Bever C, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083-92.

Cannabis Oil and seizures Charlotte’s Web    Variety of cannabis oil being studied for it’s effects on intractable  Epidiolex seizures  GW Pharmaceuticals  Genetic Analysis Between Charlotte's Web Responders Versus Non-  Orally administered cannabidiol oil Responders in a Dravet Population  Does not contain THC  University of Colorado  Double blind placebo controlled trials  “Very low” THC content 30:1 CBD:THC ratio  Dravet Syndrome  Study will look at high concentration cannabidol oil response  Lennox-Gastaut Syndrome

Available at: https://clinicaltrials.gov/ct2/show/study/NCT02397863. Accessed August 8,2016. Available at:https://clinicaltrials.gov/ct2/show/NCT02229032. Accessed August 11,2016. Available at: http://www.gwpharm.com/GW Pharmaceuticals Announces Positive Phase 3 Pivotal Study Results for Epidiolex cannabidiol.aspx. Accessed August 10, 2016 Available at: http://www.epilepsycolorado.org/news-research/medical-marijuana/efco-report-to-the-community/. Accessed August 12, 2016..

Essential oils are always safe if given topically, if diluted?  Review Questions  True  False

61 Essential oils are always safe if What has peppermint oil been given topically, if diluted? studied for?    True A) Headache relief  False B) IBS relief C) Skin moisturizing D) Seizures

What has peppermint oil been Which essential oil has been used studied for? for it’s calming effect?   A) Headache relief A) Cannabis B) IBS relief B) Thyme C) Skin moisturizing C) Lavender D) Seizures D) Castor

Which essential oil has been used Cannabis oil has been approved for it’s calming effect? for certain seizure conditions   A) Cannabis  True B) Thyme  False C) Lavender D) Castor

62 Cannabis oil has been approved for certain seizure conditions   True  False Questions?

References References    Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750330. Accessed August 14, 2016  Kolikonda MK, Srinivasan K, Enja M, Sagi V, Lippmann S. Medical Marijuana for Epilepsy? Innovations in Clinical Neuroscience. 2016;13(3-4):23-26.  Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750254. Accessed August 12, 2016.  Available at https://www.naha.org/explore-aromatherapy/about-aromatherapy/how-are-essential-oils-extracted.Accessed August  Harkenthal M, Reichling J, Geiss HK, Saller R. Comparative study on the in vitro antibacterial activity of Australian tea tree oil, cajuput 12,2016. oil, niaouli oil, manuka oil, kanuka oil, and eucalyptus oil. Pharmazie. 1999;54:460-463  Veeresham C. Natural products derived from plants as a source of drugs. Journal of Advanced Pharmaceutical Technology &  Available at: http://www.doctoroz.com/slideshow/dr-ozs-essential-oil-guide. Accessed August 14, 2016. Research. 2012;3(4):200-201. doi:10.4103/2231-4040.104709.  Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750228. Accessed August 7,2016.  Available at: http://www.fda.gov/Cosmetics/ProductsIngredients/Products/ucm127054.htm. Accessed 8/3/2016.  Kemper KJ, Romm AJ, Gardiner P. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med. 2007;356(24):2541-  Bozorg AM, Benbadis SR. Essential oils as a cause of breakthrough seizure after temporal lobectomy. Seizure. 2009;18(8):604-5. 2  Available at https://www.cff.org/News/News-Archive/2014/CF-Foundation-Recommends-Against-Using-Peppermint-Oil-in-Nebulizer.  Woelk H, Schläfke S. A multi-center, double-blind, randomized study of the Lavender oil preparation Silexan in comparison to Accessed 8/14/2016 lorazepam for generalized anxiety disorder. Phytomedicine. 2010;17(2):94-99  Available at: http://www.poison.org/articles/2014-jun/essential-oils Accessed August 10,2016  Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750296. Accessed August 22, 2016.  Borhani haghighi A, Motazedian S, Rezaii R, et al. Cutaneous application of menthol 10% solution as an abortive treatment of  Skalli S, Soulaymani bencheikh R. Epileptic seizure induced by fennel essential oil. Epileptic Disord.er 2011;13(3):345-7. migraine without aura: a randomised, double-blind, placebo-controlled, crossed-over study. Int J Clin Pract. 2010;64(4):451-6  Halicioglu O, Astarcioglu G, Yaprak I, Aydinlioglu H. Toxicity of Salvia officinalis in a newborn and a child: an alarming report. Pediatric  Cash BD, Epstein MS, Shah SM. A Novel Delivery System of Peppermint Oil Is an Effective Therapy for Irritable Bowel Syndrome Neurol. 2011;45(4):259-60. Symptoms. Dig Dis Sci. 2016;61(2):560-71  Available at: http://www.poison.org/articles/2014-jun/essential-oils. Accessed August 10,2016  Fisher K, Phillips CA. The effect of lemon, orange and bergamot essential oils and their components on the survival of Campylobacter  Tisserand R, Young R. Essential Oil Safety, A Guide for Health Care Professionals. Churchill Livingstone; 2013.Berrougui H, Cloutier jejuni, Escherichia coli O157, Listeria monocytogenes, Bacillus cereus and Staphylococcus aureus in vitro and in food systems. J M, Isabelle M, Khalil A. Phenolic-extract from argan oil (Argania spinosa L.) inhibits human low-density lipoprotein (LDL) oxidation and Appl Microbiol. 2006;101(6):1232-40. enhances cholesterol efflux from human THP-1 macrophages. Atherosclerosis. 2006;184(2):389-96.  Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750234. Accessed August 8,2016.  Available at :https://online.lexi.com/lco/action/doc/retrieve/docid/fc_rnp2/3750018. Accessed August 4, 2016.  Available at:https://draxe.com/lemongrass-essential-oil/. Accessed August 20,2016.  Boucetta KQ, Charrouf Z, Aguenaou H, Derouiche A, Bensouda Y. The effect of dietary and/or cosmetic argan oil on postmenopausal  Carmo ES, Pereira Fde O, Cavalcante NM, Gayoso CW, Lima Ede O. Treatment of pityriasis versicolor with topical application of skin elasticity. Clin Interv Aging. 2015;10:339-49. essential oil of Cymbopogon citratus (DC) Stapf - therapeutic pilot study. An Bras Dermatol. 2013;88(3):381-5.  Avsar U, Halici Z, Akpinar E, et al. The Effects of Argan Oil in Second-degree Burn Wound Healing in Rats. Ostomy Wound Manage.  Available at https://www.sciencebasedmedicine.org/oil-of-oregano/. Accessed August 10,2016 2016;62(3):26-34.

References

 Basílico MZ, Basílico JC. Inhibitory effects of some spice essential oils on Aspergillus ochraceus NRRL 3174 growth and ochratoxin A production. Lett Appl Microbiol. 1999;29(4):238-41  Available at: https://www.youngliving.com/en_EU/products/thyme-essential-oil. Accessed August 12,2016.  Giordani R, Regli P, Kaloustian J, Mikaïl C, Abou L, Portugal H. Antifungal effect of various essential oils against Candida albicans. Potentiation of antifungal action of amphotericin B by essential oil from Thymus vulgaris. Phytother Res. 2004;18(12):990-5.  Available at: Chemotherapy induced nausea and vomiting http://www.doctoroz.com/article/health-benefits-ginger. Accessed August 10, 2016.  PL, Salihah N, Mazlan N. Effects of inhaled ginger aromatherapy on chemotherapy-induced nausea and vomiting and health-related quality of life in women with breast cancer. Complement Ther Med. 2015;23(3):396-404  Antimicrobial activity of essential oils and other plant extracts. Journal of Applied Microbiology. 86(6):985  Gruenwald, J., Brendler, T., and Jaenicke, C. PDR for herbal medicines. 3rd ed. Thomson, Montvale; 2004 (p. 204–8, 285–8)  Panahi Y, Akhavan A, Sahebkar A, et al. Investigation of the effectiveness of Syzygium aromaticum, Lavandula angustifolia and Geranium robertianum essential oils in the treatment of acute external otitis: a comparative trial with ciprofloxacin. J Microbiol Immunol Infect. 2014;47(3):211-6  Kolikonda MK, Srinivasan K, Enja M, Sagi V, Lippmann S. Medical Marijuana for Epilepsy? Innovations in Clinical Neuroscience. 2016;13(3-4):23-26.  Yadav V, Bever C, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083- 92.  Available at: https://clinicaltrials.gov/ct2/show/study/NCT02397863. Accessed August 8,2016.  Available at: http://www.gwpharm.com/GW Pharmaceuticals Announces Positive Phase 3 Pivotal Study Results for Epidiolex cannabidiol.aspx. Accessed August 10, 2016  Available at: http://www.epilepsycolorado.org/news-research/medical-marijuana/efco-report-to-the-community/. Accessed August 12, 2016.  Available at: https://clinicaltrials.gov/ct2/show/NCT02229032. Accessed August 11,2016.

63

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

1:00—2:00 pm Pharmacy Legislative and Administrative Update

Jeffery D. Evans, Pharm.D. Associate Professor of Pharmacy Practice College of Pharmacy, University of Louisiana at Monroe Clinical Assistant Professor of Family Medicine and Comprehensive Care College of Medicine, Louisiana State University Health Science Center - Shreveport

0179-0000-16-035-L03-P/ 0179-000-16-035-L03-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Apply Board rule changes to current 1. Apply Board rule changes to current pharmacy practice. pharmacy practice. 2. Identify areas of positive change in 2. Identify areas of positive change in upcoming rule and law changes. upcoming rule and law changes.

Dr. Evans has disclosed that she has no relevant financial relationships.

64

Jeffery D. Evans, Pharm.D. Objectives Associate Professor of Pharmacy Practice

• At the end of this presentation the pharmacist and pharmacy technician – Apply board rule changes to current pharmacy practice 2016 Pharmacy Legislative Update – Identify areas of positive change in upcoming rule and law changes – Develop a plan to address shortcomings in current law.

How a bill becomes law in Louisiana How a bill becomes law in Louisiana

• A Legislator enters the bill • Once filed, it must be read – May be written by him/her – Not really read, but the title must be read – Maybe by a lobbyist – Then it must be ‘read’ again and sent to a committee – Maybe by another part of Government • And here death can occur • The bill is ‘filed’ – The committee must move on the bill • Or let it ‘die in committee’ – The committee votes/amends and returns to full body

How a bill becomes law in Louisiana Query Tool

• Once returned to the full body – Can be voted on – Can die – Can be amended

• If supported, sent to the other body and goes through the same process.

65 Important things to remember when Session in Session lobbying • What you are lobbying for? – Make sure you know what you are there for – Does your group have a common statement

• Time is precious – You might get two minutes • USE those two minute

• Be knowledgeable – If possible know about the persons background • Our representatives have day jobs

Senator Ronnie Johns SB 131 (Act 527)

• SB. 131 –Provides for alternative options to • Passed as ACT 527 eff January 1, 2017 prescription drugs – Amends the Pharmacy Practice Act to include a section on Affordable Alternative options to prescription drugs • Essentially, requires a dispensing pharmacist to notify a patient of • Contact information more cost effective measures – – Intent is to make a more informed patient [email protected] • Cost and effectiveness should be provided – As finalized – ‘An individual shall not be required to make a payment for 9 pharmacists' services in an amount greater than the pharmacist or pharmacy 10 providing the pharmacists' services may retain from all payment sources.’

Rep. Frank Hoffman Rep Helena Morena

• HB 174 –Provides for the method of collection of the • HB 791 –Provides limitations on pharmacy education support fee by the Louisiana Board of prescriptions for opioid drugs Pharmacy – Last year entered and passed a bill – Amends the Controlled Substance Act • Collecting $100 per licensed pharmacist and pharmacy • To limit initial opioid prescribing to 72 hour period • Given to any State Sponsored School of Pharmacy – Or emergency time if ‘longer’ – The fee was an opt‐in fee • The board also required a paper renewal if you wanted to pay it. • Require all physicians to obtain 5 hours of CE every two • This was to ease administration by the BOP years on opioid addiction – This bill forces the board to collect the fee like all other fees • Adds requirement for any opioid prescriber to check – This bill did not make it out of committee the PMP first – Did not make it out of committee

66 Rep Helena Morena Rep Helena Morena

• HB 1007 –Provides relative to the storing and • HB 671 –Provides relative to dispensing of naloxone and other opioid antagonists redispensing of drugs in correctional facility – Allows for other entities to store naloxone and other pharmacies similar agents that are ordered pursuant to a standing order – Allows ‘local’ correctional facilities to have the same • Some places ‘dispense’ these agents per standing orders ability as ‘State’ • This makes them a little more legal • Local jails would be able to redispense medications • Essentially allows any one or thing to possess naloxone – Not expired, adulterated… – Was amended to allow pharmacist dispensing without a • Limited access drugs are excluded prescription • Allows pharmacies serving local jails to accept returns and to redispense them – Does not tackle ‘who’ they may be redispensed to. • Passed and signed into law in June 2016 – Passed and became effective 08/01/2016

Kirk Talbot Marcus Hunter

• HB 920 –Provides relative to eligibility • HB 1054 –Provides relative to for a license to produce or dispense prescribing of controlled substances therapeutic marijuana – Requires PMP data to be updated ‘instantly.’ – Requires ALL C‐II prescribing to be completed – Bill adds to the list of people who can not have a electronically license • Board of Pharmacy members – The bill is justified by the growing epidemic of • Already ANYONE who has made a campaign prescription drug abuse. contribution in the last five years is prohibited – Did not make it out of committee – Did not make it out of committee

Gregory Cromer H. Bernard Lebas

• HB 961 – Requires education or marketing • HB 446 – Establishes an application fee materials for prescription drugs directed to for a new marijuana pharmacy permit and healthcare providers to include price information limits eligibility for the permit – Requires any one educating a prescriber about a – Creates a $5000 application fee for a marijuana medication they may prescribe to provide AWP pricing permit for the medication – Prohibits BOP members or their family members – Either per month or length of treatment from obtaining a marijuana license • And for two years after serving on the board • Did not make it out of committee Bill passed the House but failed in the Senate

67 H. Bernard Lebas John M. Schroder, Sr

• HB 490 –Provides for the submission • HB 570 –Provides relative to the of a remittance advice by health insurers to practice of telemedicine – Amends bill to allow for either audio communication pharmacists only – Changes the requirement to notify pharmacies – Allows Louisiana licensed physician to be in another from 7 days to on the day of payment State. – All court cases must be handled in the Parish of the patient.

• Passed and June 17, 2016

Reid Falconer Fred Mills, Jr

• HB 531 –Provides for access to prescription • SB 52 –Provides for the creation of a monitoring information by specialty courts single preferred drug list for reimbursement of – Would allow specialty court to appoint a person to Medicaid covered outpatient drugs monitor the PMP for defendants in court. – This would require the State Medicaid office to • Veterans • Drug develop ‘one’ formulary. • DWI – This formulary would be required to be used by all • Behavioral Medicaid HMOs • Mental Health • Referred to committee and never heard – Died in Committee

Fred Mills, Jr Fred Mills, Jr

• SB – 117 Provides for the Medicaid • SB180 –Provides exemption from Pharmaceutical and Therapeutics Committee prosecution for anyone lawfully in possession – Changes pharmacist selection process of medical marijuana. • Formerly, two from LPA – Provides the defense of a patient from a • Now one chain pharmacist from LPA and one marijuana dispensary in Louisiana to possess independent pharmacist from LIPA marijuana • Also changes wording on ‘new’ medications : Required – And to allow a parent to give it to a child new medications to be heard at next Medicaid review

– Passed and became effective in June 2016 • Passed and became effective 08/01/2016

68 Fred Mills, Jr Ronnie Johns

• SB 271 –Provides for medical marijuana • SB56 –Provides for the retention, archiving, – Updates diseases that marijuana may be used for …. Medicinally…. and destruction of records in the state • Wording is debilitating diseases, including prescription monitoring program – Cancer, glaucoma, HIV, AIDS – Other diseases that cause cachexia or wasting syndrome – Allows the Board of Pharmacy to create rules – Seizure disorders, epilepsy, regarding this. – Severe muscle spasms including Crohn’s disease or MS • Also changes ‘prescribing’ to ‘recommending’ – No guidance is given in the bill. – Changes prescribing to recommending but leaves dispensing • Passed and becomes law with other rules. • Bill passed and became effective 08/2016

Ronnie Johns Ronnie Johns

• SB 86 –Provides for exceptions to dispensing • SB 189 –Provides for pharmacist dispensing limits by prescribers who are practicing at a exceptions National Cancer Institute‐designated – Allows an exclusion for the 10 day opiate rule if comprehensive cancer center the prescriber includes the diagnosis of cancer or – Adds exclusion for prescribers at these centers terminal illness to the prescription when out of state and prescribing opioids. • Bill passes and is in effect • Was not heard in committee

Ronnie Johns W. Jay Luneau

• SB 133 –Provides for prescription drug access • SB 258 –Provides for coverage for refills for – Any medication available to any pharmacy in prescription eye drops Louisiana available to patients, must be available – Requires refills for topical ophthalmic medications to all pharmacies and all patients to be covered • Seeks to eliminate ‘specialty pharmacies’ – Defines refill windows for 30, 60, and 90 day supplies – Died in committee • Becomes effective 01/01/2017

69 Actions of the Board Pharmacist Provider Status

• 2016 –G –Naloxone dispensing per standing order • HR 592 – 291 cosponsors • 2016 –F – Allows for medication synchronization

• 2016 –E – Changes the requirements of Non‐resident pharmacies • S.314 –49 cosponsors

• 2016 –D – Adds wording from last year’s biosimiliar legislation

• 2016 –C –Extension of prescriptive authority

• 2016 –B –Intern hour reduction

• 2016 –A – Marijuana Dispensing

Questions/Concerns?

70 Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

2:00—3:00 p.m. Can’t Stop Bleeding, A Journey through Anticoagulation Reversal

Jill Comeau, PharmD, BCOP Gratis Assistant Professor of Internal Medicine Feist-Weiller Cancer Center Practice Site: FWCC Outpatient Clinics Louisiana State University Health-Shreveport and University Health Shreveport Shreveport, LA

0179-0000-16-030-L01-P/ 0179-0000-16-030-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technician: 1. Identify the risk for bleeding due to 1. Identify the classes and mechanisms of anticoagulants including: warfarin, heparin actions for anticoagulants. products, direct thrombin inhibitors, and 2. Review the medications available for Factor Xa inhibitors. anticoagulation reversal including their 2. Examine the available literature involving indications, doses, mechanisms of action, anticoagulation reversal. drug interactions, and adverse effects. 3. Review the current guidelines for 3. Discuss important clinical pearls for anticoagulation reversal. anticoagulation reversal related to 4. Discuss important clinical pearls for pharmacy practice anticoagulation reversal related to pharmacy practice. 5. Given a patient case, develop a treatment plan for a patient with bleeding due to anticoagulation

Dr. Comeau has disclosed that she has no relevant financial relationships.

71

PHARMACIST OBJECTIVES

CAN’T STOP BLEEDING, A JOURNEY  Identify the risk for bleeding due to anticoagulants THROUGH ANTICOAGULATION including: warfarin, heparin products, direct REVERSAL thrombin inhibitors, and Factor Xa inhibitors  Examine the available literature involving anticoagulation reversal  Review the current guidelines for anticoagulation Jill M. Comeau, PharmD, BCOP reversal Assistant Professor, ULM School of Pharmacy-Shreveport  Discuss important clinical pearls for anticoagulation Gratis Faculty of Internal Medicine, Feist-Weiller reversal related to pharmacy practice Cancer Center, LSU-H Shreveport  Given a patient case, develop a treatment plan for a October 1, 2016 patient with bleeding due to anticoagulation

TECHNICIAN OBJECTIVES DISCLOSURE

 Identify the classes and mechanisms of action for  I have nothing to disclose anticoagulants  Review the medications available for anticoagulation reversal including their indications, doses, mechanisms of action, drug interactions and adverse effects  Discuss important clinical pearls for anticoagulation reversal related to pharmacy practice

HEMORRHAGE OR BLEEDING CRITERIA PER TIMI GUSTO BLEEDING DEFINITIONS (THROMBOLYSIS IN MYOCARDIAL INFARCTION) (ACUTE CORONARY SYNDROME)

Major Minor Major • Intracerebral hemorrhage  Reductions of Hb  Observed blood loss (hemoglobin) ≥ 5 g/dL  Reduction of Hb 3-5 g/dL • Substantial hemodynamic compromise →  Reduction of Hct 10-15% treatment  Reduction of Hct (hematocrit) >15%  Unobserved blood loss Moderate  Reduction of Hb ≥ 4 g/dL  Any intracranial  Reduction of Hct ≥ 12% • Blood transfusions, not hemodynamically bleeding  Spontaneous gross compromised hematuria or hematemesis >120 mL Mild • Other bleeding

Chesebro et al. Circulation. 1987;76:142-54. Sabatine et al. Circulation. 2005;111:2042-2049.

72 UNFRACTIONATED HEPARIN (HEMOCHRON®) (UH) OTHER “HEPARIN” RELATED PRODUCTS MECHANISM OF ACTION (MOA)

Low Molecular Weight  Conformational change in AT: rapid inactivator of Fondaparinux (Arixtra®) coagulation factors Heparin (LMWH)  Thrombin (IIa)  Strong inhibitor of Xa  Almost purely  Factor Xa  Also inhibits IIa antifactor Xa  Medications  Pentasaccharide  dalteparin (Fragmin®)  enoxaparin (Lovenox®)  nadroparin (Fraxiparine®)  tinzaparin (Innohep®)

http://err.ersjournals.com/content/24/137/392 Weitz JI. N Engl J Med. 1997;337:688-98. Choay et al. Biochem Biophys Res Commun. 1983;116:492-9. Arixtra(R) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.

HEPARIN/LMWH COAGULATION MONITORING PARAMETERS BLEEDING RISKS

 Age UH LMWH  Female gender  Comorbidities  aPTT (activated partial  Controversial  Trauma thromboplastic time)  Measure at 4-6 hours  Surgery post injection  1.5-2X normal  Peptic ulcers  Bleeding risk increases if  Varies based on normal  Cancer level is >1 Anti-Factor Xa  Liver disease lab values units/mL  Hemostatic defects*  UHS:  Anti-Factor Xa for  Anemia  Contiuous IV: Baseline enoxaparin  Indication for anticoagulation then every 4 hours then  0.5-1 Anti-Factor Xa  Dosing “appropriate intervals” units/mL measured 4-6 hours after injection  Increase in APTT with UH Campbell et al. Arch Intern Med. 1996;156:857-60. Hull et al. N Engl J Med. 1990;332:1260-4. Hull et al. Arch Intern Med. 1992;152:1589-95 Heparin [package insert]. Kirland, QU: Pfizer Canada Inc; 2014. Juergens et al. Am J Cardiol. 1997;80:150-4. Hirsh et al. Chest. 2008;133:141S.

HEPARIN PRODUCTS AND FONDAPARINUX URGENT HEPARIN REVERSAL INCIDENCE OF BLEEDING MAJOR BLEEDING

 Rates vary based upon indication and patient  Stop heparin, half-life 30-60 minutes if IV specific factors  Protamine sulfate  Heparin 2-4.5%  MOA: combined with heparin to form a complex that  Enoxaparin 1.7-4.7% neutralizes anticoagulant activity  Dalteparin 1.5-3.3%  Tinzaparin 2%  Fondaparinux 1.2-2.7%

Buller et al. Ann Intern Med. 2004;140:867-73. Freedman et al. J Bone Joint Surg Am. 2000;82:929-38. FRISC II Investigators. Lancet. 1999;354:701-7. Hull et al. Arch Intern Med. 2000;160:2199-207. Mismetti et al. Chest. 2005;128:2203-10. Petersen et al. JAMA. 2004;292:89-96. http://pubs.rsc.org/en/content/articlehtml/2013/cs/c3cs60278h Simonneau et al. N Engl J Med. 1997;337:663-9. Turpie et al. Arch Intern Med. 2002;162:1833-40. Van Dongen et al. Cochrane Database Syst. Rev. 2004;CD001100 Yusuf et al. N Engl J Med. 2006;354:1464-76. Lexicomp(R) Web site. http://www.uptodate.com/contents/search. Accessed August 16, 2016.

73 PROTAMINE SULFATE DOSING FOR LMWH REVERSAL PROTAMINE HEPARIN

 Heparin: 1 mg protamine per 100 units Heparin  Cannot reverse anti-Xa activity completely  Continuous IV infusion: based on duration of heparin  Only 60-75% administration  Enoxaparin  mg protamine needed for 100 units of heparin  Administered ≤ 8 hours: 1 mg protamine for 1 mg  Immediate: 1-1.5 enoxaparin  30-60 minutes 0.5-0.75  Administered > 8 hours or need for 2nd dose: 0.5 mg  >2 hours: 0.25-0.375 protamine for 1 mg enoxaparin  Unknown administration period then one time dose of 25-50 mg followed by rechecking an aPPT  Dalteparin or tinzaparin  SC: 1-1.5 mg protamine per 100 units of heparin  1 mg protamine for 100 units  If PTT prolonged 2-4 hours after 1st dose, add second dose of 0.5 mg per 100 units

Hirsh et al. Chest. 2008;133:141S-59S Lovenox(R) [package insert]. Bridgewater, NJ: Sanofi-aventis U.S. LLC; 2013. Lexicomp(R) Web site. http://www.uptodate.com/contents/search. Accessed August 16, 2016. Masonnet-Casterl et al. Haemostasis. 1986;16:139-46.

ADVERSE EFFECTS PROTAMINE

 Hypersensitivity reactions  Administration: slow IV push over 10 minutes per  Hypotension 50 mg maximum  Cardiovascular collapse  Noncardiogenic pulmonary edema  Drug-drug interactions: none  Pulmonary vasoconstriction  Pulmonary hypertension  Risk factors: high doses, multiple doses, previous administration, fish allergy, vasectomy, severe left ventricular dysfunction, abnormal preoperative pulmonary hemodynamics  Rapid administration can cause severe hypotension and anaphylactoid reaction  Heparin rebound

Lexicomp(R) Web site. http://www.uptodate.com/contents/search. Accessed August 18, 2016. Lexicomp(R) Web site. http://www.uptodate.com/contents/search. Accessed August 18, 2016.

FONDAPARINUX REVERSAL DESMURS-CLAVEL ET AL.

 No specific antidote  Fondaparinux reversal examined in 6 healthy patients comparing PCC (prothrombin complex concentrate),  Options aPCC, and rFVIIa  activated Prothrombin Complex Concentrate, aPCC (Multiple trade names)  Utilized thrombin generation test (TGT) in platelet rich plasma obtained from patients  Non-activated II, IX, X and activated factor VII  Fondaparinux: indirectly inhibits thrombin formation  recombinant activated Factor VIIa (rFVIIa, Novoseven®)  Analyzed endogenous thrombin potential (ETP), thrombin peak, and lag time  aPCC: Decreased lag time and ETP, normalized laboratory values  PCC: Traces of heparin in product, affected outcomes  rFVIIa: Decreased lag time only but could not normalize above laboratory values Desmurs-Clavel et al. Thrombosis Research. 2009;123:796-8. Hirsh J. Thromb Res. 2003;15:S1-8 Desmurs-Clavel et al. Thrombosis Research. 2009;123:796-8.

74 APCC (FEIBA® OR FACTOR EIGHT INHIBITOR BYPASS APCC WARNINGS ACTIVITY)

 Dose in intracranial hemorrhage (ICH): 20  Most common: anemia, nausea, vomiting, diarrhea, international units/kg IV once hemarthrosis, hepatitis B surface antibody positive  Life-threatening bleeding: varies based upon  Thromboembolisms: VTE, PE, disseminated indication intravascular coagulation (DIC), myocardial  Human infarction, or stroke  Increased with higher doses  Must complete infusion within 3 hours  Caution: advanced artherosclerotic disease, crush injury, sepsis, or use of factor VIIa  Hypersensitivity  Avoid with antifibrinolytics

FEIBA(R) [package insert]. Westlake Village, NJ: Baxter Healthcare Corp.; 2013 FEIBA(R) [package insert]. Westlake Village, NJ: Baxter Healthcare Corp.; 2013

WARFARIN (COUMADIN®) RFVIIA (NOVOSEVEN RT) MOA

 Recombinant human  Competitively inhibits subunit of multi-unit vitamin K  May be used for anticoagulation reversal epoxide reductase complex 1 (VKORC1)  90 mcg/kg  Decrease vitamin K reserves  Coagulation factors and proteins that require vitamin K  Not preferred over other agents due to risk for for synthesis thrombosis  Factor II

 Factor VII

 Factor IX

 Factor X

 Protein C

 Protein S

Heidbuchel et al. Europace. 2013;15:625-51 Holbook et al. Chest. 2012;141(2 Suppl):e152S-84S. Coumadin(R) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.;2015.

WARFARIN (COUMADIN®) WARFARIN AND BLEEDING MOA

 Bleeding rates vary, around 1-4%  Bleeding risk increases with a supratherapeutic International Normalization Ratio (INR)  Patient characteristics  Drug interactions  Food Interactions

Gomes et al. CMAJ. 2013:185:E121-7. Palareti et al. Semin Hematol. 2014;51:102-11. http://err.ersjournals.com/content/24/137/392 Coumadin(R) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.;2015. Penning-van et al. Thromb Haemost. 2011;86:569-74.

75 WARFARIN REVERSAL VITAMIN K (MEPHYTON®) PER CHEST 2012 GUIDELINES

 Serious, life-threatening bleeding  MOA: Promotes synthesis of clotting factors: II, VII,  Hold warfarin IX, and X  Administer vitamin K 10 mg IV slow infusion  In bleeding emergencies, vitamin K IV is preferred  Administer 4-factor PCC  Administer slow push over 20-60 minutes  Maximum rate 1 mg/min  Evidence exists for the use of FFP and PCC 3-factor but not preferred  Peak effect: 12-24 hours for INR to return to normal  If administer PCC 3-factor, should be given with FFP  Avoid IM due to risk of hematoma and SC due to  rVIIa not recommended erratic absorption  Adverse effects  Anaphylaxis especially with IV  Orlistat may decrease serum concentration of vitamin K

Holbook et al. Chest. 2012;141(2 Suppl):e152S-84S. Holbook et al. Chest. 2012;141(2 Suppl):e152S-84S. Mephyton(R) [package insert]. Lake Forest, IL: Hospira, Inc.; 2004.

4-FACTOR, UNACTIVATED PCC (KCENTRA®) 4-FACTOR, UNACTIVATED PCC (KCENTRA®)

 Includes  Administration is quick  Factor II, VII, IX, and X  Room temperature  Protein C and S  Rate 0.12 ml/kg/min (max 8.4 mL/min)  Human plasma derived  If blood enters syringe, clot may form  Dosing  Dosing based on Factor IX units of activity  Adverse reactions  Give WITH vitamin K  >5%: hypotension, headache, hypervolemia, nausea INR (pretreatment) Dose (Maximum) and vomiting, and anemia 2-<4 25 units/kg (2500 units)  Hypersensitivity <1% 4-6 35 units/kg (3500 units)  Thrombotic events <1% >6 50 units/kg (5000 units)

 Drug interactions: none

KCentra(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014. KCentra(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014.

4-FACTOR PCC VS. FFP FOR VITAMIN K HEMOSTATIC OUTCOMES 4PCC VS. FFP ANTAGONIST (VKA) REVERSAL

 216 adults who received a VKA with INR ≥ 2 and acute major bleed

Plasma Dose 4 Factor-PCC Baseline INR mL/kg Body IU Factor IX/kg Weight 2-<4 25 10 4-6 35 12 >6 50 15

 Primary Endpoints  Hemostatic efficacy during 24 hours from start of infusion  INR reduction to ≤ 1.3 at 30 minutes after infusion

Sarode et al. Vascular Medicine. 2013;128:1234-43.

76 4-FACTOR PCC VS. FFP FOR VITAMIN K 4-FACTOR PCC VS. FFP FOR VITAMIN K ANTAGONIST (VKA) REVERSAL ANTAGONIST (VKA) REVERSAL

 Hemostatic efficacy: 72.4% vs. 65.4%, noninferior but not superior  INR correction: 62.2% vs. 9.6%, noninferior and superior

Sarode et al. Vascular Medicine. 2013;128:1234-43. Sarode et al. Vascular Medicine. 2013;128:1234-43.

3-FACTOR, UNACTIVATED, PCC (BEBULIN® PCC 3-FACTOR, UNACTIVATED (BEBULIN® OR OR PROFILNINE®) PROFILNINE®)

 Human plasma derived, unactivated II, IX, and X  Dosing per Masotti et al.:  Non-FDA approved indication  Dose in units = (target % of functional PC to be reached – current estimated % of functional PC) x kg  Dosing based on factor IX activity units  PC: estimated functional prothrombin complex  Dosing by weight per Liumbruno et al.  INR< 2: 20 units/kg  INR <2-4: 30 units/kg

 INR > 4: 50 units/kg INR ≥5 4-4.9 2.6-3.2 2.2-2.5 1.9-2.1 1.7-1.8 1.4-1.6 1-1.3  May repeat if INR >1.5 PC 5101520253040100 (%)

Bebulin VH (R) [package insert]. Westlake Village, CA: Baxter Healthcare Corporation.;2001. Bebulin VH (R) [package insert]. Westlake Village, CA: Baxter Healthcare Corporation.;2001. Profilnine SD (R) [package insert]. Los Angelis, CA: Grifols Biologicals Inc.; 2010. Profilnine SD (R) [package insert]. Los Angelis, CA: Grifols Biologicals Inc.; 2010. Masotti L et al. Int J Stroke. 2011;6:228-40. Liumbruno F et al. Blood Transfus. 2009;7:325-34.

PCC 3-FACTOR, UNACTIVATED (BEBULIN DIRECT ORAL ANTICOAGULANTS VH® OR PROFILNINE SD®) (DOAC)

 Administration Inhibits activated factor Xa Inhibits factor Iia (DTI)  Infuse at room temperature  Maximum infusion rates: 2 mL/min (Bebulin®), 10  Apixaban (Eliquis®)  Dabigatran (Pradaxa)® mL/min (Profilnine®)   Avoid fast infusions, causes vasomotor reactions Edoxaban (Savaysa®)  Adverse effects, incidence not specified  Rivaroxaban (Xarelto®)  Flushing, chills, fever  Headache, lethargy  Rash, urticarial  Paresthesia  Hypersensitivity reactions  Thrombotic events

 Drug Interactions: avoid aminocaproic acid Eliquis (R) [package insert]. Princeton, NJ: Bristol-Myers Sqibb Co.; 2016. Pradaxa (R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015. Bebulin VH (R) [package insert]. Westlake Village, CA: Baxter Healthcare Corporation.;2001. Savaysa (R) [package insert]. Tokyo, Japan: Daiichi Sankyo Co. LTD; 2015. Profilnine SD (R) [package insert]. Los Angelis, CA: Grifols Biologicals Inc.; 2010. Xarelto (R) [package insert]. Titusville, NJ: Janseen Pharmacruticals, Inc..;2016.

77 DOAC REVERSAL BLEEDING RISK DOAC VS. WARFARIN NO CLEAR GUIDELINES

 Meta-analysis including 120,607 patients Xa Inhibitor DTI  Lower rate of major bleeding, RR 0.72 (95% CI 0.62- 0.85)  PO Charcoal (within 3  PO Charcoal  Meta-analysis including 102,707 patients hours)  Idarucizumab  Lower rate of fatal bleeding, RR 0.53 (95% CI 0.43-  4-factor, unactivated  Activated PCC 0.64) PCC  Antifibrolytic therapy  Most of the benefit is due to the reduced risk of ICH  Antifibrinolytic therapy  Hemodialysis (removes  Tranexemic acid 50%)  Aminocaproic acid

Chai-Adisaksopha et a. Blood. 2014;124:2450-8. Kaatz et al. Am J Hematol. 2012;87 Suppl 1: S141-5. Chai-Adisaksopha et al. J Thromb Haemost. 2015;13:2012-20. Siegal et al. Blood. 2014;123:1152-8.

IDARUCIZUMAB (PRAXBIND®) IDARUCIZUMAB

 MOA: monoclonal antibody, binds to dabigatran and  Dose: 2.5 g IV x 2 doses ≤ 15 minutes apart metabolites with more affinity than thrombin and  May repeat if needed neutralizes anticoagulation  Adverse effects  Constipation 6%  Delirium 7%  Fever 6%  Headache 5%  Hypokalemia 7%  Pneumonia 6%  Allergic reaction  Increase in coagulation levels http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2441323  Thromboembolism

Praxbind (R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2016. Praxbind (R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2016.

RE-VERSE AD IDARUCIZUMAB IDARUCIZUMAB

 Administration  n=90 patients from June 2014-Feb. 2015  Undiluted IV bolus by syringe or infusion  Inclusion Criteria  Each vial (2.5g) should administer over 5-10 minutes  ≥ 18 years old maximum  Taking dabigatran  Avoid administration with other products through same  Group A line  Overt, uncontrollable, or life-threatening bleeding  Use within 1 hour of solution removal from vial  Group B

 Need surgery or invasive procedure in ≤ 8 hours and normal  Drug interactions: none hemostasis needed  Exclusion  None

Praxbind (R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2016. Pollack et al. New Engl J Med. 2015;373:511-20.

78 RE-VERSE AD OUTCOMES

 Intervention: idarucizumab two 2.5 g IV bolus ≤ 15  Primary Endpoint minutes apart  Maximum Percentage Reversal: 100% in both groups  Primary Endpoint: maximum percentage reversal of effects of dabigatran  Clinical Outcomes  End of first infusion-4 hours post second infusion  Time to cessation of bleeding if available (n=64): 11.4  Measure dilute thrombin time or ecarin clotting time hours  Normal intraoperative hemostasis: 92% (33 out of 36) Predose test result – minimum postdose test result x 100  Mild hemostasis: 5% Predose test result – upper limit of normal range  Moderate hemostasis: 3%  Secondary Endpoints  Clinical outcomes: varied based on indication  Adverse effects including VTEs and death

Pollack et al. New Engl J Med. 2015;373:511-20. Pollack et al. New Engl J Med. 2015;373:511-20.

EUROPEAN HEART RHYTHM ASSOCIATION ADVERSE EVENTS PRACTICAL GUIDANCE

 Thrombotic Events: 5 patients (5.56%) Thrombotic Days after Patient Event Treatment 1 DVT and PE 2 DVT, PE, and left 2 9 atrial thrombus 3DVT7 4NSTEMI13 5 Ischemic stroke 26 NSTEMI: non-ST-segment myocardial infarction

 Death:18 patients (20%)  ≤ 96 hours: related to reversal indication  > 96 hours: other comorbidities

Pollack et al. New Engl J Med. 2015;373:511-20. Heidbuchel et al. Europace. 2013;15:625-51.

ICH ANTICOAGULATION REVERSAL ICH ANTICOAGULATION REVERSAL NEUROCRITICAL CARE SOCIETY AND SOCIETY OF CRITICAL CARE NEUROCRITICAL CARE SOCIETY AND SOCIETY OF CRITICAL CARE

 UFH treatment only  Warfarin  Protamine  Vitamin K 10mg IV once, redose at 24-48 hours if INR ≥ 1.4  LMWH treatment only  If INR ≥ 1.4, administer 4-factor PCC  Protamine   Contraindication: rFVIIa FFP if PCC is not available  Fondaparinux treatment only  Direct Factor Xa Inhibitors  aPCC  Activated charcoal 50g if within 2 hours

 Not available rFVIIa  4-factor or activated PCC  DTI  Activated charcoal 50g if within 2 hours  Idarucizumab: within 3-5 half-lives

 If not available: PCC 4- factor, aPCC, or hemodialysis

Frontera J et al. Neurocrit Care. 2016:24:6-46. Frontera J et al. Neurocrit Care. 2016:24:6-46.

79 ANDEXANET ALPHA ANDEXANET ALPHA “THE DECOY” ANNEXA-A AND ANNEXA-R

 Not FDA Approved  Two phase III studies including healthy participants 50-75 years old

 MOA: recombinant, modified version of factor Xa  Patients received either direct factor Xa  Completely inactive anticoagulant at baseline depending on trial  Can bind to both direct and indirect factor Xa inhibitors  apixaban: ANNEXA-A (n=48)  Therefore, allows “normal” or endogenous factor Xa to  rivaroxaban: ANNEXA-R (n=53) continue activity  Received either andexanet alpha or placebo  Part 1: 400 or 800 mg IV bolus  Part 2: above bolus followed by 4 or 8 mg/min infusion x 2 hours

Siegal et al. N Engl J Med. 2015;373:2413-24. Siegal et al. N Engl J Med. 2015;373:2413-24.

ANDEXANET ALPHA ANDEXANET ALPHA ANNEXA-A AND ANNEXA-R

 Primary Endpoint  Adverse Events  % change anti-factor Xa activity  Constipation Bolus Only  Taste changes Andexanet  Feeling hot or flushed Placebo (%) p value Bolus (%)  Urticaria apixaban 94 21 <0.001  No reports of thromboembolism rivaroxaban 92 18 <0.001 Bolus and Infusion Andexanet Placebo (%) p value Infusion (%) apixaban 92 33 <0.001 rivaroxaban 97 45 <0.001

Siegal et al. N Engl J Med. 2015;373:2413-24. Siegal et al. N Engl J Med. 2015;373:2413-24.

CIRARANTAG (PER977) CIRARANTAG (PER977)

 Not FDA approved  Phase II trial, n=80 healthy participants  MOA: forms non-covalent hydrogen bonds with  First part: received single of IV PER977 ranging different anticoagulants and prevent these agents from 5-300 mg or placebo from interacting with thrombin and other clotting  Second part: Received edoxaban 60 mg factors followed dose of PER977 or placebo 3 hours after  Includes  Whole-blood clotting time (WBCT) was increased  Heparin by 37% from baseline with edoxaban  LMWH  Returned to within 10% above baseline at:  Factor Xa inhibitors: edoxaban, rivaroxaban, and  10 minutes: PER977 at doses 100-300 mg apixaban  10-12 hours: placebo  Direct thrombin inhibitor (DTI): dabigatran  AE: eye and facial flushing, changes in taste, and  NOT active against warfarin mild headache

Ansell et al. N Engl J Med. 2014;371:2141-2. Ansell et al. N Engl J Med. 2014;371:2141-2.

80 QUESTION 1 QUESTION 2

 RS is a 75 y/o female weighing 60 kg who presents  A patient is being anticoagulated with enoxaparin to the ER with an intracranial hemorrhage (ICH). 70 mg SC BID due to a pulmonary embolism. Her caregiver states she is on warfarin. Her INR During rounds, you find that her hemoglobin has comes back at 5.7. What treatment should she dropped 5 g/dL. The patient received her last dose receive immediately? 2 hours previously. The team asks you about  A. vitamin K PO appropriate anticoagulation reversal. After  B. vitamin K IV recommending stopping the enoxaparin, you next  C. vitamin K IV and 4-factor PCC IV recommendation would be to administer:  D. vitamin K 10 mg IV and idarucizumab IV  A. Protamine 35 mg  B. Protamine 35 mg and vitamin K  C. Protamine 70 mg  D. Protamine 70 mg and vitamin K

QUESTION 3 CONCLUSIONS

 You are staffing at your inpatient pharmacy. You  Older agents such as heparin and warfarin have see an order for idarucizumab 2.5 g IV x 2. What more concrete guidelines for treatment medication must the patient have been receiving for  Be aware of what products you have in stock anticoagulation to have a benefit from this antidote?  Consider creating protocols for use of these agents  A. apixaban due to limited evidence available  B. dabigatran  As we use more DOACs, thankfully new antidotes  C. enoxaparin are being tested  D. rivaroxaban

81

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

2:00—3:00 p.m. Would You Like Fries With That? Intro to Parenteral and Enteral Nutrition for Pharmacists

Katie Weigartz, PharmD PGY1 Pharmacy Resident University Health Shreveport Shreveport, LA

0179-0000-16-029-L01-P/ 0179-0000-16-029-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Identify common disorders requiring nutrition 1. List components of parenteral nutrition. support. 2. Predict possible obstacles when compounding 2. Apply guidelines to recommend appropriate parenteral nutrition. nutrition supplementation. 3. Identify common enteral nutrition formulas. 3. Calculate patient specific nutritional requirements. 4. Design a patient specific parenteral nutrition regimen. 5. Compare common enteral nutrition formulas.

Dr. Weigartz has disclosed that she has no relevant financial relationships.

82

. Identify common disorders requiring nutrition support . Apply guidelines to recommend appropriate nutrition supplementation . Calculate patient specific nutritional requirements . Design a patient specific parenteral nutrition regimen Parenteral and Enteral Nutrition . Compare common enteral nutrition formulas for Pharmacists Katie Weigartz PGY1 Pharmacy Resident University Health Shreveport October 2016 2

. List components of parenteral nutrition . EN- Enteral Nutrition . Predict possible obstacles when compounding parenteral nutrition . PN- Parenteral Nutrition . TPN- Total Parenteral Nutrition . Identify common enteral nutrition formulas . PPN- Peripheral Parenteral Nutrition . ABW- adjusted body weight . IBW- ideal body weight . ASPEN- American Society of Parenteral and Enteral Nutrition

3 4

. EN recommended over PN . Early assessment of patients admitted to the Intensive Care Unit (ICU) for nutrition risk, and calculation of energy and protein requirements to determine . PN not recommended until 7 days without PO or EN feedings goals of nutrition therapy . EN recommended to start 24-48 hours when it is known patient will not be . Initiation of enteral nutrition (EN) within 24−48 hours following the onset of tolerating PO feedings for 7 days (critical illness, trauma, TBI, burn, etc.) critical illness and admission to the ICU . ASPEN recommendations for caloric intake and TPN composition will be addressed . Take steps as needed to reduce risk of aspiration and improve tolerance to throughout the presentation gastric feeding . Implementation of enteral feeding protocols with institution-specific strategies to promote delivery of EN . Elimination of the use of gastric residual volumes as part of routine care to monitor ICU patients receiving EN . Initiation of parenteral nutrition early, when EN is not feasible or sufficient in high-risk or poorly nourished patients 5 6

83 7

. Paralytic Ileus . TPN . Intestinal obstruction . Central line available . Severe pancreatitis . PPN . Peripheral line available . Severe electrolyte imbalance . 2-1 . Unable to tolerate or contraindicated tube feeding . Lipids are separate . 3-1 . Lipids in the bag

9 10

MC is a 34 y/o male who presents to the SICU after a 1. Is MC a candidate for TPN? motorcycle collision resulting in multiple injuries to the a) No, patient must be NPO for 7 days prior to initiating lungs and bowels. He is sedated and intubated with a PICC TPN. line in place. After surgery, it is decided to keep NPO for 2 b) Yes, since it is known MC will be NPO > 7 days weeks while healing. The attending MD would like to start MC on TPN. c) No, patient does not require nutritional support d) Yes, patient had a bowel injury MC is 5’10” and weighs 85 kg. CMP WNL

11 12

84 1. Total Calories . Use actual body weight Kcal/kg Criteria . Unless >20% more than IBW, use ABW 20-25 Chronic Spinal Cord 2. Protein . IBW (F)= 45.5 (2.3 x every inch >60) Injury/Quadriplegia . IBW (M)= 50 + (2.3 x every inch >60) 3. Lipids 25-30 Low to moderate stress . MC weighs 85 kg and is 5’10” 4. Dextrose 30-35 Moderate to High Stress . Trauma= moderate to high stress 35-40 Severe Stress 5. Total Volume . Goal calories: 30-35 kcal/kg 6. Rate Case: 7. Percent Substrates 85 kg x30 kcal/kg = 2,550 kcal/day 85 kg x 35 kcal/kg = 2,975 kcal/day 8. Electrolytes So let’s aim for 2,750 kcal/day

13 14

Calories 2,750 kcal

Protein

Lipids 1. Calculate daily protein needs g/kg/day Criteria Dextrose 2. Calculate calories from protein 0.6-1 AKI/CKD (non-dialyzed) Total Volume . 4 kcal/g 0.8-1 Little or no stress 1-1.2 Low stress Rate 3. Double check 1.3-1.5 Moderate stress Percent Substrates 1.5-1.7 Moderately high stress Case: Protein (AA) 1.8-2 High stress Lipids Range: 1.5-1.7 g/kg/day 1.5 x 85 kg = 127.5 g 2+ Severe stress Dextrose (CHO) 1.7 x 85 kg= 144.5 g Goal: 140 g protein/day 4 kcal/g x 140 g= 560 kcal Double check: 140g/85kg= 1.65 g/kg/day

15 16

Calories 2,750 kcal

Protein 140 g (560 kcal)

Lipids . Fat calories should be < 30% of total daily calories Dextrose . Amount of kcal/ml will vary per product Total Volume . 10% = 1.1 kcal/ml . 20% = 2 kcal/ml Rate . 30% = 3 kcal/ml Percent Substrates Protein (AA) Lipids Case: Dextrose (CHO) Goal of 30% calories from lipids 2750 x 0.3 =825 kcal Stock: 3 kcal/ml 825/3= 275 ml lipids

17 18

85 Calories 2,750 kcal

Protein 140 g (560 kcal)

Lipids 825 kcal (275 ml) . Dextrose is the “filler” for the remaining calories Dextrose . Provides calories in the form of carbohydrates Total Volume . Generally ~50-60% of total kcal

Rate . Dextrose will provide 3.4 kcal/g

Percent Substrates Protein (AA) Case: Lipids Total kcal-protein kcal-lipids kcal = dextrose kcal Dextrose (CHO) 2750-560-825=1365 kcal 1365/3.4 = 401 g dextrose 401 g/85 kg= 4.7 g/kg

19 20

Calories 2,750 kcal

Protein 140 g (560 kcal)

Lipids 825 kcal (275 ml) . Add together components of TPN Dextrose 401 g . Dextrose and amino acid per ml will depend on the stock of the institution Total Volume . Estimate 200 ml for additives (trace elements and electrolytes)

Rate

Percent Substrates Case: Protein (AA) For our formulary, we have 70% dextrose and 15% amino acid formulation 140 g protein/0.15= 934 ml Lipids 401 g dextrose/0.7= 573 ml Dextrose (CHO) Lipids (previously calculated)= 275 ml Trace elements/additives= 200 ml Total = 1982 ml

21 22

Calories 2,750 kcal

Protein 140 g (560 kcal)

Lipids 825 kcal (275 ml) . To calculate the rate of the TPN, take the calculated volume and divide by the time it is to be administered over Dextrose 401 g . Generally, will be administered over 24 hours . Round Total Volume 2040 ml

. Then, given the rate calculate the new total volume Rate 85 ml/h

Case: Percent Substrates Calculated volume 1982 ml Protein (AA) 1982 ml/24 hours= 82.5 ml/h Lipids Round to 85 ml/h Dextrose (CHO) Calculate total volume: 85 x 24= 2040 ml

23 24

86 Calories 2,750 kcal

Protein 140 g (560 kcal)

Lipids 825 kcal (275 ml) . Divide the kcal provided by each component by the total kcal Dextrose 401 g

Total Volume 2040 ml Case: Rate 85 ml/h Protein 560 kcal 560/2750= 0.2 20% Lipids 825 kcal 825/2750=0.3 30% Percent Substrates Protein (AA) 20% Dextrose 1365 kcal 1365/2750=0.496 50% Lipids 30% Dextrose (CHO) 50%

25 26

. Zinc 3-4 mg/day . Copper 0.02-0.05 mg/day . Iron 1-2 mg/day . Manganese 0.15-0.80 mg/day . Selenium 0.02-0.05 mg/day . Chromium 0.01-0.015 mg/day . Molybdenum 0.075-0.250 mg/day . Iodine 0.070-0.140 mg/day.

27 28 Pogatchnik C. Trace Element Supplementation and monitoring in the adult patient on parenteral nutrition. Practical Gastroenterology. 2014:129;27-38.

Which of the following trace elements will be present in a TPN for a patient with . Sodium hepatic dysfunction: Calcium-Phosphate Precipitation . (chloride/acetate) I. Chromium Calcium and phosphate have the . Potassium potential to precipitate II. Selenium . (chloride/acetate) III. Zinc . Phosphorous Calculation: IV. Manganese . (sodium or potassium) Ca mEq + (1.7 x phos mmol) < 45 mEq/L V. Copper . Magnesium A. All of the above . Calcium B. I, II, III, IV C. I, II, III D. I, II 29 30

87 True or False: Sodium 1-3 mEq/kg/day A TPN is written for a total volume of 2100 ml to contain 5 mEq/L calcium, 12 mmol/L K-Phos, and 12 mmol/L Na-Phos. Everything else in the TPN is standard. This order is not acceptable because the bag is in danger of Potassium 0.5-2 mEq/kg/day precipitating. True Calcium 5 mEq/L female or 3 mEq/L male False Magnesium 12-16 mEq/day

Remember it is < 45 mEq/L Phosphorous 15-21 mmol/day Ca mEq + (1.7 x phos mmol) < 45 mEq/L 10 + (1.7 x 48)= 91.6 Since this TPN has a total volume of 2100: 91.6 /2.1 = 43.6 31 32

. Multivitamin Electrolyte Daily Requirement Goal for MC . Insulin Sodium 1-3 mEq/kg/day 85-255 mEq/day . Heparin Potassium 0.5-2 mEq/kg/day 42.5-170 mEq/day . Vitamin K Calcium 5 mEq/L female 3 mEq/L . H-2 blockers 3 mEq/L male

Magnesium 8-20 mEq/day 8-20 mEq/day

Phosphorous 20-40 mMol/day 20-40 mmol/day

33 34

Calories 2,750 kcal Protein 140 g (560 kcal) Lipids 875 kcal Dextrose 401 g Total Volume 2040 ml . Depending on the level of malnourishment Rate 85 ml/h . Start low and progress as tolerated Percent Substrates . If patient is tolerating well, can double everyday until at goal Protein (AA) 20% Lipids 30% . Low and slow Dextrose (CHO) 50% Additives Trace elements 1 ml MTE-5 Na 85-255 mEq/day K 42.5-170 mEq/day Mg 8-20 mEq/day Phos 20-40 mmol/day Ca 3 mEq/L

35 36

88 Goal Bag 1 Calories 2,750 kcal Protein 140 g (560 kcal) Lipids 825 kcal (275 ml) . Dextrose 401 g Definition: clinical complications that can occur as a result of fluid and electrolyte shifts during aggressive nutritional rehabilitation of Total Volume 2040 ml 2040 ml malnourished patients Rate 85 ml/h 85 ml/h . This can be fatal Percent Substrates Protein (AA) 20% 3% . Key Features: Lipids 30% 15% . Hypophosphatemia Dextrose (CHO) 50% 7% . Hypokalemia Additives (per L) . Vitamin deficiencies Trace elements 1 ml MTE-5 1 ml Na (chloride) 85-255 mEq/day 100 mEq . Congestive heart failure K 42.5-170 mEq/day 40 mEq . Peripheral edema Mg 8-20 mEq/day 6 mEq . Rhabdomyolysis Phos 20-40 mmol/day 12 mmol . Seizures Ca 3 mEq/L 3 mEq 37 . Hemolysis 38

. OSMOLALITY < 900 mOsm/L TPN PPN Lines Central Line Access Only peripheral access . Often, adding hydrocortisone or heparin can help stop irritation at injection site Osmolality < 900 mOsm/L Pros • No limitations on osmolality • Easy administration . Easier to establish IV access for this line • No pain associated with . Can start short term while waiting to get central line access infusion • Long term Cons • Requires surgery for line • Short term • Risk of phlebitis • Pain associated with infusion • Limitations on osmolality

39 40

. If actual body weight is >20% ideal body weight (IBW), use adjusted body weight for calculations . Adjusted= IBW + 0.25(actual-IBW) . If BMI > 30 consider permissive underfeeding or hypocaloric enteral feedings in the critically ill . Permissive underfeeding goal is 60-70% of target energy requirements . Hypocaloric Feedings . 22-25 kcal/kg/day IBW . BMI 30-40: 2 g/kg protein (IBW) . BMI > 40: 2.5 g/kg protein (IBW)

41

89 . Feeding that uses the GI tract to deliver part or all of a person’s caloric . G tube- Gastric requirements . J tube- Jejunal . Why we like it? Keep the gut working! . Types of Enteral Feeds: . Trophic- baseline feeding . Bolus- TID/QID . Continuous- milliliters/hour

43 44

A NJ tube is inserted through the nose and travels through the esophagus, stomach, and the pylorus and placed into the jejunum for feeding. This can be confirmed by seeing the tube cross the midline twice on an x-ray.

True or False

45 46 http://image.wikifoundry.com/image/1/r8PXglUkg-0KknpQ5lGldw878964/GW803H1011 http://www.gastrores.org/index.php/Gastrores/article/viewFile/593/656/5110

AND BACK TO OUR CASE…

. MC is approved to begin enteral feeding while still on ventilator . Jevity 1.5 . A NJ tube is in place . Vivonex . Calculate a goal EN regimen for patient . TwoCal . Nepro . Glucerna 1.5 . Oxepa . Pivot 1.5

47 48

90 Jevity Jevity 1.5 Vivonex TwoCal

Kcal/ml 1.0 1.5 1.0 2 . “Standard” formulations . High protein Nepro Pro g/L 44.3 (16.7) 63.8 (17) 50 (20) 83.7 (16.7) . Jevity . Low electrolyte Kcal/ml 1.8 (%) . Isotonic formula CHO g/L 154.7 215.7 175 (70) 217 (43.2) . Good for Pro g/L (%) 81 (18) . Contains fiber (%) (54.3) (53.6) . AKI CHO g/L (%) 166.8 (34) Fat g/L 34.7 (29) 49.8 (29.4) 12 (10) 90.9 (40.1) . Vivonex . Dialysis Fat g/L (%) 96 (48) . Only 10% fat calories (%) . Hyperkalemia NPC:N2 114 . Malabsorption NPC:N2 125 122 111 125 mOsm/kg 600 . TwoCal mOsm/ 300 525 630 690 kg . Kcal dense H2O ml/L 727 H2O ml/L 835 760 848 700 . Volume Restriction Na/K mEq/L 46.1/27.2 Na/K 40.4/ 60.9/55.1 29/31 57/62.8 PO4/mg mg 700/210 mEq/L 40.2 PO4/mg 760/305 1200/400 670/270 1052/421 50

. High protein Glucerna 1.5 . Antioxidants Pulmocare . Low carbohydrates Kcal/ml 1.5 . 20% of fat from MCT Kcal/ml 1.5 . Good for: Pro g/L (%) 82.7 (22) . High fat Pro g/L (%) 62.6 (16.7) . Diabetic patients CHO g/L (%) 132.9 (33) . Long term… CHO g/L (%) 105.7 (28.2) . COPD patients Fat g/L (%) 75.1 (45) . Good for: Fat g/L (%) 93.3 (55.1) NPC:N2 88 . COPD NPC:N2 125 . Ventilator patients mOsm/kg 875 mOsm/kg 475 . Hyperglycemia H2O ml/L 759 H2O ml/L 785 Na/K mEq/L 60/64 Na/K mEq/L 57/50.1 PO4/mg mg 1000/400 PO4/mg mg 1060/425

51 52

. EPA/GLA Opexa . Very high protein Pivot 1.5 . Antioxidants Kcal/ml 1.5 . Contains: Kcal/ml 1.5 . Arginie . Good for: Pro g/L (%) 62.6 (16.7) Pro g/L (%) 93.8 (25) . Glutamine . AKI CHO g/L (%) 105 (28.1) CHO g/L (%) 172 (45) . . ARDS EPA Fat g/L (%) 94 (55.2) . DHA Fat g/L (%) 51 (30) . Sepsis NPC:N2 125 . Antioxidants NPC:N2 91 . Expensive ($$$) mOsm/kg 493 . Good for: mOsm/kg 595 H2O ml/L 785 . Trauma H2O ml/L 759 Na/K mEq/L 57/50.1 . Burn Na/K mEq/L 61/51 PO4/mg mg 1060/ 425 PO4/mg mg 1000/400

53 54

91 Jevity Jevity Vivonex Nepro Glucerna Pulmocare Oxepa Pivot 1.5 TwoCal 1.5 1.5 Kcal/ml 1.0 1.5 1.0 1.8 1.5 1.5 1.5 1.5 2 Pro g/L 44.3 63.8 (17) 50 (20) 81 (18) 82.7 (22) 62.6 (16.7) 62.6 93.8 (25) 83.7 (%) (16.7) (16.7) (16.7)

CHO g/L 154.7 215.7 175 (70) 166.8 132.9 (33) 105.7 (28.2) 105 172 (45) 217 . Same kcal and protein requirements (%) (54.3) (53.6) (34) (28.1) (43.2) . Often have to play with it a little more to find something that fits Fat g/L 34.7 49.8 12 (10) 96 (48) 75.1 (45) 93.3 (55.1) 94 51 (30) 90.9 . Can be administered as continuous or bolus feeding (%) (29) (29.4) (55.2) (40.1)

NPC:N2 125 122 111 114 88 125 125 91 125 Case: mOsm/ 300 525 630 600 875 475 493 595 690 Total kcal: 2550-2975 kcal/day kg Total protein: 127.5-153 g/day H2O 835 760 848 727 759 785 785 759 700 Let’s Use Pivot 1.5: (1.5 kcal/ml and 93.8 g/L) ml/L Calories: 2250 kcal/day x 1.5 kcal/ml= 1700 ml/day = 71 ml/h Na/K 40.4/ 60.9/55.1 29/31 46.1/ 60/64 57/50.1 57/50. 61/51 57/62.8 2975 kcal/day x 1.5 kcal/ml= 1983 ml/day = 83 ml/h mEq/L 40.2 27.2 1 Protein: 127.5 g/day x 0.0938 g/ml = 1359 ml/day = 57 ml/h 153 g/day x 0.0938 g/ml = 1631 ml/day = 68 ml/h PO4/mg 760/305 1200/400 670/270 700/210 1000/400 1060/425 1060/ 1000/400 1052/421 mg 425 56

. EleCare (Infant and Pediatric) . Make sure we are seeing the ENTIRE picture . 1.01 kcal/ml . Bowel movements . 30.53 g protein/L . UOP . PediaSure + Fiber (Pediatric) . . 1 kcal/ml Residuals . 30 g protein/L . Labs . CMP . Juven (HMB, Arginine, Glutamine) . Pre-albumin . 1 packet BID to support lean body mass . Magnesium . 70-80 kcal/pack . Phosphorous . Triglycerides . Glucose

57 58

1. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine and amercian society for parenteral and enteral nutrition. Journal of parenteral and enteral nutrition. 2016:40(2);159-211.

2. Boullata J, Gilbert K, Sacks G, et al. A.S.P.E.N. clinical guidelines: parenteral nutrition ordering, order review, compounding, labeling, and dispensing. Journal of parenteral and enteral nutrition. 2014:38(3);334-377.

3. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39- S70

4. University of Virginia Health System Department of Nutrition Services. Adult Enteral and Parenteral Nutrition Handbook. 5th ed. Charlottesville, VA: University of Virginia Health System; 2011. http://www.healthsystem.virginia.edu/ pub/dietitian/nutrition_manual/adultenteral-parental-nutrition-handbook

5. Crook MA, Hally V, PPogatchnik C. Trace Element Supplementation and monitoring in the adult patient on parenteral nutrition. Practical Gastroenterology. 2014:129;27-38.

6. Vanteli JV. The importance of refeeding syndrome. Nutrition. 2001:17;632-7.

7. Canada T, Crill C, Guenter P, et al. ASPEN Parenteral Nutrition Handbook. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2009. Parenteral and Enteral Nutrition

8. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm. 2005;62:1663-1682. for Pharmacists Katie Weigartz 9. Huntsville Hospital Department of Pharmacy Services Quick Reference Guide: Pharmacist Edition. May 2015. PGY1 Pharmacy Resident University Health Shreveport 59 October 2016

92

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

3:00 p.m.—4:00 p.m. Review of Current Treatment for Acute Coronary Syndromes Olivia Antosz, PharmD PGY1 Pharmacy Resident University Health Shreveport Shreveport, LA

0179-0000-16-031-L01-P/ 0179-0000-16-031-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Summarize the pathophysiology of ACS. 1. Recognize common medications used in the 2. Compare the utilization of medications in treatment of ACS. the treatment guidelines(2014 ACC/AHA) 2. Describe preparation, storage and handling based on current literature. requirements of medications used in the 3. Formulate treatment regimens based on treatment of ACS. patient specific parameters.. 4. Explain adverse events and common monitoring parameters of medications.

Dr. Antosz has disclosed that she has no relevant financial relationships.

93

Review of Current Pharmacist Objectives Treatment for 1. Summarize the pathophysiology of acute Acute Coronary Syndrome coronary syndrome (ACS)

2. Compare the utilization of medications in the Olivia Antosz, PharmD treatment guidelines based on current literature Post Graduate Year 1 University Health-Shreveport 3. Formulate treatment regimens based on patient specific parameters

4. Explain adverse effects and common monitoring parameters of medications

2

Technician Objectives Acute Coronary Syndrome

• Definition: rupture of plaque or thrombotic event 1. Recognize common medications used in the that leads to symptomatic ischemia or infarction treatment of ACS • NSTE-ACS 2. Describe preparation, storage and handling • Unstable angina (UA) requirements of medications used in the • Non-ST elevation myocardial infarction (NSTEMI) treatment of ACS • ST-elevation myocardial infarction (STEMI)

3 4 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

Pathophysiology Presentation

Atherosclerotic plaque • Chest pain • Severe new-onset or increasing angina Platelets Rupture of plaque Thrombin • Typically, at rest Inflammatory Cells • Heavy, substernal squeezing, crushing Thrombus formation over lesion • Radiates to arms, abdomen, neck and vasoconstriction of vessel • Not always relieved by rest or NTG sublingual

Acute decrease in coronary blood flow (Reduced oxygen)

Unstable angina or MI

5 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014) 6 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

94 Cardiac Enzymes Diagnosis

Unstable Angina NSTEMI STEMI

Symptoms + + +

No change, No change, EKG T-wave inversion, or T-wave inversion, or ST- segment elevation ST-segment depression ST-segment depression

Cardiac − ++ Enzymes

7 Biomerieux. Acute Coronary Syndrome panel (2016). 8 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

Diagnosis General Treatment

• Dual Antiplatelet Therapy • Aspirin

• P2Y12 inhibitor EKG • Clopidogrel, Ticagrelor, or Prasugrel

• Anticoagulant • UFH, LMWH, Fondaparinux, Bivalirudin

Cardiac Unstable Enzymes NSTEMI Angina

9 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014) 10 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

Guidelines Class of Recommendation & Level of Evidence

Class I Class IIa Class IIb Class III •STEMI Benefit > Risk Benefit >>> Risk Benefit >> Risk Harm or “May Be • 2013 ACCF/AHA Guideline for the Management of “Should” “Reasonable” No Benefit ST-Elevation Myocardial Infarction Considered”

Multiple Limited Very limited • NSTE-ACS populations populations populations • 2014 AHA/ACC Guideline for the Management of evaluated evaluated evaluated Data from Data derived Only consensus Level A Level B Patients with Non-ST-Elevation Acute Coronary single from a single Level C opinion of randomized trial randomized trial experts, case Syndrome or or studies, or nonrandomized nonrandomized standard of care studies studies

O’Gara, et al. ACCF/AHA STEMI guideline (2013) O’Gara, et al. ACCF/AHA STEMI guideline (2013) Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 11 12 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

95 Patient Case #1

• TJ is a 50 yo male who presents to the ER with STEMI complaints of “the worst pain in his life”. He describes it as a substernal, pressure-like pain radiating to his neck. The pain started 3 hours ago when he was watching football. His chest pain was unrelieved by SL NTG 0.4mg x3. • EKG: 2-3 mm ST-segment elevation in leads V1-V4 • Cardiac enzymes • CK-MB: 10 ng/mL • Troponin: 8.6 ng/mL Normal EKG ST-segment elevation

13 14 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

Early Recognition Early Recognition

• Faster times to reperfusion lead to reduced

morbidity and mortality Primary Percutaneous 2013 ACCF/AHA Guideline Coronary OR Fibrinolytic therapy Reperfusion therapy should be administered to all eligible patients Intervention with STEMI with symptom onset within the prior 12 hours. (PCI) (Class I, Level of Evidence: A)

Reperfusion therapy is reasonable for patients with STEMI and 2013 ACCF/AHA Guideline symptom onset within the prior 12 to 24 hours who have Primary PCI is the recommended method of reperfusion when it clinical and/or ECG evidence of ongoing ischemia. can be performed in a timely fashion by experienced operators. (CLASS IIa, Level of Evidence: B) (Class I, LOE: A)

15 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 16 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

Primary PCI + Stent vs. Fibrinolysis Early Recognition

Trial Results (% PCI/stent vs. % Fibrinolysis) • PCI-capable hospital (Class I, LOE: A) Significant reduction in primary end point of mortality, • First Medical contact (FMC) within 90 minutes (“Door reinfarction, or stroke at 30 days with primary PCI to balloon”) DANAMI-2 •(8 vs 13.7%)

N=1572; tPA Benefit remained significant at 3 years (19.5 vs 25.2%). • Non-PCI-capable hospital (Class I, LOE: B) At median follow of 7.8 years, combined endpoint death or reinfarction significantly lower in primary PCI group (34.8 vs. • Transfer for primary PCI: FMC within 120 minutes 41.3), primarily due to lower reinfarction rate (11.7 vs. 18.5%) (“Door to balloon”) • Administer fibrinolytic within 30 minutes (“Door to needle”)

17 Andersen, et al. DANAMI-2. Am Heart J (2003) 18 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

96 Definitions of Reperfusion: Reperfusion Options TIMI Flow Grade Primary PCI Fibrinolysis TIMI Grade Degree of Reperfusion • Ischemic symptoms < 12 h • > 120-Minute Delay from (Class I, LOE: A) 0 No reperfusion FMC to Primary PCI • Contraindication to • Ischemic symptoms < 12 h 1 Penetration without reperfusion fibrinolytic therapy (Class I, LOE: A) irrespective of time delay 2 Partial reperfusion from FMC (Class I, LOE: B) • Ongoing ischemia 12-24 h after symptoms onset and 3 Complete reperfusion • Cardiogenic shock or acute a large area of myocardium severe HF irrespective of at risk (Class IIa, LOE: B) time delay from MI onset (Class I, LOE: B) • Ongoing ischemia 12- 24 after symptom onset and • Ongoing ischemia 12-24 h hemodynamic instability after symptom onset (Class IIa, LOE: B) (Class IIa, LOE: B)

19 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 20 Gibson, et al. Circulation. 2002 Apr 23;105(16):1909-13.

Summary

Percutaneous Coronary Intervention Fibrinolytics

PROs CONs PROs CONs • Enhanced survival • Must undergo procedure • Good efficacy in first 3 • Less effective than PCI Fibrinolytic Therapy (>90% TIMI 3 flow in timely manner hours (primarily the 1st ( ~40-50% TIMI 3 flow restoration) hour) of symptom onset rate vs. >90% for PCI) • Limited availability of • Superior long term Primary PCI capable • Availability in most • Less effective after 3 outcomes centers hospitals/EDs and 6 hours

• Lower rate of • Not feasible in all • Results less dependent • Risk of bleeding and intracranial circumstances on physician experience stroke/ICH  hemorrhage and contraindications recurrent MI • Variable outcomes based • Lower system costs on operator experience

Andersen, et al. DANAMI-2. Am Heart J (2003) Boersma, et al. Lancet. 1996;348:771–775. 21 Falsoleiman, et al. Heart Views. 2012 Oct;13(4):129-31. 22

Fibrinolytics Contraindications

Absolute Contraindications Relative Contraindications • MOA: Converts plasminogen to plasmin, which in History of chronic, severe, poorly controlled Any prior intracranial hemorrhage turn cleaves fibrin hypertension Significant HTN on presentation Known structural cerebral vascular region • Causes clot dissolution and restoration of blood flow (SBP > 180 or DBP > 100 mm Hg) Known malignant intracranial neoplasm History of prior ischemic stroke > 3 months to ischemic tissues Ischemic stroke within 3 months Dementia (Except: acute ischemic stroke within 4.5 hours) Known intracranial pathology not covered in absolute Suspected aortic dissection Fibrinolytic Cis Active bleeding or bleeding diathesis (not menses) Traumatic or prolonged ( > 10 min) CPR Significant closed head or facial trauma within 3 months Major surgery (< 3 weeks) Plasminogen Plasmin Intracranial or intraspinal surgery within 2 months Recent (within 2 to 4 wk) internal bleeding For streptokinase, prior treatment within previous 6 mo Noncompressible vascular punctures Pregnancy Degraded Active peptic ulcer fibrin Oral anticoagulant therapy Fibrin

23 Lijnen, Collen. Thromb Haemost. 1995 Jul;74(1):387-90. 24 O’Gara, et al. ACCF/AHA STEMI guideline (2013) .

97 Fibrin-Specific Fibrinolytic Preparation & Handling

Drug Dose Dosing Alteplase (tPA) Max: 100mg over 1.5 • >67 kg: 15mg IV bolus over 1-2 min, • Sterile water for hours then 50mg over 30 min, then 35mg over Tenecteplase 1 Reteplasehour injection (SWFI) • <67 kg: 15 mg IV bolus over 1-2 min, • Store• Store at then2 – 2 25°C0.75 - 30°C mg/kg (36- (36 77°F)over – 30 86°F) minutes, then 0.5 mg/kg over 1 hour • Avoid excessive • Keep• Reconstitute box sealed before with usesupplied to Reteplase (rPA) 10 units + 10 unitsSterile 10 units Water IV bolus, for then Injection, 2nd 10 unit IV bolus agitation protect30 from min lightlater exposure USP Tenecetplase Weight based: 30-• 50 Reconstitute mg Single IV with bolus supplied over 5 seconds Sterile • <60kg: 30 • Use within 8 hours • Reconstitute no more • >60 to <70 kg: 35 mgWater• Precipitation for Injection, mayUSP (withoutoccur with than 8 hours before • >70 to <80 kg: 40mg dextrose-containing lines • >80 to <90kg: 45 mgpreservative) use • >90 kg: 50 mg • Use within 4 hours

25 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 26 Alteplase package insert. South San Francisco, CA: Genentech, Inc.; 2015.

Percutaneous Coronary Intervention Percutaneous Coronary • Aspirin inhibitor

Platelet •P2Y12 inhibitor Intervention Activation • Glycoprotein IIb/IIIa inhibitor

• Unfractionated Heparin Thrombin • Low molecular weight Activation heparin • Bivalirudin

Vessel Wall • Moderate- High dose statin Inflammation

27 28 Design Engineering. Angioplasty Stent. (2012)

Question #1

Which of the following is an absolute contraindication to fibrinolytic therapy? Antiplatelet Therapy A) Severe hypertension

B) Pregnancy

C) Prior intracranial hemorrhage

D) Internal bleeding within past month

29 30

98 Aspirin P2Y12 Receptor Antagonists

Aspirin • Clopidogrel • Ticagrelor • Prasugrel Cyclooxygenase-1 Thromboxane Synthase Arachidonic Prostaglandin Thromboxane A P2Y12 inhibitor Acid 2 No special storage or handling • Fibrinolysis P2Y12 subtype requirements • 162 – 325 mg loading dose Platelet of Platelet • Continue indefinitely, may use 81 mg dose aggregation ADP receptor aggregation •PCI • 162- 325 mg loading dose given before primary PCI • Continually 81 – 325 mg indefinitely after PCI • 81 mg dose preferred (Class IIa, LOR: B) Glycoprotein IIb/IIIa receptor complex Platelet

31 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 32 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

Clopidogrel Ticagrelor

MOA SE Notes MOA Dose for PCI Side Effects Irreversible inhibition • Bleeding • Hypo responders Reversible inhibition Loading dose • Bleeding • Thrombotic • 180 mg • Dyspnea Requires in vivo transformation thrombocytopenia Maintenance dose •  SCr to active metabolite, “prodrug” purpura (TTP) • 90 mg BID • Uric Acid • Ventricular pauses

• Fibrinolysis • < 75 years – 300 mg loading dose • > 75 years – no loading dose needed Black Box Warning: Aspirin Dose and Brilinta Effectiveness • Continue 75 mg for at least 14 days and up to 1 year Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial dose, use with aspirin •PCI 75-100 mg/ day. • 600 mg loading dose, given as soon as possible or at time of PCI • Continue 75 mg daily for 1 year

O’Gara, et al. ACCF/AHA STEMI guideline (2013) O’Gara, et al. ACCF/AHA STEMI guideline (2013) 33 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20) 34 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20)

Ticagrelor Ticagrelor vs. Clopidogrel

Intervention Endpoints Results (Ticagrelor% vs. Clopidogrel %)

PLATO Primary Primary- Adverse Events: (2009) Ticagrelor • CV death + MI + 9.8 vs. 11.2, (P <0.001) • Dyspnea: 13.8 vs. 7.8 Potential Drug Related stroke at 12 mo • % increase in SCr at Potential Harm 180mg LD, then Benefit Considerations 90mg BID Secondary 1 month: 10 + 22 vs. (additional 90mg • CV death 4.0 vs. 5.1 (P=0.001) 8 + 21 NSTEMI •MI 5.8 vs. 6.9 (P=0.005) • %increase in uric acid (mod-high pre-PCI) • Reversible •Stroke 1.5 vs. 1.3 (P=0.22) at 1 month: 14 + 46 • Reversible • Twice daily risk) or Vs. STEMI (if Clopidogrel • Total death 4.5 vs 5.9 (P<0.001) vs 7 + 44 • Greater • Bleeding dosing primary PCI) If pre-treated, no • Stent thrombosis, 1.3 vs. 1.9 (P=0.009) • >3 sec ventricular definite pause: 5.8 vs. 3.6 platelet N=18,624 additional LD. If • High dose • Unique naïve, 300mg LD, Safety inhibition adverse then 75 mg/day • Major bleeding 11.6 vs 11.2 (P=0.43) aspirin • Major or minor 16.1 vs 14.6 (P=0.008) • CABG- effects • Non-CABG related 4.5 vs. 3.8 (P=0.03) major bleeds reduction in mortality without excess bleeding Conclusion: Compared to clopidogrel, ticagrelor significantly reduced the rate of CV death, MI, or stroke without an increase in the rate of overall major bleeding (but increase in combined major/minor and non-CABG related bleeds. Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20) Wallentin , et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. 35 Wallentin , et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. 36 Held, et al. N Engl J Med. J Am Coll Cardiol. 2011;57(6):672-684.

99 Prasugrel Prasugrel

Intervention Endpoints Results (% Prasugrel vs. % Clopidogrel) MOA Dose in PCI Side Effects Primary Primary- 9.9 vs. 12.1, (P <0.001) Irreversible inhibition Loading dose • Bleeding- BBW • CV death, MI, • Non-fatal MI: 7.3 vs. 9.5 % (P<0.001) • 60mg stroke • CV death: 2.1 vs. 2.4 (P = 0.31) Prodrug- metabolized to active Maintenance dose • Nonfatal Stroke: 1.0 vs. 1.0 (P= 0.93) Secondary Urgent target vessel revascularization: 2.5 vs. 3.7 and inactive metabolites • 10 mg once daily TRITON- Prasugrel • CV death, MI, (P<0.001) TIMI 38 60mg LD, stroke, re-ischemia Stent thrombosis: 1.1 vs 2.4 (P<0.001) 10mg • CV death, MI, Diabetics Vs. UTVR Primary- 12.2% vs. 17% (P<0.001) Black Box Warning: Bleeding Risk UA/NSTEMI Clopidogrel • Stent thrombosis TIMI major bleeding: 2.6 vs 2.5% • Do not use in patients with active pathological bleeding or a history of or STEMI and 300 mg LD, 75 (ACR MI- 8.2% vs. 12.3% (P<0.001) - ↓ 40% vs. ↓ 18% mg definite/probable) among non-DM subjects (7.2 vs 8.7%, P=0.006) transient ischemic attack or stroke. Planned PCI N=13,608 Safety • In patients > 75, prasugrel generally not recommended due to Safety • TIMI major bleeding: CABG (13.4 vs. 3.2, P < increase risk of fatal and intracranial bleeding and uncertain benefit, • TIMI major bleeds, 0.001) and non-CABG (2.4 vs 1.8, P=0.03) life-threatening • Life threatening bleeding 1.4 vs 0.9% (P<0.01) except in high risk patients (diabetes or prior myocardial infarction) bleeds Prior stroke/TIA: HR= 1.54 (1.02-2.32), P=0.04 • Do not start in patients likely to undergo CABG. Age > 75 years: HR=0.99 (0.81-1.21), P=0.92 • Additional risk factors for bleeding include : <60 kg, propensity to Weight <60kg: HR= 1.03 (0.69-1.53), P=0.89 bleed, concomitant medications that increase risk of bleeding. Conclusion: In patients with ACS and scheduled PCI, prasugrel reduces CV morbidity and mortality but increases bleeding when compared to clopidogrel.

37 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 38 Wiviott, et al. N Engl J Med. 2007 Nov 15;357(20):2001-15.

Prasugrel vs. Clopidogrel Overview: Selection of Appropriate Agent

• Clopidogrel • Potential Benefit • If < 60 kg, age > 75 (NSTEMI), history of TIA/stroke and/or at • Mortality benefit in PCI higher bleeding risk, least expensive • Faster onset • Ticagrelor • Less response variability • If unknown coronary anatomy and/or high likelihood of nonurgent CABG, no ICH, clopidogrel hypo-responder, good • Potential Harm compliance • Increased risk of bleeding • Prasugrel • If primary PCI in STEMI (especially high risk DM or prior MI), age <75, >60kg, clopidogrel hypo-responder, no CVA/TIA

39 40

Kengreal (cangrelor) Kangreal (cangrelor)

• Approved: June 2015 CHAMPION- Intervention Results Cangrelor infusion vs. No significant difference in the primary endpoint placebo (death, MI, or ischemia-driven revascularization) at 48 PLATFORM 30 minutes before PCI, hours • IV Non-thienopyridine P2Y12 receptor antagonist (n= 5000; ACS or followed by 600mg of • (7 vs 8 %) stable angina) clopidogrel after procedure in • Use: patients undergoing PCI who have not been both groups Cangrelor infusion vs. No significant difference in the primary endpoint PCI clopidogrel 600mg (death, MI, or ischemia-driven revascularization) at 48 loaded with a P2Y12 platelet inhibitor and are not (n=8000; ACS or 30 min before PCI hours stable angina) being given a glycoprotein IIb/IIIa inhibitor • (7.5 vs 7.1%) Less rate of primary endpoint (death, MI, ischemia- Cangrelor bolus and driven revascularization, stent thrombosis) at 48 Clopidogrel Cangrelor infusion vs. clopidogrel hours PHOENIX 300mg or 600mg loading dose • (4.7 vs 5.9%, adjusted OR: 0.78, 95% CI 0.66- (n=11,145; urgent or • Inter individual • Rapid 0.93) elective PCI) response onset/offset No significant difference in severe/life-threatening • Irreversible • Reversible bleeding at 48 hours • (0.16 vs 0.11%, OR 1.5, 95% CI 0.53 – 4.22) MOA • Greater degree of platelet inhibition Bhatt, et al. N Engl J Med. 2009 Dec 10;361(24):2330-41. Harrington, et al. N Engl J Med. 2009 Dec 10;361(24):2318-29. 41 Cangrelor package insert. Parsippany, NJ: The Medicines Company; 2015 June. 42 Bhatt, et al. N Engl J Med. 2013 Apr 4;368(14):1303-13.

100 Kangreal (cangrelor) Question #2

•Dosing • PCI: 30 mcg/kg IV bolus prior to PCI, followed immediately Which of the following is an appropriate dosing by 4 mcg/kg/min infusion continued for at least 2 hours or for regiment for TJ, who is undergoing PCI? the duration of PCI, whichever is longer

• Transition to oral P2Y12 antagonist therapy A) Aspirin 81 mg + Clopidogrel 300mg • to clopidogrel: 600mg clopidogrel immediately after discontinuing cangrelor infusion. B) Aspirin 81 mg + Clopidogrel 600 mg • to prasugrel: Administer 60 mg of prasugrel immediately after discontinuing cangrelor infusion C) Aspirin 325 mg + Ticagrelor 180 mg • to ticagrelor: Administer 180 mg of ticagrelor at any time during cangrelor infusion or immediately after discontinuing cangrelor infusion. D) Clopidogrel 300 mg + Cangrelor 30 mcg/kg IV bolus

*Note: Do not administer clopiodgrel or prasugrel prior to cangrelor discontinuation

43 Cangrelor package insert. Parsippany, NJ: The Medicines Company; 2015 June. 44

Unfractionated Heparin

• Potentiates antithrombin III  inactivates thrombin, factors IXa, Xa, Anticoagulants XIa, XIIa, and plasmin  prevents conversion of fibrinogen to fibrin

Coagadex. Coagulation Cascade (2016) 45 46 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20)

Low Molecular Weight Heparin Heparin

Dose SE Monitoring Fibrinolysis: 60 U/kg (max 4,000 IU), • Bleeding • Hgb/ Hct • Inhibits factor IIa and factor Xa then 12 U/kg/hr (max 1,000 IU/hr) • Thrombocytopenia • Platelets PCI: 50-100 U/kg to achieve therapeutic •aPTT ACT; dose dependent on GP IIb/IIIa use

Advantages Disadvantages

• Immediate anticoagulation • Inconsistent anticoagulation • Short acting effect • Easy to monitor • Frequency of monitoring • Long clinical use history • Heparin induced • Reversible with protamine thrombocytopenia (HIT/ HITTS) • Inexpensive • Use in renal dysfunction

Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20) Coagadex. Coagulation Cascade (2016) 47 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 48 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20)

101 Enoxaparin Fondaparinux

Dose SE Monitoring Fibrinolysis: • Bleeding • SCr/ CrCl Age < 75: 30 mg IV bolus, then 1 mg/kg SQ Q12* • Thrombocytopenia • Anti-Xa level (if • Selective inhibitor of factor Xa Age > 75= no bolus, then 0.75 mg/kg SQ Q12h using for longer durations)

Advantages Disadvantages

• More predictable and sustained • Less reversible than UFH anticoagulation • Renally cleared • More effective thrombin • Longer half life than UFH inhibition than UFH • Increased bleeding vs. UFH • No routine monitoring required (SYNERGY) • Lower risk of HIT • Long history of clinical use • Ease of dosing (BID)

O’Gara, et al. ACCF/AHA STEMI guideline (2013) Coagadex. Coagulation Cascade (2016) 49 Ferguson, et al. JAMA. 2004 Jul 7;292(1):45-54. 50 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20)

Fondaparinux Bivalirudin

Dose SE Monitoring Fibrinolysis: 2.5 mg IV, 2.5 mg SQ q24h • Bleeding Contraindications • Specific and reversible direct thrombin inhibitor • CrCl < 30 mL/min PCI: Not recommended as sole • Weight < 50 kg anticoagulant (use with UFH or • Active bleeding bivalirudin)

Advantages Disadvantages

• Similar ischemic events • More catheter thrombosis vs. enoxaparin (OASIS- 5) during PCI (OASIS-5), • Less bleeding vs. therefore must use with enoxaparin (OASIS-5) UFH or bivalirudin during • Ease of dosing PCI • No monitoring • Contraindications • Longer half-life

Coagadex. Coagulation Cascade (2016) 51 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 52 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20)

Bivalirudin

Dose/ Duration SE Monitoring Glycoprotein IIb/IIIa

PCI: 0.75 mg/kg, 1.75 mg/kg/hr • Bleeding • aPTT/ ACT (adjust dose for renal dysfunction) • Renal function Inhibitors

Advantages Disadvantages

• ACUITY trial: • Expensive • Similar ischemic events • Limited data in renal P2Y12 subtype Platelet • Eliminates need for GP insufficiency of ADP receptor IIb/IIIa inhibitor aggregation • Less bleeding • Good option if high bleed risk, thrombocytopenia or HIT Glycoprotein IIb/IIIa • Short acting receptor complex Platelet O’Gara, et al. ACCF/AHA STEMI guideline (2013) 53 White, et al. J Am Coll Cardiol. 2008 May 6;51(18):1734-41. 54 54 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

102 Glycoprotein IIb/IIIa Inhibitors Glycoprotein IIb/IIIa Inhibitors

•MOA Platelet • Bind to GP IIb/IIIa receptor • Selected Contraindications Storagebound & Handling t ½ Platelet Agent Molecule Dose Elimination Bleeding and inhibit final common • Active bleeding or history of ------binding plasma t ½ pathway of platelet bleeding diathesis • Tirofiban: Store at room temperature. Protect from aggregation • History of intracranial Tirofiban Small (non-light during0.25mg/kg, storage. then 0.15 Seconds Renal (40-70%) Reversible 10-12% hemorrhage peptide) mcg/kg/min ------Adjust dose CrCl < • Side effects 2 hours 30 mL/min • History of stroke within 30 • Eptifibatide: Refrigerate (2-8°C; 36-46°F). Protect • Bleeding days or any history of Eptifibatide Small from 180light mcg/kg until x2, administration. then 2 Seconds Renal (50%) Reversible 9-11% hemorrhagic stroke (peptide) mcg/kg/min ------Adjust dose CrCl < • Thrombocytopenia 2.5 hours 50mL/min • Recent major surgery or • Abciximab: Refrigerate (2-8°C; 36-46°F). Stable for • Monitor parameters severe trauma (month) Abciximab Monoclonal12 hours0.25 mg/kg, after then preparation 0.125 Hours Plasma Irreversible 14% • Severe hypertension (SBP Antibody mcg/kg/min (max 10 ------• Hematoma mcg/min) Minutes *reversible with >200 mmHg or DPB > 110 Lexicomp® Online [Internet]. Wolters Kluwer Health, (citedplatelets 2016 (24-48 Aug 20) • IV lines hr) mmHg) • CBC

55 Lexicomp® Online [Internet]. Wolters Kluwer Health, (cited 2016 Aug 20) 56 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

Overview: Overview: Anticoagulant Antiplatelet Therapy Therapy Fibrinolytics Primary PCI Fibrinolytic Antiplatelet Loading Dose Maintenance Dose • Unfractionated Heparin • Unfractionated Heparin Aspirin 162-325mg before procedure 81*- 325mg x indefinitely • With planned GP IIb/IIIa receptor • IV bolus of 60 U/kg (maximum 4000 units) Clopidogrel antagonist? followed by infusion of 12 U/kg/hr • Age < 75 mg daily x > 14 days and up to (maximum 1000 units) 300 mg • Yes: 50- 70 U/kg IV bolus 75 years 1 year in absence of bleeding • No: 70 – 100 U/kg IV bolus • Adjust to maintain aPTT at 1.5 to 2.0 • Age > 75mg daily x > 14 days and up to times control (~50-70 secs) for 48 hours None 75 years 1 year in absence of bleeding • Bivalirudin or until revascularization Primary PCI • 0.75 mg/kg IV bolus, then 1.75 • Enoxaparin mg/kg/h infusion with or without prior • Age < 75: 30mg IV bolus, followed in 15 Antiplatelet Loading Dose Maintenance Dose treatment with UFH min by 1 mg/kg subcutaneously every 12 Aspirin 162-325mg before procedure 81*- 325mg x indefinitely • Reduce infusion to 1 mg/kg/hr with hour (maximum 100mg for the first 2 doses) estimated CrCl < 30 ml/min Clopidogrel 600 mg ASAP or at time of PCI 75 mg daily x 1 year (if stent placed) • Age > 75 year: no bolus, 0.75mg/kg • Preferred over UFH with GP IIb/IIIa subcutaneously every 12 hour (maximum Prasugrel 60 mg ASAP or at time of PCI 10 mg daily x 1 year (if stent placed) receptor antagonist in patients at high 75 mg for the first 2 doses) Ticagrelor 180 mg ASAP or at time of PCI 90 mg BID x 1 year (if stent placed) risk of bleeding (Class IIa, LOR: B) • Fondaparinux • Fondaparinux Abciximab 0.25 mg/kg IV bolus 0.125 mcg/kg/min (max 10mcg/min) • Initial dose 2.5 mg IV, then 2.5 mg Tirofiban 25 mcg/kg IV bolus 0.15 mcg/kg/min • Not recommended as sole subcutaneously daily starting the following (If CrCl< 30= reduce infusion by 50%) anticoagulant for primary PCI day, for the index hospitalization up to 8 (Class III, LOE: B) days or until revascularization Eptifibatide 180 mcg/kg IV bolus 2 mcg/kg/min (a second 180 mcg/kg bolus (If CrCl < 50 mL/min, reduce infusion by • Contraindicated if CrCl < 30 ml/min administered 10 min after first bolus) 50%); avoid in patients on HD 57 O’Gara, et al. ACCF/AHA STEMI guideline (2013) 58 O’Gara, et al. ACCF/AHA STEMI guideline (2013)

Patient Case #2

RJ is a 50 yo male who presents to the ER with complaints of NSTE-ACS substernal squeezing radiating to arms and lower jaw. The pain started 2 hours ago when he was sitting in his recliner, and was unrelieved by NTG 0.4mg SL. Patient is short of breath, excessively diaphoresing, and is light-headed. He called 911 and was brought to the hospital.

• EKG: 2 mm of ST-segment depression in leads V1-V4

• Cardiac enzymes • CK-MB: 10 ng/mL Normal EKG T-wave inversion ST-segment • Troponin: 2 ng/mL depression

59 60 Spinler, et al. Pharmacotherapy: Handbook, 9e. (2014)

103 Early Hospital Care Early Hospital Care

• Oxygen- maintain O2 > 90% • Nitroglycerin • Cholesterol Management • SL 0.4 mg Q 5 min x 3 for continuing ischemic pain • High intensity statin initiated or continued • IV: 5 – 10 mcg/min for persistent ischemia, HF, or HTN • Morphine • Renin-Angiotensin- Aldosterone System inhibitors • Continued ischemic chest pain despite maximally tolerated anti- • ACE inhibitor ischemic medications • Beta Blocker • Started and continued indefinitely in patients with LVEF < 40%, • Within 24 hours unless contraindicated DM, HTN, stable CKD • Calcium channel blockers • Use ARB if intolerant to ACEi • Non-dihydropyridine • Aldosterone antagonists • USE: recurring ischemia and contraindicated to beta-blocker • Recommended in post-MI patients without significant renal • Do NOT administer immediate release nifedipine in absence of a dysfunction or hyperkalemia who are receiving therapeutic beta blocker (Class III, LOE: B) doses of ACEi and BB and have LVEF <40%, DM, or HF

61 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 62 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Risk Stratification- TIMI Risk Stratification Score Predict risk of future morbidity and mortality Medical History Clinical Presentation Age > 65 years ST- segment depression ( > 0.5 mm)

3+ risk factors for CAD > 2 episodes of chest discomfort in past 24 • TIMI: Thrombolysis In Myocardial Infarction • Hypercholesterolemia hours • Hypertension • GRACE: Global Registry of Acute Coronary Events • Diabetes Mellitus •Smoking • Family history of premature CAD • PURSUIT: Platelet Glycoprotein IIb/IIIa in Unstable Known CAD (50% stenosis of coronary Positive biochemical marker for infarction Angina: Receptor Suppression Using Integrilin artery) Therapy Use of aspirin within past 7 days

• NCDR-ACTION: National Cardiovascular Data Low Risk Medium Risk High Risk Registry- Acute Coronary Treatment and Intervention • 0-2 points • 3-4 points • 5-7 points Outcomes Network

Antman, et al. JAMA.2000;284(7):835-842. 63 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 64 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Risk Stratification- TIMI Bleeding Risk Score • CRUSADE Bleeding Score (0-100) All Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent • Estimates baseline risk of in-hospital major bleeding TIMI Risk Score Revascularization through 14 days after randomization, % Admission clinical variables and Baseline Patient Characteristics laboratory values 0-1 4.7 Hematocrit (%) Diabetes Mellitus

28.3 GFR: Cockcroft- Gault Signs of CHF on admission

3 13.2 Heart Rate on admission Gender Systolic Blood Pressure on admission

4 19.9 Prior Vascular Disease

5 26.2 Very Low Moderate Very High Low Risk High Risk Risk Risk Risk 6-7 40.9 •<21 • 21- 30 • 31-40 • 41-50 •> 50

CRUSADE. Bleeding Score Calculator (2008) 65 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 66 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

104 Ischemia-Guided vs. NSTE-ACS: Definite or Likely Early Invasive Strategy Ischemia Guided Strategy Early Invasive Strategy Initiate DAPT and Anticoagulant Strategy Factors Associated with Appropriate Selection Therapy 1. Aspirin – (Class 1; LOE: A) Ischemia-guided Low-risk score (TIMI 0 or 1, GRACE <109); Low risk troponin-negative females 2. P2Y i (+ ASA) – (Class 1; LOE: A) Patient or clinical preference in the absence of high-risk features 12 strategy • Clopidogrel Immediate invasive Refractory Angina • Ticagrelor Signs or symptoms of HF or new or worsening mitral regurgitation 3. Anticoagulant: (within 2 hr) Hemodynamic instability • Enoxaparin – (Class 1; LOE: A) Recurrent angina or ischemia at rest or with low-level activities despite intensive •UFH – (Class 1; LOE: B) medical therapy • Fondaparinux – (Class 1; LOE: B) Sustained VT or VF • Bivalirudin – (Class 1; LOE: B) Early invasive (within None of the above, but GRACE risk score > 140 Can consider GPI in addition to ASA+ P2Y Temporal change in troponin 12 24 hr) New or presumably new ST depression in high risk patients – (Class IIb; LOE: B) • Eptifibatide Delayed invasive None of the above but diabetes mellitus • Tirofiban Renal insufficiency (GRF < 60 mL/min/1.73 m2) (within 25-72 h) Reduced LV systolic function (EF < 0.40) Early post infarction angina Therapy Effective PCI within 6 months Medical Therapy Prior CABG chosen based on GRACE risk score 109-140; TIMI score > 2 Therapy cath findings Ineffective 67 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 68 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Initial Management Initial Management Ineffective Ineffective

PCI with Stenting CABG (initiate/continue antiplatelet and anticoagulant therapy) (Initiate/continue ASA therapy and discontinue P2Y12 and/or GPI therapy) 1. Aspirin – (Class 1; LOE: B) 1. Aspirin – (Class 1; LOE: B) 2. Elective CABG 2. P2Y12 inhibitor (+ASA) – (Class 1; LOE: B) • Clopidogrel, Prasugrel, or Ticagrelor • D/C clopidogrel/ticagrelor 5 day before, prasugrel at least 7 days before 3. GPI (if not treated with bivalirudin at time of PCI) 3. Urgent CABG – (Class 1; LOE: B) • High risk features, not adequately treated with clopidogrel – (Class 1; LOE: A) • D/C clopidogrel/ticagrelor up to 24 h before. May perform <5 d after • High risk features, adequately treated with clopidogrel – (Class IIa; LOE: B) clopidogrel/ticagrelor and < 7 d after prasugrel discontinued 4. Anticoagulant 4. CABG (Class 1; LOE: B) • Enoxaparin – (Class 1; LOE: A) • D/C eptifibatide/tirofiban at least 2-4 hour before, and abciximab > 12 h before • Bivalirudin – (Class 1; LOE: B) •UFH– (Class 1; LOE: B) • Fondaparinux as sole anticoagulant – (Class III; LOE: B)

69 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 70 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Initial Management Effective Initial Antiplatelet Therapy

• Aspirin • 162 -325 mg given to all patients as soon as possible Late Hospital/Post-hospital Care • 81 – 325 mg daily continued indefinitely •P2Yinhibitor 1. ASA indefinitely – (Class I, LOE: A) 12 • Administer in addition to aspirin for up to 12 months in all 2. P2Y12 inhibitor (clopidogrel or ticagrelor) x 12 months if medically treated OR if treated with coronary stenting – (Class I, LOE: B) patients • Clopidogrel 300 mg or 600 mg loading dose, then 75 mg daily • Ticagrelor 180 mg loading dose, then 90 mg twice daily

2014 AHA/ACC NSTE-ACS Guideline

It is reasonable to choose ticagrelor over clopidogrel for P2Y12 inhibition treatment in patients with NSTE-ACS treated with an early invasive or ischemia-guided strategy (Class IIa, level B)

71 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 72 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

105 Antiplatelet Therapy During Initial Anticoagulant Therapy PCI • Aspirin • 162 -325 mg given to all patients as soon as possible • Enoxaparin • 81 – 325 mg daily continued indefinitely • 1 mg/kg SQ Q 12 hr

•P2Y12 inhibitor •UFH • Administer in addition to aspirin for up to 12 months in all • 60 IU/kg (max 4,000 IU), then 12 IU/kg/h (max 1,000 patients IU/hr) • Clopidogrel 600 mg loading dose, then 75 mg daily • Ticagrelor 180 mg loading dose, then 90 mg twice daily • Fondaparinux • Prasugrel 60 mg loading dose, then 10 mg daily • 2.5 mg SQ daily • Bivalirudin 2014 AHA/ACC NSTE-ACS Guideline • 0.10 mg/kg LD followed by 0.25 mg/kg/hr “It is reasonable to choose prasugrel over clopidogrel for P2Y12 treatment in • Only in patients managed with early invasive strategy patients with NSTE-ACS who undergo PCI who are not at high risk of bleeding complications” (Class IIa; LOE: B) 73 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 74 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Anticoagulant Therapy Question #3 During PCI True or False? Drug Received Prior Anticoagulation No prior anticoagulation Enoxaparin • 8-12 hr earlier: 0.3 mg/kg 0.5 mg/kg – 0.75 mg/kg IV The purpose of the ischemia guided strategy is to • Within 8 hr: none loading dose avoid unnecessary treatment for those at low risk for significant coronary heart disease. Bivalirudin • Received UFH: 0.75 mg/kg IV, then 0.75 mg/kg loading dose, 1.75 mg/kg/h IV 1.75 mg/kg/hr IV infusion • Already receiving Bivalirudin infusion: True 0.5mg/kg, then 1.75 mg/kg/h UFH • UFH as needed to achieve ACT of • Planned GPI: 50-70 U/kg “This approach tailors therapy to risk and optimizes clinical efficacy and cost- 200- 350 (ACT based on planned GPI • Not planned: 70-100 U/kg effectiveness because high risk patients are identified and treated, while low- or not) risk patients avoid costly invasive procedures that are unlikely to confer clinical Fondaparinux NOT recommended: Administer either N/A benefit and may actually cause harm” UFH or Bivalirudin due to risk of catheter thrombosis

75 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 76 McKay. J Am Coll Cardiol. 2003;41(4s1):S96-S102.

Discharge Management

• Dual Antiplatelet Therapy Discharge • Aspirin • 162- 325 mg loading dose, then 81 mg daily maintenance dose x 1 year

• P2Y12 • Clopidogrel 75 mg daily x 1 year Ischemia Stentguided placedstrategy • Ticagrelor 90 mg BID starting 12 hours after LD x 1 year during PCI • If stent placed during PCI: Prasugrel 10mg daily is also an option

O’Gara, et al. ACCF/AHA STEMI guideline (2013) 77 78 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

106 Discharge Management Discharge Management

• Nitroglycerin PRN • If on aspirin and P2Y12 inhibitor in addition to • Cholesterol management warfarin, consider initiating proton pump inhibitor • High intensity statin initiated or continued within 24 h • Avoid use of NSAIDs • Lipitor 40 – 80 mg • Crestor 20 – 40 mg • Angiotensin-converting enzyme inhibitor • Initiate or continue within 24 hr • Beta-Blocker • Initiate or continue within 24 hr unless contraindicated

O’Gara, et al. ACCF/AHA STEMI guideline (2013) O’Gara, et al. ACCF/AHA STEMI guideline (2013) 79 Amsterdam, et al. AHA/ACC NSTE-ACS (2014) 80 Amsterdam, et al. AHA/ACC NSTE-ACS (2014)

Question #4 Review of Current Treatment for Upon discharge, what is the recommended antiplatelet therapy for patients with ACS? Acute Coronary Syndrome

A) Eptifibatide Olivia Antosz, PharmD B) Aspirin 81 mg + Clopidogrel 75 mg Post Graduate Year 1 University Health-Shreveport C) Ticagrelor 90 mg BID

D) Enoxaparin

81

107

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

3:00—4:00 p.m. Antifungal Therapies for Systemic Infections

Ashley Trojcak, PharmD PGY1 Pharmacy Resident University Health Shreveport Shreveport, LA

0179-0000-16-032-L01-P/ 0179-0000-16-032-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Identify antifungal agents used to treat 1. Identify antifungal agents used to treat systemic fungal infections. systemic fungal infections. 2. Compare antifungal therapies based on 2. Review preparation and storage sensitivities and adverse drug events. requirements of antifungal medications. 3. Design a regimen based on fungal infection 3. Differentiate between amphotericin B and patient factors. formulations.

Dr. Trojcak has disclosed that he has no relevant financial relationships.

108

Pharmacist Objectives

1. Identify antifungal agents used to treat systemic Antifungal Therapies for fungal infections

Systemic Infections 2. Compare antifungals therapies based on sensitivities and adverse drug events Ashley Trojcak, PharmD PGY-1 Pharmacy Resident 3. Design a regimen based on fungal infection and University Health Shreveport patient factors

Pharmacy Technician Objectives Goals

1. Identify antifungal agents used to treat systemic • Which fungi cause infections in humans? fungal infections

• What populations are most affected? 2. Review preparation and storage requirements of antifungal medications • What are the treatment options? 3. Differentiate between amphotericin B formulations

Types of Fungus

Dimorphic Yeast Molds Fungi What & •Candida •Histoplasma •Aspergillus species species species Who are We •Cryptococcus •Blastomyces •Fusarium neoformans •Coccidioides species Treating? •Scedosporium species •Zygomycetes

Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html

109 Fungal Cell Type of Infection by Organism

Infection Organism Rate of Occurrence Cryptococcosis Cryptococcus neoformans In people with HIV/AIDS, approximately 1 million cases worldwide each year Disseminated Mucor species Account for 8% of invasive fungal Mucormycosis Rhizopus species infections in stem cell transplant Apophysomyces species recipients and 2% in solid organ Lichtheimia species transplant recipients Coccidiomycosis Coccidioides species In endemic areas (Arizona), account for 15 – 30% of community-acquired pneumonias Invasive Aspergillus species Annual incidence in hematopoetic stem Aspergillosis cell transplant (HSCT) is 3.9% Histoplasmosis Histoplasma species Rate of occurrence in the Midwest is approximately 6.1 cases per 100,000 population in those with HIV/AIDS, organ transplant recipients, and the immune suppressed

Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Vallabhaneni et al. The global burden of fungal diseases. Infect Dis Clin N Am. 2016.

Candidemia Candidemia

Candidemia is the 4th leading cause of nosocomial bloodstream infections and is associated with a mortality rate as high as 47%

Risk Factors Lack of rapid • Central venous catheter (CVC) diagnostics Increased in-hospital + Delay in therapy • Intensive care unit mortality • Weakened immune system (HIV/AIDS, chemotherapy, stem Slow growth of cell/organ transplant) cultures • Neutropenia (ANC<1,500) • Renal failure or receiving hemodialysis

Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html Vallabhaneni et al. The global burden of fungal diseases. Infect Dis Clin N Am. 2016. Vallabhaneni et al. The global burden of fungal diseases. Infect Dis Clin N Am. 2016.

Candidemia Populations at Risk

• Receiving immune-suppression therapy • Morrell et al found a delay in therapy at >12 hours after a positive blood culture is associated with increase in mortality • Undergoing chemotherapy • HIV/AIDS • Garey et al concluded that delay • Organ transplant in therapy in hospitalized • patients was associated with Diabetes increased mortality and ICU • Intensive Care Unit (ICU) admission length of stay • Elderly • Pregnant

Fungal infections are associated with a high rate of morbidity and mortality, and increased cost and length of hospital stay

Morrell M et al. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005. Garey et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006. Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html

110 History of Systemic Antifungals

Antifungal Therapies Amphotericin B Micafungin Lipid Complex Amphotericin B Fluconazole Deoxycholate Flucytosine Voriconazole Amphotericin B Isavuconazole Colloidal Dispersion

1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s

Ketoconazole Liposomal Anidulafungin Amphotericin B Itraconazole Caspofungin

Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html

History of Systemic Antifungals Amphotericin B

Amphotericin B Lipid Complex Micafungin • Discovered in 1953 Amphotericin B Fluconazole Amphotericin B Deoxycholate • Product of Streptomyces nodosus as 2 forms, Flucytosine Voriconazole Colloidal Isavuconazole Dispersion amphotericin A &B • First intravenous antifungal 1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s • Liposomal formulations became available in the 1990’s for less toxicity. Ketoconazole Liposomal Anidulafungin Itraconazole Amphotericin B Caspofungin

Baum, GL. Antifungal Therapy. Postgraduate Medical Journal. 1978. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006

Mechanism of Action Spectrum of Activity

Organism Spectrum Aspergillus species A. flavus ± A. fumigates + A. niger + A. terreus - Candida species C. albicans + C. glabrata + C. krusei + C. lusitaniae - C. parapsilosis + C. tropicalis + Cryptococcus species + Coccidoides species + Blastomyces + Histoplasma species + Fusarium species ± Scedosporium species ±/- Zygomycetes ± Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006 Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006

111 Dosage Forms & Stability Pharmacokinetics

Amb ABCD ABLC LAB AmB ABLC LAB Amphotec Abelcet Ambisome Bioavailability <5% <5% <5% Typical Dose: Typical Dose: Typical Dose: Typical Dose: • 0.5-1.5mg/kg/day • 3–4 mg/kg/day • 3-5mg/kg/day • 3-5mg/kg/day Little CSF & Little CSF & urine penetration minor urine penetration Compatibility: Compatibility: Compatibility: Compatibility: Distribution • D5W • D5W • D5W • D5W >95% protein binding >95% Protein bound

Final Product: Final Product: Final Product: Final Product: Metabolism Unknown – not metabolized • Transparent & • Cloudy & bright • Cloudy & bright • Cloudy & bright bright yellow yellow yellow yellow Elimination Unchanged in the feces and urine

Protect from light Not currently available Protect unused vials Must be filtered during Renal/ Hepatic from light preparation impairment None adjustment 3mg/kg/day ABLC ≠ 3mg/kg/day LAB

Lexi-Comp Online. August 2016. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006

Safety Concerns Indications for Use

AmB ABCD ABLC LAB Amphotericin B Lipid-based Amphotericin B Hepatotoxicity ++ ++ ++ ++ deoxycholate formulations

rd nd Nephrotoxicity ++++ +++ +++ ++ Candidemia 3 line agent 2 line agent

Infusion- Reserved for when other Reserved for those who +++ +++ +++ ++ Aspergillosis related options are not available can’t tolerate azoles Electrolyte +++ ++ ++ ++ abnormalities

Nett & Andes. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am. 2016. Pappas et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of america. Clin Infect Dis. 2016. Lexi-Comp Online. August 2016. Patterson et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of america. Clin Infect Hamill. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013. Dis. 2016.

Treatment Question #1

Amphotericin B Lipid-based Amphotericin B An amphotericin B order for a 65 year old male is written for deoxycholate Formulations 1mg/kg per day. Which amphotericin B formulation should be

Disseminated Alternative for those at low risk of dispensed? 1st line agent Histoplasma nephrotoxicity

Mucormycosis - 1st line agent A. Amphotericin B deoxycholate (AmB) HIV-infected patients with or B. Amphotericin B colloidal dispersion (ABCD) HIV-infected & Cryptococcal predisposed to renal dysfunction. non-HIV infected in C. Amphotericin B lipid complex (ABLC) Organ transplant recipients with Meningitis combination with flucytosine flucytosine (LAB or ABLC) D. Liposomal amphotericin B (LAB)

Nett & Andes. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am. 2016. Wheat et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of america. Clin Infect Dis. 2007. Perfect et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010.

112 Question #1 Question #2

An amphotericin B order for a 65 year old male is written for When comparing an IV bag of amphotericin B deoxycholate 1mg/kg per day. Which amphotericin B formulation should be (conventional) and liposomal amphotericin B, what do you dispensed? expect the liposomal formulation to look like?

A. Amphotericin B deoxycholate (AmB) A. Bright yellow and transparent B. Amphotericin B colloidal dispersion (ABCD) B. Bright yellow in color with a hazy tint C. Amphotericin B lipid complex (ABLC) C. Clear and completely transparent D. Liposomal amphotericin B (LAB) D. Red and non-transparent

Question #2 History of Systemic Antifungals

Amphotericin B When comparing an IV bag of amphotericin B deoxycholate Lipid Complex Micafungin (conventional) and liposomal amphotericin B, what do you Amphotericin B Fluconazole expect the liposomal formulation to look like? Deoxycholate Flucytosine Voriconazole Amphotericin B Isavuconazole Colloidal Dispersion

A. Bright yellow and transparent 1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s B. Bright yellow in color with a hazy tint C. Clear and completely transparent Ketoconazole Liposomal Anidulafungin D. Red and non-transparent Amphotericin B Itraconazole Caspofungin

Flucytosine: the Sidekick Mechanism of Action

• Discovered in 1957, but not reported for antifungal use until 1964. • Pyrimidine • Similar structure to the antineoplastic 5-fluorouracil analogue

• Inhibits DNA & protein synthesis

Baum, GL. Antifungal Therapy. Postgraduate Medical Journal. 1978. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006.

113 Spectrum of Activity Pharmacokinetics

Organism Spectrum Aspergillus species - Flucytosine Candida species Bioavailability 80% C. albicans + C. glabrata + Good CSF & urine penetration C. krusei + Distribution C. lusitaniae ± <5% protein binding C. parapsilosis + Metabolism Minimal C. tropicalis + Elimination Urine Cryptococcus species + Renal impairment Decrease dose if CrCl < 40mL/min Coccidoides species + adjustment Blastomyces - Hepatic impairment None Histoplasma species - adjustment Fusarium species - Oral capsule 250mg, 500mg Scedosporium species - Zygomycetes -

Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006.

Combination Amphotericin B deoxycholate with Safety & Treatment Flucytosine

Determine whether amphotericin B deoxycholate plus CrCl > 40mL/min CrCl 20 – 40mL/min CrCl < 20mL/min flucytosine had mortality benefit over amphotericin B alone Adjunctive therapy for 50–150mg/kg/day Decrease dose to Decrease dose to Candida and in divided doses 50% of standard 25% of standard Treatment Groups Cryptococcal every 6 hours dose dose All patients received Amb 1mg/kg/day infections No adjunct therapy + flucytosine 100mg/kg + fluconazole 400mg Side effects: Agranulocytosis, thrombocytopenia, gastrointestinal effects twice daily Monitoring 4 weeks of treatment 2 weeks of treatment 2 weeks of treatment Trough: 25 – 50mcg/mL Peak: 50 – 100mcg/mL >100mcg/mL associated with bone Primary endpoint: all-cause mortality at day 14 and day 70 marrow toxicity & hepatotoxicity

Lexi-Comp Online. August 2016. Lewis. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011. Perfect et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010. Day et al. Combination antifungal therapy for cryptococcal meningitis. NEJM. 2013.

Combination Amphotericin B deoxycholate with Flucytosine Question #3

Mr. Crypto is starting flucytosine in conjunction with amphotericin B deoxycholate. His creatinine clearance is currently ~30mL/min. Does his flucytosine dose need to be adjusted due to his renal function?

A. Yes B. No AmB + flucytosine versus AmB alone • 14 days: 15 vs 25 deaths (P=0.08) • 70 days: 30 vs 44 deaths (P=0.04)

Combination therapy exhibited mortality benefit got cryptococcal meningitis in patients with HIV

Day et al. Combination antifungal therapy for cryptococcal meningitis. NEJM. 2013.

114 Question #3 History of Systemic Antifungals

Mr. Crypto is starting flucytosine in conjunction with Amphotericin B Micafungin Lipid Complex amphotericin B deoxycholate. His creatinine clearance is Amphotericin B Fluconazole Deoxycholate Amphotericin B Flucytosine currently ~30mL/min. Does his flucytosine dose need to Voriconazole Lipid Complex Isavuconazole be adjusted due to his renal function?

1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s A. Yes B. No Ketoconazole Liposomal Anidulafungin Amphotericin B Itraconazole Caspofungin

History of Azoles Isavuconazole

• Fluconazole first introduced in 1990 Isavuconazole FDA approved - • Lack activity against opportunistic molds and resistance in C. glabrata • Prodrug – Isavuconazonium and C. krusei • Greater water solubility without the need for β-cyclodextrin • Itraconazole (1992) – improved activity for Aspergillus • Oral formulation with improved coverage • Voriconazole (2002) and Posaconazole (2006) provided a broad- spectrum option extending coverage to molds

Fluconazole Itraconazole Voriconazole Posaconazole

Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805-17. Nett & Andes. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am. 2016. Rybak et al. Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent. Pharmacotherapy. 2015.

Mechanism of Action Azole Spectrum

Organism Flu Itr Vor Pos Isa Aspergillus species A. flavus - + + + + A. fumigates - + + + + A. niger - ± + + + A. terreus - + + + + Candida species C. albicans + + + + + C. glabrata ± ± + + + C. krusei - ± + + + C. lusitaniae + + + + + C. parapsilosis + + + + + C. tropicalis + + + + + Cryptococcus species + + + + + Coccidoides species + + + + + Blastomyces + + + + + Histoplasma species + + + + + Fusarium species - ± + + + Scedosporium species - - ± ± + Zygomycetes - - - + + Dodds Ashley, ES, et al. Pharmacology of Systemic Antifungal Agents. CID 2006. Dodds Ashley, ES, et al. Pharmacology of Systemic Antifungal Agents. CID 2006.

115 Dosage Forms & Stability Pharmacokinetics

Flu Itr Vor Pos Isa Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole Bioavailability 95% 50% 96% Formulation 98% dependent Formulations: Formulations: Formulations: Formulations: Formulations: • Intravenous • Capsule • Intravenous • Suspension • Intravenous Good CSF & urine Low CSF & urine Fair CSF No CSF & Low CSF • Tablet • Tablet • Suspension • Tablet • Capsule penetration penetration Low urine Low urine • Oral solution • Oral solution penetration penetration • Tablet Distribution >99% >50% protein >99% protein Compatibility: Capsules: Compatibility: Suspension Compatibility: <10% protein >99% Protein protein bound binding • D5W • Taken with • D5W • Taken with • D5W binding bound binding • NS food • NS meals or • NS Metabolism Hepatic • LR Solution: • LR acidic • Taken beverages Elimination Urine Hepatic Renal Feces Feces & without food Suspension & Urine tablets Oral suspension Renal ≠ Caution with • Taken 1 hour impairment Decreased dose None CrCl<50mL/min None None before or Delayed Release adjustment after meals Tablets Hepatic Decreased dose Avoid in impairment none None with mild-to- None severe hepatic adjustment moderate impairment

Lexi-Comp Online. August 2016. Dodds Ashley, ES, et al. Pharmacology of Systemic Antifungal Agents. CID 2006. Falci & Pasqualotto. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013. Rybak et al. Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent. Pharmacotherapy. 2015.

Safety Drug Interactions

Flu Itr Vor Pos Isa

Hepatotoxicity X X X X - Flu Itr Vor Pos Isa

QTc Inhibitor XX XX- prolongation 2C19 + +++ Hypokalemia - X X X - 2C9 ++ + ++ Nausea & 3A4 ++ +++ ++ +++ Limited XX XXX Vomiting Substrate Data Rash X - X X - 2C19 +++ 2C9 + Negative Visual QTc inotropic effect disturbances shortening 3A4 +++ + Others - (20-25%) - Contraindicated Hallucinations Abdominal in heart failure Photosensitivity pain

Sheehan et al. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999. Sheehan et al. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999. Falci & Pasqualotto. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013. Falci & Pasqualotto. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013.

Differences in Treatment SECURE Study

Treatment with Azole Antifungals Efficacy and safety of Isavuconazole in invasive aspergillosis Fluconazole Candidemia (not C. IV: 800mg x 1 day krusei or C. glabrata) 400mg daily for 14 days Randomized 1:1

Itraconazole Histoplasmosis Oral: 200mg daily up to Isavunconazonium sulfate 372mg Voriconazole 6mg/kg 400mg daily (isavuconazole 200mg) • Twice daily IV day 1 • Three times daily IV on day 1 & 2 • Then 4mg/kg IV twice daily on day 2 Voriconazole Aspergillosis IV: 6mg/kg every 12 hours x 2 • Then once daily oral or IV • Then 4mg/kg IV or 200mg orally 4mg/kg every 12 hours twice daily

Posaconazole Mucormycosis Oral: 800mg daily in 2 or 4 divided doses Primary endpoint: all-cause mortality from first dose to day 42 • 10% non-inferiority margin Isavuconazole Aspergillosis or IV/Oral: 372mg every 8 hours Mucormycosis for 6 hours then 372mg once Safety assessed in patients receiving the first dose of study drug daily

Sheehan et al. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999. Maertens et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a Falci & Pasqualotto. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013. phase 3, randomized-controlled non-inferiority trial. The Lancet, 2016.

116 SECURE Study SECURE Study

Safety endpoint • Significantly less hepatobiliary, eye disorders, & skin disorders in the voriconazole group

Isavuconazole was non-inferior to voriconazole for the primary endpoint of all-cause mortality with fewer adverse effects.

All cause mortality in the intention-to-treat group Isavuconazole 19% versus Voriconazole 20% (p=0.744)

Maertens et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a Maertens et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomized-controlled non-inferiority trial. The Lancet, 2016. phase 3, randomized-controlled non-inferiority trial. The Lancet, 2016.

Question #4 Question #4

What unique adverse drug reaction occurs with voriconazole What unique adverse drug reaction occurs with voriconazole and not other azole antifungals? and not other azole antifungals?

A. Hepatotoxicity A. Hepatotoxicity B. QTc prolongation B. QTc prolongation C. Rash C. Rash D. Visual disturbances D. Visual disturbances

History of Systemic Antifungals Echinocandins: New Kids on the Block

• First echinocandin, caspofungin, released in 2001 Amphotericin B Micafungin • Lipopetides derived from various fungi: Amphotericin B Fluconazole Lipid Complex Deoxycholate Amphotericin B • Anidulafungin - Aspergillus nidulans Flucytosine Voriconazole Isavuconazole Colloidal Dispersion • Caspofungin - Glarea lozoyenisi • Micafungin - Coleophoma empedri

1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s

Ketoconazole Liposomal Anidulafungin Amphotericin B Itraconazole Caspofungin Anidulafungin Micafungin

Caspofungin Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Cappelletty & Eiselstei-Mckitrick. The echinocandins. Pharmacotherapy. 2007.

117 Mechanism of Action Echinocandin Spectrum

Organism Ani Caspo Mica Aspergillus species + + + • Fungicidal activity Candida species C. albicans + + + against yeast C. glabrata + + + • Highly active C. krusei + + + against C. lusitaniae + + + C. parapsilosis ± ± ± • C. albicans C. tropicalis + + + • C. glabrata Cryptococcus species - - - • C. tropicalis Coccidoides species ± ± ± • C. krusei Blastomyces ± ± ± • Less active against Histoplasma species ± ± ± • C. parapsilosis Fusarium species - - - • C. lusitaniae Scedosporium species - - - Zygomycetes - - -

Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Cappelletty & Eiselstei-Mckitrick. The echinocandins. Pharmacotherapy. 2007.

Candida glabrata Resistance Dosage Forms & Stability

• One third of all candidemia cases in the United States • Intrinsic resistance to azole antifungals • Echinocandins are treatment of choice Anidulafungin Caspofungin Micafungin

Resistance mechanism: FKS mutation Formulation: Intravenous Formulation: Intravenous Formulation: Intravenous

Compatible Solutions: Compatible Solutions: Compatible Solutions: • D5W • Lactated Ringers • D5W • NS • NS • NS

Stable at room Stable at room Stable at room temperature for 48 hours temperature for 24 hours temperature for 48 hours or refrigerated for Protect from light 48 hours

Vallabhaneni et al. Epidemiology and risk factors for echinocandin nonsusceptible candida glabrata bloodstream infections: data from a large multisite population- based candidemia surveillance program, 2008-2014. Open Forum Infect Dis. 2015. Beyda et al. FKS mutant candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 2014. Lexi-Comp Online. August 2016.

Pharmacokinetics Safety Concerns

Anidulafungin Caspofungin Micafungin • Echinocandins generally have a low side effect profile and are generally well tolerated Bioavailability <5% <5% <5%

Little CSF & urine penetration Adverse Drug Reactions from Echinocandins (%) Distribution Highly protein bound Anidulafungin Caspofungin Micafungin Metabolism None Hepatic Hepatic Phlebitis < 1 3.5 – 25 1.6 Elimination Feces Urine Feces Abdominal Pain < 2 3.6 1 Renal Diarrhea 3.1 3.6 1.6 impairment None Leukopenia < 1 6.2 1.6 adjustment Thrombocytopenia < 2 3.1 < 1 Hepatic Decrease for Hypokalemia 3–10 1–15 1 –8 impairment None None moderate Abnormal liver adjustment 3 –5 1 –15 1 –8 function tests

Dodds Ashley et al. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006. Cappelletty & Eiselstei-Mckitrick. The echinocandins. Pharmacotherapy. 2007.

118 Treatment with Echinocandins Fluconazole versus Anidulafungin

• Approved indication invasive candidiasis Methods: • Used as an alternative for invasive aspergillosis in HIV-infected patients • Patients were stratified based on APACHE II score and absolute neutrophil count Treatment Anidulafungin Caspofungin Micafungin length Randomized 1:1 Fluconazole 800mg x 1 day, then Anidulafungin 200mg x 1 day, then 200mg x 1 day, 70mg x 1 day, 14 days or longer Candidemia 100mg daily after last positive 400mg daily 100mg daily 100mg daily 50mg daily culture Infection 200mg x 1 day, 70mg x 1 day, 100 – 150mg resolves and Primary Efficacy Endpoint: Aspergillosis 100mg daily 50mg daily daily CD4 count > 200 • Global response at the end of intravenous therapy for cells/mm3 patients with a positive baseline culture

Cappelletty & Eiselstei-Mckitrick. The echinocandins. Pharmacotherapy. 2007. Reboli et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007.

Fluconazole vs Anidulafungin for Invasive Candidiasis

Applying the Information

Anidulafungin was not inferior to and possibly more efficacious than fluconazole for treatment of candidemia

Reboli et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007. Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html

Case Case

WB is admitted to the hospital for fever, malaise, altered mental WB is admitted to the hospital for fever, malaise, altered mental status, with suspected infection. Past medical history includes end- status, with suspected infection. Past medical history includes end- stage renal disease for which she receives hemodialysis. Once stage renal disease for which she receives hemodialysis. Once admitted, blood cultures were obtained and she was started on admitted, blood cultures were obtained and she was started on empiric antimicrobial therapy. As her condition worsened, blood empiric antimicrobial therapy. As her condition worsened, blood cultures resulted positive for Candida glabrata at 5 days. Which is the cultures resulted positive for Candida glabrata at 5 days. Which is the best option to start WB on at this time? best option to start WB on at this time?

1) Fluconazole 800mg IV x 1 dose, then 400mg IV daily 1) Fluconazole 800mg IV x 1 dose, then 400mg IV daily 2) Micafungin 100mg IV daily 2) Micafungin 100mg IV daily 3) Liposomal amphotericin B 5mg/kg/day IV 3) Liposomal amphotericin B 5mg/kg/day IV

119 Conclusion Thank you! Most common invasive infections: • Candidemia • Aspergillosis in HSCT patients

These infections are associated with high rates of mortality and primarily affect the immune compromised

Treatment depends on mycologic and patient specific factors

Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/index.html

References References

1. Centers for Disease Control and Prevention. (2016). Fungal Diseases. Retrieved from 10. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the http://www.cdc.gov/fungal/index.html Management of Candidiasis: 2016 Update by the Infectious Diseases Society of 2. Dodds Ashley ES, Lewis R, Lewis JS, Martin C, Andes D. Pharmacology of systemic America. Clin Infect Dis. 2016;62(4):e1-50. antifungal agents. Clin Infect Dis 2006; 43:S28-39. 11. Patterson TF, Thompson GR, Denning DW, et al. Practice Guidelines for the Diagnosis 3. Vallabhaneni S, Mody RK, Walker T, Chiller T. The global burden of fungal diseases. and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of Infect Dis Clin North Am. 2016;30(1):1-11. America. Clin Infect Dis. 2016. 4. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream 12. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the infection until positive blood culture results are obtained: a potential risk factor for management of patients with histoplasmosis: 2007 update by the Infectious Diseases hospital mortality. Antimicrob Agents Chemother. 2005;49(9):3640-5. Society of America. Clin Infect Dis. 2007;45(7):807-25. 5. Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts 13. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. management of cryptococcal disease: 2010 update by the infectious diseases society 2006;43(1):25-31. of america. Clin Infect Dis. 2010;50(3):291-322. 6. Baum GL. Antifungal therapy, 1978. Postgrad Med J. 1979;55(647):587-92. 14. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291-302. 7. Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; August 20th, 2016 15. Nett JE, Andes DR. Antifungal Agents: Spectrum of activity, pharmacology, and clinical 8. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73(9):919-34. indications. Infect Dis Clin North Am. 2016;30(1):51-83. 16. Rybak JM, Marx KR, Nishimoto AT, Rogers PD. Isavuconazole: Pharmacology, 9. Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805-17. Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacotherapy. 2015;35(11):1037-51.

References

17. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12(1):40-79. 18. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of Antifungal Therapies for severe invasive fungal infections. Infect Drug Resist. 2013;6:163-74. 19. Maertens, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomized-controlled non-inferiority trial. The Lancet, 2016. Systemic Infections 20. Cappelletty D, Eiselstein-mckitrick K. The echinocandins. Pharmacotherapy. 2007;27(3):369-88. 21. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24):2472-82. 22. Vallabhaneni S, Cleveland AA, Farley MM, et al. Epidemiology and Risk Factors for Ashley Trojcak, PharmD Echinocandin Nonsusceptible Candida glabrata Bloodstream Infections: Data From a Large Multisite Population-Based Candidemia Surveillance Program, 2008-2014. PGY-1 Pharmacy Resident Open Forum Infect Dis. 2015;2(4):ofv163. 23. Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW. FKS mutant Candida University Health Shreveport glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 2014;59(6):819-25.

120

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting

4:00—5:00 p.m. Appropriate Use of Antipsychotics in the Inpatient Setting Alyssa Simpson, PharmD PGY1 Pharmacy Resident University Health Shreveport Shreveport, LA

0179-0000-16-033-L01-P/ 0179-0000-16-033-L01-T 1 contact hour (0.1 CEU) Knowledge-based activity

Objectives:

Pharmacists: Technicians: 1. Discuss medications classified as 1. List medications classified as antipsychotics. antipsychotics. 2. Explain adverse drug reactions associated 2. Identify adverse drug reactions associated with antipsychotics. with antipsychotic use. 3. Evaluate appropriateness of antipsychotic 3. Recall appropriate indications for the use of use in the inpatient setting. antipsychotics in the inpatient setting. 4. Recommend drug therapy modifications to decrease the inappropriate use of inpatient antipsychotics.

Dr. Simpson has disclosed that he has no relevant financial relationships.

121

. Discuss medications classified as antipsychotics. . Explain adverse drug reactions associated with antipsychotics. . Evaluate appropriateness of antipsychotic use in the inpatient setting. by Alyssa Simpson, PharmD. . Recommend drug therapy modifications to decrease the inappropriate use of inpatient antipsychotics.

2

.List medications classified as antipsychotics. . 2001 to 2011: 28 million to 54 million annual prescriptions .Identify adverse drug reactions associated . 2007: 1 in 7 nursing home residents had claims for with antipsychotic use. atypical antipsychotics .Recall appropriate indications for the use of . 83% for off‐label indications antipsychotics in the inpatient setting. . 88% for indications specified in the FDA‐warning . 2010: >$16 billion on antipsychotics

3 Use of Antipsychotics. Centers for Medicare & Medicaid Services (CMS). Clinical Quality Measures Draft. 2016. 4 Smith B. Inappropriate Prescribing. American Psychological Association. 2012; 43:6, 36.

Smaller Trial Larger Trial . 17,775 admissions . 300 hospital study . Centers for Medicare & Medicaid Services (CMS) (excluded psych patients) . 2,695,081 admissions . Improve care in those who receive antipsychotics . 9% on antipsychotics in inpatient setting 55% initiations . 6% received antipsychotics . 26% of initiations were . Inappropriate use of antipsychotics in inpatient discharged on these setting medications . Unnecessary continuation of antipsychotics after discharge

Herzig SJ, Rothberg MB, Guess JM, et al. Antipsychotic Use in Hospitalized Adults: Rates, Indications, and Predictors. J Am Geriatr Soc 2016; 64:299–305. Herzig SJ, Rothberg MB, Guess JM, et al., Antipsychotic medication utilization in nonpsychiatric hospitalizations. J Hosp Med 2016; 11: 543–549. 5 Use of Antipsychotics. Centers for Medicare & Medicaid 6 Services (CMS). Clinical Quality Measures Draft. 2016.

122 .Health and safety requirements for hospitals . Measuring inpatient use of antipsychotics

. Gather data and provide to CMS . Including inpatients ≥65 years who received an antipsychotic order .Participation in Medicare/Medicaid . Excluding FDA‐labeled indications and those with .Reimbursement documented indication for risk of harming self or others

7 Use of Antipsychotics. Centers for Medicare & Medicaid 8 Services (CMS). Clinical Quality Measures Draft. 2016.

Conventional (1st Generation) Atypical (2nd Generation) Chlorpromazine Aripiprazole Medications Droperidol Asenapine Fluphenazine Clozapine 9 classified as Haloperidol Iloperidone Loxapine Lurasidone antipsychotics Molindone Olanzapine Perphenazine Paliperidone Pimozide Quetiapine Prochlorperazine Risperidone OBJECTIVE Thioridazine Ziprasidone Thiothixene Trifluoperazine 10

. Diagnosis of dementia .Elderly patients with dementia‐related . 1st gen vs. 2nd gen vs. no antipsychotic psychosis treated with antipsychotic drugs . 2nd gen significantly higher mortality rate than no antipsychotic use are at an increased risk of death . 30 to 180 days after the initial prescription . HR 1.31 in community‐dwelling elderly . HR 1.55 in long‐term‐care elderly

11 Gill SS, Bronskill SE, Normand ST, et al. Antipsychotic Drug Use and Mortality 12 in Older Adults with Dementia. Ann Intern Med. 2007;146:775‐786.

123 . Not for behavioral problems related to dementia .May increase risks of confusion, sleepiness, unless non‐drug or safer drug options are not working and a patient is a threat to self or others blurred vision, difficulty urinating, dry . May increase the chance of stroke and death in mouth, constipation, stroke, and death in people with dementia . May worsen symptoms of Parkinson’s disease people with dementia. and/or cause Parkinson’s‐like symptoms . Not quetiapine, clozapine

AGS Updated Beers Criteria for Potentially Inappropriate 13 AGS Updated Beers Criteria for Potentially Inappropriate 14 Medication Use in Older Adults. J Am Geriatrics Soc 2012. Medication Use in Older Adults. J Am Geriatrics Soc 2012.

Conventional Atypical (1st Generation) (2nd Generation) 15 . Dopamine‐2 antagonists . Serotonin‐2A and Dopamine‐2 antagonists . More extrapyramidal effects . Less extrapyramidal effects . More metabolic effects OBJECTIVE

16

D2 D2 5HT 5HT 5HT Drug D3 5HT7 α1 M1 M3 H1 Receptor Effect Ant PA 1A 2A 2C

D2 Ant Reduced positive symptoms Aripiprazole +++ +++ +++ ++ ++ +++ ++ ++ D2 PA Reduced positive symptoms Reduced positive symptoms; reduced negative symptoms; pro‐cognitive; Olanzapine ++ ++ +++ ++ + ++ ++ ++ +++ D Ant 3 antidepressant

Quetiapine +++* ++* +* ++* +++ ++* ++* +++* 5HT1A Ant Reduced EPS; reduced hyperprolactinemia; antidepressant; anxiolytic 5HT Ant Reduced EPS; reduced hyperprolactinemia Risperidone +++ +++ + ++++ ++ +++ +++ ++ 2A 5HT2C Ant Antidepressant Ziprasidone +++ +++ ++ ++++ ++ +++ ++ ++ Reduced circadian rhythm dysfunction, reduced negative symptoms; pro‐ 5HT Ant 7 cognitive ↓ Benefits ↓ psychosis ↓ EPS ↓ EPS Hypnotic nightmares α1 Ant Reduced nightmares Metabolic effects Hypotx, Anti‐ EPS, sedation Sedation M1 Ant Reduced EPS Side Effects QT prolongation sedation cholinergic M2 Ant Reduced EPS + weak binding affinity (100>Ki<1000) ++ moderate binding affinity (10>Ki<100) H1 Ant Hypnotic +++ strong binding affinity (1>Ki<10) ++++very strong binding affinity (Ki<1) 17 18 *binding due to norquetiapine metabolite Correll CU. Eur Psychiatry 2010;25(Suppl 2):S12‐21. Correll CU. Eur Psychiatry 2010;25(Suppl 2):S12‐21.

124 Receptor Effect EPS; Hyperprolactinemia; increased negative symptoms; increased cognitive D Ant 2 deficits; sedation Antipsychotic Sedation D2 PA Relatively lower EPS risk Aripiprazole Low D3 Ant Unknown

5HT1A Ant Unknown Haloperidol Low

5HT2A Ant Metabolic Risperidone Low 5HT2C Ant Metabolic 5HT Ant Unknown 7 Olanzapine Moderate α1 Ant Dizziness; hypotension; sedation

M1 Ant Constipation; sedation; dry mouth; blurred vision Quetiapine Moderate

M2 Ant Metabolic; constipation; sedation; dry mouth; blurred vision

H1 Ant Metabolic; sedation Ziprasidone Moderate

19 20 Correll CU. Eur Psychiatry 2010;25(Suppl 2):S12‐21. Comparison of Atypical Antipsychotics. Pharmacist's Letter. 2016.

st .Antihistamines –1 generation Diabetes Risk Antipsychotic Weight Gain Dyslipidemia .Hypnotics (↑ BG) Aripiprazole Low Low Low . Anxiolytics Haloperidol Low Low Low .Opioid analgesics Ziprasidone Low Low Low Risperidone Moderate Moderate Low .Barbiturates Quetiapine Moderate Moderate Moderate .Alcohol Olanzapine High High High

21 22 Comparison of Atypical Antipsychotics. Pharmacist's Letter. 2016.

Antipsychotic QTc Prolongation .Chronic use Aripiprazole Low .Weight gain Haloperidol Low .SSRIs Olanzapine Low .Sulfonylureas, thiazolidinediones Risperidone Moderate .Steroids Haloperidol (high dose High .Not ideal for: injection) .Diabetes Quetiapine High .Overweight/obese Ziprasidone Highest

23 24 Comparison of Atypical Antipsychotics. Pharmacist's Letter. 2016.

125 .Average: 380‐450ms .Threshold for potential discontinuation .Prolonged .QT/QTc >500ms .Men: >440 ms .>60ms increase from baseline .Women >460 ms .Sudden death .Clinically, QTc >500 considered prolonged

Fadi T. Khasawneh and Gollapudi S. Shankar, “Minimizing Cardiovascular Adverse Effects of Atypical 25 Fadi T. Khasawneh and Gollapudi S. Shankar, “Minimizing Cardiovascular Adverse Effects of Atypical 26 Antipsychotic Drugs in Patients with Schizophrenia,” Cardiology Research and Practice, 2014. Antipsychotic Drugs in Patients with Schizophrenia,” Cardiology Research and Practice, 2014.

. Congenital long QT syndrome . Antiarrhythmics . Pre‐existing heart disease . Macrolide antibiotics . Ischemia, bradycardia, arrhythmias, CHF . Electrolyte imbalance . Azole antifungals + 2+ 2+ . ↓ K , Ca ,Mg . Serotonin receptor agonists . Female sex . Anti‐malarial agents . Concomitant medication . Tricyclic antidepressants

Fadi T. Khasawneh and Gollapudi S. Shankar, “Minimizing Cardiovascular Adverse Effects of Atypical 27 28 Antipsychotic Drugs in Patients with Schizophrenia,” Cardiology Research and Practice, 2014.

.Delirium guidelines say monitor .No specific recommendation 30 .Not required regularly .Exceptions: .Cardiac risk factors OBJECTIVE .High risk QT‐prolonging agents

Abdelmawla N, Mitchell AJ.Sudden cardiac death and antipsychotics. Part 2: Monitoring and prevention. Adv Psychiatr Treat.2006;12:100–9. Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010. 29

126 .Continuation of home medications for Delirium Dementia chronic conditions . Acute state of . Slowly evident confusion .Initiation for chronic conditions . Changes in memory . Abrupt and intellect .Aggressive behavior in hospitals due to . Days or weeks . Subtle decline delirium and at risk for harming self or others

31 32

. Literature review –19 cohorts . Higher prevalence of delirium

. Used valid measurement tools for delirium . Hospitalized elderly: 10% to 40%

. CAM, DMS III, DSM III‐R, DSM IV . 22%– 76% chance of mortality during the hospitalization . Prevalence on admission: 10% to 31%

. Incidence of development inpatient: 3% to 29%

Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of Patients with Delirium. American Psychiatric Occurrence and outcome of delirium in medical in‐patients: a 33 34 Association Practice Guidelines, 2010. systematic literature review. Age Aging 2006; 35:350–64. Rabins PV, Folstein MF: Delirium and dementia: diagnostic criteria and fatality rates. Br J Psychiatry 1982; 140:149–153

.CNS disorders – degenerative disease .Associated with: .Metabolic disorders .Poor clinical outcomes .Cardiopulmonary disorder – arrhythmias, .Poor quality of life shock, CHF .Cognitive decline .Systemic illness –post‐operative, substance intoxication/withdrawal, infection, sensory .Institutionalization after hospital discharge deprivation, temperature dysregulation .Increase in mortality

Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of 35 Witlox J, Eurelings LS, de Jonghe J, et al. Delirium in elderly patients and the risk of postdischarge 36 Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010. mortality, institutionalization, and dementia: A meta‐analysis. JAMA 2010;304:443–451.

127 .Psychiatric management .Antipsychotics .Identify etiology ‐ think of reversible causes .Many studies comparing haloperidol to .Environmental interventions other first generations or benzodiazepines .Concomitant medications .Limited data for second generation . Discontinue non‐essential meds antipsychotics . Lowest effective dose

Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of 37 Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of 38 Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010. Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010.

.Antipsychotics .Unexplained altered mental status .Severe agitation that poses risk to therapy .Dementia .Risk to self or others .Unusual behavior .Extremely distressing symptoms of .Disruptive behavior that is not harmful psychosis to self or others

Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of 39 40 Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010.

.Therapy should be short‐term (≤1 week) . Aripiprazole: 2 mg once daily . Haloperidol PO: 0.25–0.5 mg daily .Lowest clinical dose, titrate up to response . Haloperidol IM: 2‐5mg once; may repeat in 1 hr .Haloperidol most used –shorter half‐life . Olanzapine: 1.25–5 mg daily .Quetiapine, olanzapine, risperidone also . Quetiapine: 12.5 to 50 mg daily commonly used . Risperidone: 0.25 to 1 mg daily . Ziprasidone: 10 mg IM once; may repeat in 2 hr

Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, et al. American Psychiatric Association practice guideline for Trzepacz P, Breitbart W, Frankin J, et al. Practice Guideline for the Treatment of 41 42 the treatment of patients with Alzheimer's disease and other dementias. Second edition. Am J Psychiatry. 2007;164: 5‐56 Patients with Delirium. American Psychiatric Association Practice Guidelines, 2010.

128 .Quetiapine: shorter duration of delirium . Clinical response rate (Delirium Rating Scale ‐ DRS) compared to placebo in 2 small trials with 78 patients1,2 . 74% with haloperidol 0.25‐10 mg/day (PO or IM) – 243 patients

.No significant differences in rates of delirium . 84% with quetiapine 25‐300 mg/day – 146 patients resolution in 3 trials1‐3 . 78% with risperidone 0.5‐3 mg/day – 170 patients . Antipsychotics vs. placebo . 73% with olanzapine 1.25‐20 mg/day – 255 patients . Haloperidol, ziprasidone, or quetiapine

Friedman JI, Soleimani L, McGonigle DP, et al. Pharmacological treatments of non‐substance‐ 43 Meagher DJ, McLoughlin L, Leonard M, et al. What do we really know about the treatment of delirium with 44 withdrawal delirium: a systematic review of prospective trials. Am J Psychiatry. 2014 Feb;171(2):151‐9. antipsychotics? Ten key issues for delirium pharmacotherapy. Am J Geriatr Psychiatry. 2013 Dec;21(12):1223‐38.

.No significant difference in delirium .Small trial (n=30) prevention post‐operatively .Haloperidol vs. chlorpromazine vs. .Antipsychotics vs. placebo4‐9 lorazepam .Risperidone, haloperidol, olanzapine . Antipsychotics > benzodiazepines .Symptom improvement –DRS

Neufeld KJ, Yue J, Robinson TN, et al. Antipsychotic Medication for Prevention and Treatment of Delirium in Breitbart W, Marotta R, Platt MM, et al. A double‐blind trial of haloperidol, chlorpromazine, and lorazepam 45 46 Hospitalized Adults: A Systematic Review and Meta‐Analysis. J Am Geriatr Soc. 2016 Apr;64(4):705‐14. in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–237.

.No specific recommendations 47 .Therapy >3‐6 months, consider taper .Short‐term –no taper .Withdrawal symptoms: . Agitation, activation, anticholinergic rebound, rebound psychosis OBJECTIVE .Close monitoring

Ramaswamy S, Malik S Dewan V. Tips to manage and prevent 48 discontinuation syndromes. Curr Psych Online. 2005;4(9).

129 .25‐50% weekly reductions .Antipsychotics are overused .Less frequent if tolerating or if indicated .Double check appropriateness .More frequent if closely monitoring .Adverse effects inpatient .Cardiac patients .Diabetic patients

Ramaswamy S, Malik S Dewan V. Tips to manage and prevent 49 50 discontinuation syndromes. Curr Psych Online. 2005;4(9).

.Reviewing medication lists during transitions of care (i.e. care unit to floor) 52 .Discharge medication reconciliation .Assessing appropriateness of antipsychotics . Patient specific factors . Indication .Gradual dose reduction recommendations

51

a. Haloperidol a. Haloperidol b. Clonazepam b. Clonazepam c. Risperidone c. Risperidone d. Clozapine d. Clozapine

53 54

130 a. Decreased appetite a. Decreased appetite b. QT prolongation b. QT prolongation c. Insomnia c. Insomnia d. Skin rash d. Skin rash

55 56

a. No additional treatment a. No additional treatment b. Diazepam 5 mg every 6 hours as needed b. Diazepam 5 mg every 6 hours as needed c. Quetiapine 300 mg twice daily, indefinitely c. Quetiapine 300 mg twice daily, indefinitely d. Haloperidol 2 mg IM, may repeat in 1 hr d. Haloperidol 2 mg IM, may repeat in 1 hr

57 58

. 1Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double‐blind, placebo‐controlled pilot study. Crit Care Med 2010; 38:419–427 . 2Tahir TA, Eeles E, Karapareddy V, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010; 69:485–490 . 3Girard TD, Pandharipande PP, Carson SS, et al. MIND Trial Investigators: Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo‐controlled trial. Crit Care Med 2010; 38:428–437

. 4Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on‐pump cardiac surgery in the elderly: A randomized trial. Anesthesiology 2012;116:987–997.

. 5Kalisvaart KJ, de Jonghe J, Bogaards MJ, et al. Haloperidol prophylaxis for elderly hip‐surgery patients at risk for delirium: A randomized placebo‐controlled study. J Am Geriatr Soc 2005;53:1658–1666. . 6Kaneko T. Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonago Acta Med 1999;42:179–184. . 7Larsen KA, Kelly SE, Stern TA, et al. Administration of olanzapine to prevent postoperative delirium in elderly joint‐ replacement patients: A randomized, controlled trial. Psychosomatics 2010;51:409–418. by Alyssa Simpson, PharmD. . 8Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care 2007;35:714–719. . 9Vochteloo AJ, Moerman S, van der Burg BL, et al. Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high‐risk patients, but does not reduce the incidence of delirium. BMC Geriatr 2011;11:39.

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131 Louisiana Society of Health System Pharmacists 2016 Midyear Meeting NOTES

132

Louisiana Society of Health System Pharmacists 2016 Midyear Meeting NOTES

Thanks for attending the 2016 LSHP Midyear Meeting.

We hope to see you next year!

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