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Compounded drugs—A literature update

Veterinarians face a myriad of challenges when balancing optimal treatment protocols and overall cost burden

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In exciting times of new approved drug formulations for animal species, veterinarians face a myriad of challenges when balancing optimal treatment protocols and overall cost burden. Compounded drugs may offer an enticing alternative to an approved animal drug in terms of palatability and cost to the owner; however, the legal status of compounded drugs is often difficult to evaluate.

Compounding rules and regulations vary on a state-by-state basis, and the U.S. Food and Drug Administration (FDA) is in the process of developing a new draft guidance regarding animal drug compounding.1 Recently, there has been a spate of publications in the veterinary literature assessing a variety of compounded drugs intended for animal use and the impact compounding has on a drug’s bioavailability.

The FDA defines compounding as “generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.”2 It is important to clarify the definition of compounding does not include the actual preparation of a drug by mixing that is in accordance with the manufacturer’s instructions on an approved drug product.

Legal status?

Compounded drugs are not subject to the same rigorous review of safety and efficacy studies as drugs approved for animal use. There also is no legal requirement mandating that compounded drugs demonstrate their product’s strength as described on the product label.3 While the compounding world may be fraught with limited oversight and the potential for treatment failures, compounded drugs play an essential role in several veterinary scenarios.

Cisapride, a prokinetic drug used for gastrointestinal motility disorders, was withdrawn from the human market in 2000 due to safety concerns. However, cisapride is a valuable prokinetic option for veterinary patients, especially for cats with colonic motility disorders. Currently, veterinarians must rely on compounded cisapride preparations due to lack of an approved animal product. The same reliance on compounded formulation applies to potassium bromide, an anticonvulsant used for treating idiopathic epilepsy in dogs.

While compounded drugs certainly have a place in veterinary medicine, veterinarians must be aware of the potential pitfalls when using an unapproved animal drug; altering drug formulations may lead to catastrophic changes in drug bioavailability, stability, and overall treatment success.

Several recent publications in the veterinary literature analyzed the overall drug content of various compounded medications and reported marked variations from FDA-approved products. These studies provide veterinarians with compelling evidence that may aid in client discussions about the potential risks and benefits of various drug options, as well as insights on drugs that may be inherently unsuitable for compounding due to their physical and chemical characteristics.

Antifungal drugs

Fungal infections pose unique treatment challenges in veterinary species, as the duration of therapy can extend from months to years and patients may relapse after treatment interruptions. The antifungal drugs itraconazole and fluconazole are mainstays when treating systemic fungal infections, and costs for each have fluctuated throughout the years; some products may be cost-prohibitive for months of therapy. Itraconazole is available in an FDA-approved capsule and the new FDA-approved animal drug solution, Itrafungol. Due to absorption differences in the two formulations, the capsules should be given with a meal and the solution can be administered with or without a meal.5 Several studies have investigated compounded itraconazole and reported poor absorption in dogs4 as well as cats.5 Anecdotally, at the author’s institution, a cat was presented to the teaching hospital for a second opinion on poorly responding pulmonary histoplasmosis. The cat was managed on compounded itraconazole following the initial diagnosis; after supportive care in hospital and transition to the FDA-approved itraconazole product, the cat improved clinically and thrived in outpatient care.

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Fluconazole is another commonly prescribed antifungal drug with oscillating costs. A 2017 study by Laporte, et al assessed compounded capsules and suspensions from a cross section of veterinary compounding pharmacies. The authors found discrepancies amongst the various products in terms of drug strength and physical properties, which led to the conclusion that interchanging products between pharmacies (or even within the same pharmacy) could result in treatment failure or toxicity.6

Dermatitis

Cyclosporine is labeled for canine atopic dermatitis (capsules) and feline allergic dermatitis (oral solution); it also represents a crux of treatment for many immune-mediated conditions in both dogs and cats. Cyclosporine is available in a variety of formulations and veterinarians must take heed of the key differences in those preparations due to potential bioavailability implications. The first cyclosporine product on the market was an unmodified formulation in a vegetable oil base (Sandimmune) that had extreme absorption fluctuations from one patient to the next. It is not recommended to use the unmodified version of cyclosporine in veterinary patients. The newer form of cyclosporine is modified, which leads to more predictable drug absorption.7 The modified cyclosporine formulation is available as a human-approved (Neoral) and veterinary-approved (Atopica) drug. One study assessed compounded cyclosporine products and found several drugs labeled as oral solutions were in fact actual suspensions, and the drug strength did not always match the label claims.8 While the study did not draw any conclusions in terms of overt prescribing recommendations, a comprehensive review of cyclosporine7 concluded compounded preparations should not be prescribed “unless no alternative preparations exist that meet the needs of the patient.”

Bacterial infections

Doxycycline is an antimicrobial drug frequently used for the treatment of bacterial infections in dogs and cats. While there are currently three FDA-approved doxycycline formulations on the market (tablets, capsules, and liquid suspension), the solid forms can be cumbersome in smaller patients. A study from Kansas State University9 evaluated the doxycycline content in the various FDA-approved formulations, as well as various compounded doxycycline products from three different national compounding pharmacies. The results demonstrated the most reliable compounded doxycycline product was the tablet formulation; however, the authors cautioned that splitting the scored tablets led to wide swings in overall drug content and thus the practice should be strongly discouraged for veterinary patients.9 Additionally, the compounded liquid doxycycline products did not have drug content matching the label throughout the duration of the three-week study; thus, the authors advise that if a liquid formulation best fits the patient’s need, the FDA-approved product is recommended.9

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Hyperadrenocorticism

Medical management of canine hyperadrenocorticism can be frustrating and costly for owners, as some dogs require frequent dose adjustments before their clinical signs are controlled. Trilostane is the only FDA-approved drug for treatment of both pituitary-dependent and adrenal-dependent canine hyperadrenocorticism. Numerous capsule strengths range from 5 mg to 120 mg, and there has been much debate as to the optimal trilostane treatment protocol. Regardless of the treatment protocol, the most important aspect guiding trilostane treatment decisions is the dog’s clinical signs; any aberration in the underlying drug may impact overall clinical control. Cook, et al examined several batches of compounded trilostane products from a sampling of national compounding pharmacies and discovered extreme variability in the drug content.10 As hyperadrenocorticism is a complex entity in which owner-perceived changes in clinical signs hold great weight, substituting the FDA-approved product for compounded trilostane products may put a delicate clinical balance into a sudden deviation.

Neoplasia

Lomustine is an alkylating agent often used in chemotherapy protocols for various neoplastic diseases. It has a narrow therapeutic index, and potential adverse effects include bone marrow suppression and significant hepatotoxicity. Neutropenia is an anticipated effect and thus, veterinarians routinely monitor complete blood counts at various intervals for patients on lomustine therapy. After a drug discontinuation affected the lomustine supply at a veterinary teaching hospital, oncologists turned to compounded lomustine to continue chemotherapy protocols for their patients. Remarkably, only 25 percent of the patients on the compounded lomustine became neutropenic, as compared to the 100 percent of the patients that were neutropenic after treatment with the FDA-approved product. Additional investigation into the strength of the compounded lomustine revealed marked differences in actual drug concentration with respect to label concentration.11 A recent study interrogating the lomustine content of various compounded formulations concluded the compounded preparations “frequently did not contain the stated content of the active drug.”12

Compounded drugs certainly have a place within veterinary medicine to address specific patient needs and provide alternative therapeutics during drug shortages. However, it is incumbent on veterinarians to consider carefully the risks and benefits of compounded drugs, especially when an FDA-approved formulation already exists. The burgeoning growth of veterinary literature assessing various compounded drug preparations offers veterinarians a source of evidence when confronting difficult client conversations. There is not a simple right or wrong way to approach the vast complexities of the compounded drug discussion and potential patient implications. Rather, it is an ever-evolving topic awaiting additional FDA clarification.

References
1 “FDA Announces Withdrawal Of Draft Guidance For Industry #230 Regarding Animal Drug Compounding”. 2018. Fda.Gov. https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm580525.htm.

2 “Human Drug Compounding”. 2018. Fda.Gov. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/default.htm.
3 Davidson, Gigi. 2017. “Veterinary Compounding: Regulation, Challenges, And Resources”. Pharmaceutics 9 (4): 5. doi:10.3390/pharmaceutics9010005.
4 Mawby, D.I., J.C. Whittemore, S. Genger, and M.G. Papich. 2013. “Bioequivalence Of Orally Administered Generic, Compounded, And Innovator-Formulated Itraconazole In Healthy Dogs”. Journal Of Veterinary Internal Medicine 28 (1): 72-77. doi:10.1111/jvim.12219.
5 Mawby, Dianne I., Jacqueline C. Whittemore, Leanne E. Fowler, and Mark G. Papich. 2018. “Comparison Of Absorption Characteristics Of Oral Reference And Compounded Itraconazole Formulations In Healthy Cats”. Journal Of The American Veterinary Medical Association252 (2): 195-200. doi:10.2460/javma.252.2.195.
6 Laporte, Carine M., Crisanta Cruz-Espindola, Kamoltip Thungrat, Anthea E. Schick, Thomas P. Lewis, and Dawn M. Boothe. 2017. “Quality Assessment Of Fluconazole Capsules And Oral Suspensions Compounded By Pharmacies Located In The United States”. American Journal Of Veterinary Research 78 (4): 421-432. doi:10.2460/ajvr.78.4.421.
7 Archer, T.M., D.M. Boothe, V.C. Langston, C.L. Fellman, K.V. Lunsford, and A.J. Mackin. 2013. “Oral Cyclosporine Treatment In Dogs: A Review Of The Literature”. Journal Of Veterinary Internal Medicine 28 (1): 1-20. doi:10.1111/jvim.12265.
8 Umstead, Meghan E., Dawn M. Boothe, Crisanta Cruz-Espindola, John M. MacDonald, Robert Kennis, and Donna Angarano. 2012. “Accuracy And Precision Of Compounded Ciclosporin Capsules And Solution”. Veterinary Dermatology 23 (5): 431-e82. doi:10.1111/j.1365-3164.2012.01078.x.
9 KuKanich, Kate, Butch KuKanich, Tanner Slead, and Matt Warner. 2017. “Evaluation Of Drug Content (Potency) For Compounded And FDA–Approved Formulations Of Doxycycline On Receipt And After 21 Days Of Storage”. Journal Of The American Veterinary Medical Association 251 (7): 835-842. doi:10.2460/javma.251.7.835.
10 Cook, Audrey K., Cornelia D. Nieuwoudt, and Susan L. Longhofer. 2012. “Pharmaceutical Evaluation Of Compounded Trilostane Products”. Journal Of The American Animal Hospital Association 48 (4): 228-233. doi:10.5326/jaaha-ms-5763.
11 Burton, J.H., S.D. Stanley, H.K. Knych, C.O. Rodriguez, K.A. Skorupski, and R.B. Rebhun. 2015. “Frequency And Severity Of Neutropenia Associated With Food And Drug Administration Approved And Compounded Formulations Of Lomustine In Dogs With Cancer”. Journal Of Veterinary Internal Medicine 30 (1): 242-246. doi:10.1111/jvim.13805.
12 KuKanich, Butch, Matt Warner, and Kevin Hahn. 2017. “Analysis Of Lomustine Drug Content In FDA-Approved And Compounded Lomustine Capsules”. Journal Of The American Veterinary Medical Association 250 (3): 322-326. doi:10.2460/javma.250.3.322.

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Carly A. Patterson, DVM, DACVIM (SAIM), holds a bachelor of science from Cornell University. She received her doctor of veterinary medicine degree from the University of Illinois at Urbana-Champaign in 2011. Dr. Patterson completed her small-animal rotating internship and small-animal internal medicine residency at Texas A&M University and became a Diplomate of the American College of Veterinary Internal Medicine-Small Animal Internal Medicine in 2015. She is currently a clinical assistant professor in the veterinary physiology and pharmacology department at Texas A&M University. In addition to teaching veterinary pharmacology in the second-year DVM curriculum, Patterson facilitates communication training, develops adaptive case-based learning, and serves as a senior clinician in the small animal teaching hospital. She can be contacted via email at cpatterson@cvm.tamu.edu.

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