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Veterinary Forum March 2007 (Vol 24, No 3)

Clinical Report: "Drug compounding: a precarious practice"

by Sophia Yin, DVM, MS (Animal Science)

    When dealing with fractious hyperthyroid cats that refuse to take oral medications or 5-lb Yorkshire terriers that require small doses of medication, a compounding pharmacist can be a veterinarian's best friend. But choosing the right pharmacist is paramount, according to Gigi Davidson, RPh, DICVP, director for clinical pharmacy services at North Carolina State University, Raleigh.

    "Drug integrity, stability, bioavailability and efficacy depend on a solid background in pharmacology and a skilled compounding technique. Not all pharmacists are trained in veterinary pharmacotherapy or specialized compounding techniques," Davidson says. Compounding pharmacists undergo specific training in compounding in addition to veterinary pharmacy and adhere to the public standards published by the US Pharmacopeial (USP) Convention (www.usp.org). The USP standards include requirements for labeling expiration dates (beyond use dating) as well as information on appropriate excipients or vehicles. Drug compounding should be based on peer-reviewed research evidence conducted by veterinary teaching institutions or other credible resources, according to Davidson.

    Essential guidelines

    Davidson warns that failure to follow these guidelines and the lack of veterinary-specific knowledge can have serious consequences. For example, compounding alters the bioavailability of a product. "If the dose form is changed from a solid 500-mg tablet of mitotane to an oil suspension, the bioavailability increases dramatically," says Davidson. "If the clinician is unaware of a change in dose form, a toxic crisis could develop fairly quickly."

    The excipients and vehicles used in drug compounding can cause problems as well. Alcohols are commonly used in human preparations and can cause clinical complications in cats and birds. Xylitol, which is used as a sugar-free sweetener, has been associated with hypoglycemia and liver disease in dogs. Sometimes the excipients and vehicles can interfere with the drug's stability and solubility.

    "In one case, we saw a myasthenic dog on pyridostigmine prepared as an oral formulation with methylcellulose," describes Davidson. "The methylcellulose bound the drug, preventing it from being absorbed, and the dog came out of remission. The dog was facing euthanasia because of an assumed nonresponsiveness to treatment. Luckily, a veterinary student realized that the owner had switched the dog from the commercially available product to a drug that was compounded in a formulation that altered the bioavailability of the drug." Inadequate amounts of the drug were being absorbed from the intestines, and the dog failed to respond to therapy.

    Not surprisingly, unknown potency is the greatest potential problem associated with compounded preparations. It is most commonly attributable to early breakdown of the unstable compound as a result of an inappropriate expiration date or improper storage conditions.

    But the problems do not end there, says Mark Papich, DVM, MS, professor in the department of molecular biomedical sciences at North Carolina State University. "Veterinarians need to know what they are buying. According to a regulatory letter issued by the FDA on Oct. 31, 2006, some compounded medications are considered 'adulterated animal drugs' as per the Food, Drug, and Cosmetic Act. The FDA considers it a violation to sell adulterated drugs."

    For example, preparing batches of compounded medications, such as ophthalmic 1% cyclosporine, on a large scale to stock in veterinary hospitals and resell to clients is a violation of this act, according to the FDA website. Although compounding is allowed — and often necessary — on a case-by-case basis for individual patients, it is not intended to provide a mechanism to circumvent the drug approval requirements for new animal drugs.

    Problematic procedures

    A second questionable practice is the compounding of drugs that are approved in other countries but not yet approved in the United States (e.g., pimobendan and trilostane). The FDA claims that new animal drug substances for which there are no approved New Animal Drug Applications or Investigational New Animal Drug Exemptions may not be used for drug compounding in private veterinary practices or by other manufacturers and distributors. Therefore, the FDA considers it illegal for a compounding pharmacy to sell compounded versions of drugs, such as pimobendan and trilostane, that are in violation of the Food, Drug, and Cosmetic Act because they are adulterated and/or misbranded. These compounded versions are not in violation if the recipient or distributor has approval from the FDA, an exemption for preparation from that particular bulk drug source or approval is not required at that time by regulation or policy.

    Veterinarians can obtain FDA permission to import such drugs. "We have about 65 dogs on pimobendan. The permission process takes about 2 weeks. Subsequent turnaround time on ordering and receiving the product is typically 48 hours," Davidson explains. "Despite this solution, some veterinarians have ordered from compounding pharmacies or distributors in violation of the Food, Drug, and Cosmetic Act.

    "Circumventing the FDA drug approval process in this manner can put a veterinarian in jeopardy," says Papich. "If the drug is not approved in the United States, you don't know what you're receiving because there is no quality control, demonstration of safety or proof of efficacy of the product.

    "A compounded version of a foreign drug may also differ significantly from the finished formulation that is actually marketed in another country," Papich warns. "Violating the Food, Drug, and Cosmetic Act decreases the incentive for pharmaceutical companies that have to go through the rigorous and expensive FDA approval process. Using an unapproved drug also places a liability burden on the veterinarian if there is an adverse drug reaction."

    Protect your practice

    What can veterinarians do to protect themselves? First, choose a local compounding pharmacist and be sure to verify his or her credentials. The pharmacist should be a member of the International Academy of Compounding Pharmacists, the Professional Compounding Centers of America or the American College of Apothecaries' College of Veterinary Pharmacists and should have undergone special training in veterinary pharmacy and pharmaceutical compounding. A trustworthy compounding pharmacist does not engage in any of the described illegal practices, can reveal their source of raw chemicals and can provide a Certificate of Analysis of purity (all chemicals should be obtained from approved sources that provide certification that the chemicals are pure).

    Refer to the FDA website (www.fda.gov) for FDA warning letters or actions, or contact your state board of pharmacy to verify in-state compliance.

    NEXT: Complex task treating older dog with chronic renal disease


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