VETERINARY COMPOUNDING: A REGULATORY OVERVIEW AND SAFETY ASSESSMENT

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VETERINARY COMPOUNDING: A REGULATORY OVERVIEW AND SAFETY ASSESSMENT Lauren Eichstadt Forsythe, PharmD, DICVP, FSVHP 2

HOUSEKEEPING Cell Phones Download the Slides Questions No photography, audio, or video recordings https://education.lp3network.com/wcc2018 3

COPYRIGHT/DISCLAIMER DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding, is FOR EDUCATIONAL PURPOSES ONLY and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO MEDICAL OR ALLIED HEALTH PROFESSIONAL: Any treatments, therapies, or standards of practice must be fully investigated and prescribed by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia. 4

ACCREDITATION PHARMACIST & PHARMACY TECHNICIAN CREDITS CPE Consultants, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education and complies with the Accreditation Standards for continuing education activities. Activity Type Pharmacist Pharmacy Technician Pharmacist UAN 0864-9999-18-080-L07-P 0864-9999-18-080-L07-T Credits 1 CPE Hours = 0.1 CEUs 1 CPE Hours = 0.1 CEUs Release Date October 27 th 2018 October 27 th 2018 Expiration Date October 27 th 2019 October 27 th 2019 5

ACCREDITATION HOW TO OBTAIN CREDITS 1 2 3 4 Create your LP3 Account Register for WCC 2018 Workshops Note the Tacking Code at the END OF THE PRESENTATION Submit a completed Evaluation (within 14 days) online for each Workshop. 5 Statement of credits will be provided within 30 days. 6

LAUREN FORSYTHE, PharmD, DICVP, FSVHP Clinical Veterinary pharmacist at the University of California Davis Veterinary Medical Teaching Hospital Completed Doctor of Pharmacy degree at the University of Findlay, College of Pharmacy Completed a residency in Veterinary Pharmacy at the Purdue Veterinary Teaching Hospital Associate editor of Plumb s Veterinary Drug Handbook Research interests include behavioral therapy in cats and safety and efficacy of compounded products for veterinary patients. Disclosure: Associate Editor, Plumb s Veterinary Drug Handbook. 7

LEARNING OBJECTIVES PHARMACISTS 1. Explain when compounding is appropriate for animal patients. 2. Identify appropriate ingredients for use in veterinary compounds. 3. Review potential pitfalls with medications commonly compounded for veterinary patients. 4. Consider ways to improve veterinarian-pharmacist relationships. 8

LEARNING OBJECTIVES PHARMACY TECHNICIANS 1. Explain when compounding is appropriate for animal patients. 2. Identify appropriate ingredients for use in veterinary compounds. 3. Review potential pitfalls with medications commonly compounded for veterinary patients. 4. Consider ways to improve veterinarian-pharmacist relationships. 9

OUTLINE Compounding regulations What do the studies say? How do we respond to studies? Safety concerns and toxicities Transdermal medications Working with veterinarians 10

COMPOUNDING REGULATIONS: Strict legal framework or wild west? 11

REGULATORY TIMELINE AMDUCA Legalized ELDU in certain situations 1994 1968 FD&C Act Amended to include veterinary medications 2013 DQSA Addressed office use for humans Separate pharmacy categories 12

FOOD, DRUG, AND COSMETIC ACT (FD&C) Established requirement of safety for human medications in 1938 Amended in 1968 to include veterinary medications Drugs were unsafe unless FDA approved All ELDU became illegal 1968 FD&C Act Amended to include veterinary medications 13

FOOD, DRUG, AND COSMETIC ACT (FD&C) Note to Self: Only Use Drugs Per Label Species Indication Route Dose Frequency Duration 1968 FD&C Act Amended to include veterinary medications 13

ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT (AMDUCA) Legalized Extra-label drug use (ELDU) in certain situations Legalized compounding but not from bulk chemicals Food animal and non-food animal algorithms AMDUCA Legalized ELDU in certain situations 1994 15

FOOD ANIMALS Drug used as labeled ELDU prohibited for certain medications! Food animal drug used extra Extended withdrawal time Non-food animal or human drug used extra-label Compound AMDUCA Legalized ELDU in certain situations 1994 16

NON-FOOD ANIMALS Cost is NOT a valid reason Compound Drug used as labeled or identical human drug Cost is a valid reason Human or animal drug used extralabel AMDUCA Legalized ELDU in certain situations 1994 17

PERFORMANCE ANIMALS Legal to compound for performance animals Caution when compounding because of drug testing If compound contains more than stated on the label, a positive drug test may occur 18

DRUG QUALITY AND SECURITY ACT (DQSA) Created in response to Meningitis outbreak Created 503B/outsourcing facilities Office use compounds can only come from 503B pharmacies Excludes animal patients! 2013 DQSA Addressed office use for humans Separate pharmacy categories 19

DQSA PHARMACY 503A PHARMACY Traditional compounding pharmacy Patient-specific prescriptions Follows USP Non-sterile and sterile compounding Overseen by State Board of Pharmacy 503B PHARMACY Outsourcing facility Non-patient specific Follows cgmp Sterile compounding Overseen by FDA 2013 DQSA Addressed office use for humans Separate pharmacy categories 20

COMPOUNDING FROM BULK CHEMICALS FDA maintains that this is illegal Certain compounds require the use of bulk chemicals Dosage forms adversely affected by excipients Drugs non-commercially available Drug shortages 21

COMPOUNDING FROM BULK CHEMICALS FDA maintains that this is illegal Certain compounds require the use of bulk chemicals Dosage forms adversely affected by excipients Drugs non-commercially available Drug shortages 22

CPG 608.400 Developed shortly after AMDUCA Modified in early 2000s Obsolete in May 2015 Draft GFI #230 Released May 2015 Comment period Removed November 2017??? 23

OFFICE USE Compounding regulated by the states Office-use compounding questions arise AVMA website summarizes state requirements AVMA supports dispensing a 120 hours supply 2 2012-2013 meningitis outbreak Drug Quality and Security Act (DQSA) gave FDA more oversight 24

Does USP <800> Apply to Veterinary Compounding? Yes! All USP <800> requirements for handling hazardous drugs apply regardless of whether compounding for humans or animals Veterinary drugs are not considered for NIOSH inclusion must consider whether they are similar to NIOSH drugs and therefore, warrant inclusion. 25

CANADIAN SPECIFICS Approved veterinary drug (DIN): Label instructions Approved veterinary drug (DIN): Extra-label drug use (ELDU) Approved human drug (DIN): ELDU Compounding product: From approved drug: ELDU Compounded product: From API: ELDU 26

CANADIAN SPECIFICS Compounders must report annual sales data for all medically important antimicrobials (List A) sold for veterinary use. Data collected throughout 2018 Reported between January 1 and March 31, 2019 List A: https://www.canada.ca/en/public-health/services/antibiotic-antimicrobialresistance/animals/veterinary-antimicrobial-sales-reporting/list-a.html Additional information: https://www.canada.ca/en/public-health/services/antibiotic-antimicrobialresistance/animals/veterinary-antimicrobial-sales-reporting.html 27

AUSTRALIAN SPECIFICS 28

AUSTRALIAN SPECIFICS Excerpt from the AVA Guidelines to the preparation and use of compounded pharmaceuticals choosing a compounded medication over an available registered product on the basis of price along should only occur where: 1. The veterinarian has recommended the registered product in the first instance, making no mention of the cheaper compounded alternative. Versus 2. The patient s animal owner has then refused treatment with the registered product on the basis of price; and 3. The veterinarian has then clearly confirmed that the sole or dominant reason for the owner s refusal is that the registered product is not affordable for that owner on that occasion Australian Journal of Pharmacy Online Version published 1 st of March 2017 29

WHAT DO THE STUDIES SAY? 30

EXPERIMENTAL FINDINGS CONCENTRATION Burton, et al. 2016: Potency of lomustine capsules from 5 pharmacies found to range from 50-115% with only one being within +/- 10% Burton, et al. 2017: Chemotherapy agents from five pharmacies 71-104% variation for chlorambucil 58-109% variation for melphalan 92-107% variation for cyclophosphamide 31

EXPERIMENTAL FINDINGS STABILITY Papich, et al. 2013: Doxycycline suspension lacked stability after 7 days 32

EXPERIMENTAL FINDINGS EFFICACY Cook, et al. 2012: Trilostane dissolution in compounded products was lower than with commercial Mawby, et al. 2014 and 2018: Compounded itraconazole is not as effective as commercially available itraconazole for dogs and cats Merritt, et al. 2003 and Nieto, et al. 2002: Compounded omeprazole paste is not as effective as the commercial product for horses Pimobendan?? 33

HOW DO WE RESPOND TO STUDIES? 34

SUPPORTING EVIDENCE Base compounds on studies showing efficacy Have references on hand specific to veterinary safety and efficacy Use conservative beyond-use dates 35

STABILITY STUDIES Can be used to extend the BUD beyond USP guidelines Must be performed using a validated method with forced degradation Allows the analyte and degradant(s) to be fully resolved on HPLC Much more expensive than strength over time studies Published stability studies and USP monographs can be used Putting medications into oil can extend the BUD legally, but may not be a good idea clinically 36

POTENCY OF A SINGLE ANALYTE 6 37

FULLY RESOLVED PEAKS STABILITY INDICATING 6 38

SAFETY CONCERNS and TOXICITIES 39

CANINE COMPANIONS Limited acetylation ABCB1 (MDR1) Mutation Ivermectin Acepromazine Butorphanol Loperamide Erythromycin NSAIDs Isoniazid Sulfonamides Hydralazine Efficient Bile Excretors Estrogen (estriol) Opportunistic Gorgers 40

FICKLE FELINES Lack/poorly express UDP-glucouronyl transferase isoforms No glucuronide conjugation/ poor conjugation -OH -COOH -NH 2 -NH -SH Limited demethylation Primidone Chloramphenicol Acetaminophen Phenozypyridine NSAIDs Plant-derived medications Limited hydroxylation Phenytoin Barbiturates Warfarin Finicky picnickers Grooming 41

XYLITOL Toxic threshold: 100 mg/kg for dogs Symptoms: Vomiting, hypoglycemia, loss of appetite Concerns: hyperinsulinemia and hepatic necrosis Products to watch for: Oral suspensions, ODT tablets, gum, low carb products, toothpaste, dental rinses Amount in product not required to be listed 42

POLYSORBATE 80 (TWEEN 80) Solubilizing agent Non-immune anaphylactic reaction due to histamine release and complement cascade activation Well documented post IV administration; unclear post PO 43

AZO DYES Metabolized to 2 toxic products rhabdomyolysis, kidney damage, methemoglobinemia, hepatotoxicity, and death Use vitamins (i.e. cyanocobalamin) instead 44

BENZENE RINGS Toxic Threshold: 200 mg/kg/day Symptoms: ataxia, blindness, aggression, coma, convulsions, respiratory failure Products to watch for: Benzyl alcohol and benzoic acid Metronidazole benzoate??? Glucuronide Conjugate Benzyl Alcohol Benzoic Acid Glycine Conjugate 45

THE METRONIDAZOLE QUESTION Metronidazole approved in US as HCl salt BAD taste! Metronidazole benzoate: 16 48 mg/kg q12 to 24 hours Toxic dose: 200 mg/kg/day toxicity unlikely Normal hepatic and renal function 46

TRANSDERMAL MEDICATIONS 47

ADVANTAGES Reduction of first pass metabolism Non-invasive Avoid gastric route Decreased degradation Decreased gastric irritation Improved owner compliance 48

DISADVANTAGES Unknown bioavailability Potential variability between dose and response between individuals Potential for adverse reactions from vehicle Unknown long-term stability of formulation 49

EVIDENCE OF DRUG ABSORPTION Measurable blood levels of the drug Detectable excretion of the drug and/or its metabolites in the urine Clinical response of the patient to the therapy 50

AVAILABLE RESEARCH Amitriptyline Amlodipine Atenolol Buspirone Cyclosporine Dexamethasone Enrofloxacin Fluoxetine Glipizide Methimazole Mirtazapine commercially available Ondansetron Phenobarbital Theophylline 51

DRUGS TO AVOID Drug Class Reason to Avoid Antibiotics Cytotoxic medications Photosensitizing agents Diagnostic agents Medications exerting their effect in the GI tract Medications toxic to humans Prodrugs metabolized by gut enzymes Medications requiring dosages > 25mg Likely to lead to resistance and lack of efficacy due to low blood levels Unnecessary risk to caregiver and likely to cause damage to the ear Exposure to sunlight (outside or through a window) may cause irritation Unpredictable absorption will affect test results Medication will not reach site of action Unnecessary risk to caregiver Medication will not be metabolized to active form Maximal absorption based on surface area of the ear is 25mg 52

DRUGS TO USE CAUTIOUSLY Drug Class Reason to Avoid Corticosteroids Irritating medications Narrow therapeutic index Likely to cause cartilage atrophy if used long term May cause irritation to the ear Unpredictable absorption may lead to ineffective or toxic drug levels 53

WORKING WITH VETERINARIANS 54

LAUREN S TOP 10 LIST 1. Call with questions/ Don t assume 2. Provide studies to support formulations 3. Stand firm on formulations that are not a good idea clinically (i.e. transdermal antibiotics) 4. Have a veterinary reference handy 5. Take time to explain why you can t do something (i.e. legal, safety, efficacy, etc.) 55

LAUREN S TOP 10 LIST 6. Develop relationships with local vet clinics 7. Provide options/suggest dosage forms for difficult patients 8. If requested formulation doesn t work, suggest other options 9. Think outside the box, but stay within the law and efficacy evidence 10.Develop a network of resources that you can call upon with questions. 56

REFERENCES 1. Burton, J.H., Stanley, S.D., Knych, H.K., et al. J Vet Intern Med 2016;30(1):242-6. 2. Burton, J.H., Kynch, H.K., Stanley, S.D., et al. Vet Comp Oncol 2017:1-6 3. Papich, M.G., Davidson, G.S., Fortier, L.A. JAVMA 2013;242(12):1674-1678. 4. Merritt, A.M., et al. Equine Vet J 2003;35(7):691-695. 5. Nieto, J.E., et al. JAVMA 2002;221(8):1139-43. 6. USP Compounding Expert Committee, et al. Strength and Stability Testing for Compounded Preparations. Published 13 Jan 2014. 7. Davidson, G. To benzoate or not to benzoate: cats are the question. IJPC; 5(2): 89-90 8. Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract. 2013;43(5):1039-54. 9. Rost, E. What lies beneath: potentially harmful excipients to avoid when compounding for small animals a note of caution. IJPC; 20(6): 526-7. 10. Peterson, M.E. Topical Review: Xylitol. Topics in Compan An Med; 28: 18-20. 57

Lauren Eichstadt Forsythe, PharmD, DICVP, FSVHP UC Davis Veterinary Medical Teaching Hospital Leichstadt@ucdavis.edu 58

TRACKING CODE WCC2018VET 59

THANK YOU FOR LISTENING ANY QUESTIONS? 60