The Script The Script Spring 2015, Issue 6 A Publication of the Department of Pharmacy, Norman Regional Health System

Vitamin K Route of Administration for Warfarin Reversal By Elizabeth Rathgeber, Pharm.D., Samantha Sepulveda, Pharm.D., Lysse Vadder, Pharm.D. In This Issue: Warfarin is an anticoagulant that works by inhibiting the synthesis of vitamin K-dependent clotting factors. Excessive anticoagulation can lead to an elevated international normalized ratio (INR), increasing the risk of bleeding complications. Vitamin K Route of Administration Phytonadione (vitamin K1) is used to reverse the effects of warfarin by promoting synthesis of for Reversal of Warfarin ...... 1 clotting factors. Vitamin K is available for several routes of administration: oral (PO), intravenous (IV), subcutaneous (SC), and intramuscular (IM). The low-dose (1 to 2.5 mg) PO formulation should The 2014-2015 NRHS be used in patients not requiring urgent reversal, which takes approximately 1.4 days for the INR to Pharmacy Residents ...... 2 reach less than 4.0 if the INR is between 6 and 10. Vitamin K 5 mg PO and 1 mg IV produce similar effects at twenty-four hours after administration.1 Higher doses of vitamin K can lead to warfarin Pharmacy and Therapeutics resistance and thrombosis. The IV route works more rapidly than PO or SC administration with INR Committee Update...... 2 reduction beginning within 2 hours and full correction occurring within 24 hours. However, IV Humulin® R U-500 (Concentrated) administration has been associated with a small risk of anaphylactic reactions and is not 2 Added to NRHS Formulary ...... 3 recommended unless another route is not feasible and the increased risk involved is justified. The SC route is less effective and less predictable than oral and the intravenous formulations. Critical Medication Shortages . . . . . 3 Studies have shown less than 50% of patients with an INR greater than 4.0, but less than 10.0 will achieve an INR between 1.8 and 4.0 within 24 hours after SC administration of vitamin K.3 Prevention and Treatment of Intramuscular phytonadione administration is not recommended due to the risk of developing Extravasation ...... 4 hematomas. For this reason, SC administration is preferred over IM if parenteral therapy is required.4 Choosing the appropriate route of administration for vitamin K depends on several factors. While We welcome your thoughts, SC administration has been associated with less anaphylaxis, it has also shown less efficacy and comments and/or suggestions. predictability, when compared to IV vitamin K. Intravenous vitamin K has the quickest onset, but is associated with increased risk of anaphylaxis, thus should only be used if the risk is justified. Due to Do you have an idea for a story? Is there erratic absorption and risk for hematomas, IM administration of vitamin K should be avoided. Oral information we can provide you? is the preferred route of administration for non-urgent reversal of vitamin K antagonists due to its predictable pharmacokinetics according to the American College of Chest Physicians (ACCP) All correspondence concerning guidelines. The Script should be sent to: ACCP Recommendations for Vitamin K Administration5 INR Management Lisa Mayer, Pharm.D., BCPS 901 N Porter Ave., Box 1308 4.5 to 10.0, ! Hold warfarin Norman, OK 73070 without bleeding ! Recommend against routine use of vitamin K [email protected] ! Hold warfarin and give vitamin K PO (2 and 2.5 mg doses only studied > 10.0, and demonstrated low rates of major bleeding) without bleeding ! Allow 24-48 hours for INR reduction ! Hold warfarin and give vitamin K 5 to 10 mg IV Serious bleed, ! Administer Factor IX complex concentrate (four-factor PCC) any elevated INR ! May repeat vitamin K after 12 hours References 1. Ageno W, Gallus AS, Wittkowsky A, et al. Oral Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e44s–e88S. 2. Product information. Phytonadione Injectable Emulsion. So. El Monte, CA: Amphastar Pharmaceuticals Company, 2013. 3. Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation 2012;125:2944-7. 4. Kearney TE. Vitamin K1 (phytonadione). In: Olson KR, ed. Poisoning and drug overdose. 6th ed. New York, NY: McGraw-Hill, 2012. www.accessmedicine.com. Accessed January 12, 2015. 5. Holbrook A, Schulman S, Witt DM, et al. Evidence-Based Management of Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, (9th ed.) American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST Ansell J, Hirsh J, Hyle KE, et al. Oral Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e44s–e88S.

Spring 2015, Issue 6 The Script

The 2014-2015 NRHS Pharmacy Residents By Kim Whitley, Pharm.D. NRHS offers a year-long accredited Post Graduate Year 1 (PGY1) Pharmacy Residency that begins each year in July and ends in June of the following year. It allows pharmacists to accelerate their growth beyond entry-level competencies, to refine their clinical skills in a broad range of disease states and to provide evidence-based, patient-centered medication therapy. Residents are also cross-trained in distribution activities and can be found staffing at the HealthPlex on Monday through Thursday evenings. The Pharmacy department is proud to announce our pharmacy residents for the 2014-2015 year: Elizabeth Rathgeber, Samantha Sepulveda and Lysse Vadder. All three are 2014 graduates of The University of Oklahoma College of Pharmacy. Elizabeth Rathgeber was born in Alva, OK. Her current pharmacy interests include critical care, internal medicine, pediatrics, diabetes, and especially infectious diseases with a strong focus on HIV pharmacotherapy. After completion of her residency, Elizabeth plans to pursue a clinical pharmacy position in an inpatient setting. Samantha Sepulveda was born in Springfield, MO, raised in the Southwest United States, and moved to Oklahoma City, OK in 2009 from Southern Florida. Her pharmacy interests include internal medicine and infectious disease. She plans to pursue a clinical pharmacy position in a health system upon completion of her residency. Lysse Vadder was born in the town of Helena, located in Northwest Oklahoma. Her pharmacy interests include infectious diseases and gerontology/geriatrics. Upon completion of her residency, Lysse plans to be employed as a clinical pharmacist at Integris Bass Baptist in Enid, OK. She plans to obtain Board Certified Pharmacotherapy Specialist (BCPS) certification upon completion of her residency. Left to right: Elizabeth Rathgeber, Lysse Vadder, and Samantha Sepulveda Each resident undertakes a project during their residency, in which they present their research at local and national pharmacy conferences. Elizabeth’s project involves evaluating the appropriate use of Visipaque® and Omnipaque® in catheterization lab patients, taking into consideration their eGFR and procedure type. Lysse’s project involves reducing adverse drug events associated with opioid use by investigating the effectiveness of our existing protocols and evaluating the use of naloxone. Samantha’s project focuses on evaluation of anticoagulant reversal agents. Please take a moment to congratulate our residents as they conclude their residency! Pharmacy and Therapeutics Committee Update Dosage and Drug Indication Usual Dose P&T Action Strength 100 mg PO once daily prior to the first meal of the Canagliflozin Diabetes mellitus, type 2 - 100 and 300 mg day; may increase to 300 mg once daily (only in Added to formulary (Invokana®) adjunct therapy tablets patients with eGFR ≥60 mL/min/1.73m2) Treatment of diarrhea due Added to formulary – Fidaxomicin to Clostridium difficile 200 mg PO twice daily for 10 days 200 mg tablet restricted to GI and (Dificid®) (CDAD) ID physicians Fluticasone 100 Fluticasone/vilanterol One oral inhalation (fluticasone 100mcg/vilanterol mcg/vilanterol 25 COPD Added to formulary (Breo® Ellipta®) 25 mcg) once daily (maximum dose) mcg powder for inhalation Myelosuppressive Prefilled syringe of 5 mcg/kg/day SC; continue until anticipated nadir Tbo-filgrastim chemotherapy recipients 300 mcg/0.5 mL has passed and neutrophil count has recovered to Added to formulary (Granix®) with nonmyeloid and 480 mcg/0.8 normal range malignancies mL Added to formulary 200 mg tablet and Tedizolid Acute bacterial skin and with restrictions – 200 mg IV/PO once daily for 6 days 200 mg solution (Sivextro®) skin structure infections see Policy Addendum for reconstitution 40700-066.1 300 mg inhaled every 12 hours (do not administer 300 mg/5 mL Tobramycin inhaled Cystic fibrosis < 6 hours apart); administer in repeated cycles of 28 nebulization Added to formulary (Bethkis®) days on drug followed by 28 days off drug solution

2 Spring 2015, Issue 6 The Script

Humulin® R U-500 (Concentrated) Added to NRHS Formulary

U-500 (500 units/mL) regular insulin contains FIVE times as much insulin in 1 mL than standard U-100 (100 units/mL) regular insulin. It is useful in treating patients with insulin resistance (requiring doses of more than 200 units/day) because it allows for large doses of insulin to be given in smaller volumes and less frequently. The onset of action for U-500 regular insulin is 30 minutes, but because of its high concentration it has a l ong duration of action (up to 24 hours following a single subcutaneous dose). Based on its unique pharmacokinetic properties, U-500 regular insulin should be dosed with 2-3 injections per day and NEVER given intravenously. There are several safety issues that arise with the use of U-500 regular insulin. ! Its prolonged duration increases the risk for delayed secondary hypoglycemic reactions that may occur 18-24 hours after injection. ! There are no U-500 insulin syringes available; therefore, patients are usually instructed to take “XX unit marks on a U- 100 syringe” of U-500 regular insulin. This can lead to One vial of Humulin® R U-500 contains as many units of insulin as 10 vials of U-100 problems upon medication reconciliation if that same patient reports “U-500 regular insulin XX units” instead of “XX unit marks” as the dose. All patients who report U-500 regular insulin should be asked: what type of syringe is used at home, how many units per dose and what measurement unit is drawn up for each insulin dose. Good patient interview questions to elicit the desired response include: “How do you administer this at home?” “Can you show me?” ! At NRHS, U-500 regular insulin orders must be written with both the actual units of Humulin® R U-500 and the volume (in mL) to be measured on a TB syringe. (eg. 50 units of U500 regular insulin = 0.1 mL) ! Incomplete orders will require clarification by the pharmacy. ! Patients may NOT use their own U-500 regular insulin. U- 500 regular insulin cannot be stored on the nursing unit to avoid a potential error. ! U-500 regular insulin will be dispensed from pharmacy, pre-drawn in TB syringes with a needle attached. Each dose will need to be demanded from the pharmacy (include FSBS if relevant). ! U-500 regular insulin doses will be hand-delivered to the nursing staff by the pharmacy; nursing may also pick up the doses in the pharmacy. ! U-500 regular insulin doses need to be verified by a second licensed healthcare professional prior to administration.

Critical Medication Shortages By Donna Wilk, CPhT

Medication Action Plan Diltiazem IV Diltiazem drips have been changed back to 100mg/100mL ADD-Vantage bag and loaded back into Pyxis machines. Droperidol IV Out of stock with no release date. Alternatives include: Metoclopramide, Ondansetron, Prochlorperazine, and Scopolamine. Famotidine IV Product is available again and has been loaded back into Pyxis machines. Fomepizole IV Unavailable with a release date of April 2015. We currently have a decent supply on hand at this time. Indigo Carmine IV Unavailable with no release date. Alternatives include: Indocyanine Green, Methylene Blue, and Isosulfan Blue. IV Fluids All plain IV fluid bags (i.e. Normal Saline, Lactated Ringers and Dextrose) are currently available from the manufacturer. Ketorolac IV Product is currently being allocated by the manufacturer with no release date. Pharmacy is able to maintain stock at this time. Unavailable with a release date of April to September 2015. Alternatives include: Ampicillin/Sulbactam IV, Cefepime IV, Piperacillin/ Ceftazidime IV, and Ciprofloxacin IV/PO. Metronidazole is required in addition to one of the above listed alternatives for certain Tazobactam (Zosyn®) IV indications. Unavailable with no release date. Current stock is reserved for use in OR surgery trays, ER, PACU and GYN/C-Section areas. Prochlorperazine IV Alternatives include: Dexamethasone IV, Methylprednisolone IV, Ondansetron IV/PO, and Promethazine IVPB or topical gel. Sincalide IV Product is available again. Pharmacy is mixing IVPB for patient specific doses again, primarily at the Porter campus. Due to a nationwide shortage on Dextrose 70% and Sterile Water used to compound TPNs, we have switched to a premix TPN Components formulation of Clinimix 5/15 and Clinimix 5/15 + Electrolytes for adult TPNs. Baby TPNs are not affected. 3 Prevention and Treatment of Extravasation

By Lisa Mayer, Pharm.D., BCPS, Jerri Cody, Pharm.D., and Fran Esfahani, Pharm.D., BCPS

Extravasation is defined as escape of a drug into the extravascular space by either leakage from a vessel or direct infiltration. While many drugs are irritating upon exposure to the extravascular tissues, extravasation of a vesicant drug can potentially cause tissue damage with severe and/or lasting injury. A vesicant is an agent that produces blisters and causes tissue necrosis if it escapes from the intended venous system. A vesicant drug can be a cytotoxic (chemotherapy) or non-cytotoxic agent. Infiltration differs from extravasation in that the leakage is due to a non-vesicant drug rather than a vesicant drug.

Risk Factors For a Peripheral Vein Risk Factors For a Central Vein ! Obesity ! Catheter migration from vein to tissue ! Multiple previous venipunctures resulting in compromised circulation ! Device misplacement with the catheter tip outside of the venous system ! Disseminated skin disease (e.g. eczema, psoriasis) ! Difficult catheter insertion ! Large gauge cannula relative to vein size ! Long dwell time (six months or longer) ! Small and/or fragile veins AND undesirable cannula sites (e.g. antecubital fossa, ! Presence of a fibrin sheath or thrombus at the catheter tip dorsum of hand or wrist, and areas of joint flexion) ! Deeply implanted port ! Patient movement ! Peripheral neuropathy or another medical condition that impairs a patient’s ability to detect a change in sensation at the site of drug administration Signs and Symptoms Early signs and symptoms of extravasation may include local burning or tingling at the injection site, mild erythema, pruritus and swelling. More extensive extravasations such as necrosis, eschar formation, and ulceration may develop over several weeks. If left untreated, complications can include development of nerve compression syndrome, permanent joint stiffness, contractures and neurologic dysfunction. Prevention of Extravasation ! Infusion sites in order of preference: forearm, dorsum of hand, wrist, antecubital fossae ! Avoid sites with thrombosis, sclerosis or scar formation as well as limbs with impaired circulation ! Avoid previously irradiated areas if possible ! A clear dressing such as Tegaderm should cover the skin entry site to allow for examination ! Educate the patient to notify a healthcare professional immediately if they experience any pain, leaking or changes in sensation at the injection site ! Continuous infusion vesicants or vesicants given for longer than 1 hour should only be administered via a central line Initial Management of Extravasation ! Stop the infusion of the suspected drug. DO NOT flush the line and AVOID applying pressure to the site. ! Elevate the affected extremity ! Notify the physician ! If an antidote is to be administered, DO NOT remove the catheter/needle. It should be left in place to attempt aspiration of the extravasation site and to facilitate antidote administration. ! If an antidote WILL NOT be administered, then remove the catheter/needle after attempted aspiration of the drug from the subcutaneous tissues Treatment of Extravasation Irritant/Vesicant drug Non-Pharmacologic Treatment Pharmacologic Treatment* Cytotoxic Drugs Ifosfamide: hyaluronidase. Alkylating Agents (Irritants) - Cyclophosphamide, Dacarbazine, Ifosfamide Apply cold compresses for 20 min QID Cyclophosphamide and Dacarbazine: Sodium thiosulfate 25% Apply cold compresses. Withhold cooling 15 Anthracyclines (Vesicant) - DAUNOrubicin, DOXOrubicin, EPIrubicin, IDArubicin Dexrazoxane min before and after dexrazoxane. Apply cold compresses. *Conflicting Platin Salts (Irrirant) - CARBOplatin, CISplatin, oxaliplatin* information regarding use of warm or cold Sodium thiosulfate 25% compresses for oxaliplatin Conflicting information regarding use of Taxanes (Vesicant) - DOCEtaxel, PACLitaxel Hyaluronidase warm or cold compresses Vinca alkaloids (Vesicant) - vinCRIStine, vinBLAStine, vindesine, vinorelbine Apply warm compresses for 20 min QID. Hyaluronidase Etoposide Use of ice is contraindicated. Non-Cytotoxic Drugs Acidic and Alkaline Agents (amiodarone, acyclovir, conivaptan, doxycycline, Apply warm compresses for 20 min QID Hyaluronidase phenytoin, pentamidine, promethazine, sodium thiopental, vancomycin) 1. Hyaluronidase Hyper-osmolar Agents (ampicillin, Ca2+ solutions, dextrose ≥10%, hypertonic saline, Apply warm or cold compresses for 20 min 2. Sodium thiosulfate 25% mannitol, TPN, K+ solutions, radiocontrast media, sodium bicarbonate) QID 3. NTG paste 2% (preferred for TPN) Hypo-osmolar Agents (aminophylline, nafcillin) Apply warm or cold compresses Hyaluronidase Substances containing Propylene glycol Apply warm or cold compresses for 20 min (diazepam, digoxin, etomidate, lorazepam, nitroglycerin (NTG), phenytoin, Hyaluronidase QID phenobarbital) Vasopressors 1. NTG paste 2% (DOBUTamine, DOPamine, EPINEPHrine, norepinephrine, phenylephrine, Apply warm compresses for 20 min QID 2. NTG patch 0.5 mg/hr vasopressin) 3. Terbutaline *Consult Lexi-comp or another drug information resource for preparation and dosage of pharmacologic treatment; a laminated reference chart will soon be posted in the medication rooms Editor in Chief: Contributors: Lisa(A Mayer, Pharm.D., BCPS Jerri Cody, Pharm.D. Fran Esfahani, Pharm.D., BCPS Elizabeth Rathgeber, Pharm.D. Samantha Sepulveda, Pharm.D. Lysse Vadder, Pharm.D. Kim Whitley, Pharm.D. Donna Wilk, CPhT Clinical Pharmacy Specialist Clinical/Staff Pharmacist Clinical Pharmacy Specialist PGY1 Pharmacy Resident PGY1 Pharmacy Resident PGY1 Pharmacy Resident Clinical/Staff Pharmacist Clinical Pharmacy Technician

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