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New Animal Drugs, Extralabel Drug Use, Compounded Drugs, and Generic Drugs

By Mary A. Robinson , BS, PhD, VMD, DACVCP, University of Pennsylvania, School of Veterinary Medicine, Department of Clinical Studies - New Bolton Center Reviewed/Revised Jun 2023

According to the US Code (21 USC § 321[v]), a new animal drug (NAD) is “any drug intended for use in animals other than man, including any drug intended for use in animal feed but not including such animal feed.” The "Green Book" provides a list of all approved NADs in the US, and Animal Drugs@FDA is a searchable database of approved NADs. Applications for the production and marketing of an NAD are reviewed by the FDA Center for Veterinary Medicine (CVM) and require demonstration of safety and efficacy in the target species, human food safety when applicable, adequate quality control of the manufactured product, acceptable environmental impact, and a clear and complete product label. A drug’s label consists of the label on the product itself, as well as any accompanying material in or on the package, including the package insert. To prescribe an NAD, state and federal law requires that veterinarians have a valid veterinary-client-patient relationship (VCPR). They must also fill out a complete prescription. Veterinary Prescription Requirements:

  • Printed or stamped name, address, and telephone number of the licensed veterinarian

  • Legal signature of the licensed veterinarian

  • Name and strength of the drug

  • Directions for use of the drug

  • Full name and address of the client

  • Animal identification (name or species)

  • Cautionary statements, including, if applicable, withdrawal times for food animals

  • Number of refills, if any

Source: Riviere JE, Papich MG. Veterinary Pharmacology and Therapeutics. Wiley; 2017:chap 56, table 56.9. As of January 1, 2017, NADs added to the food or drinking water of food-producing animals require a veterinary feed directive (VFD) per CVM GFI #213 New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals. A VFD enables existing supply chains to continue supplying medicated feeds while ensuring veterinary oversight of medications included in the feed. If a suitable NAD is not available, veterinarians can consider prescribing a drug in an extralabel manner. Extralabel drug use, whether actual or intended, is use of a drug in a manner that is not in accordance with approved label directions (eg, different dosage, interval, route, indication, or species). In 1994, the Animal Medicinal Drug Use Clarification Act (AMDUCA) legalized extralabel drug use by veterinarians as long as specific criteria and restrictions are met: a valid veterinary-client-patient relationship (VCPR) must exist and the drug must already have been approved for use in animals or humans for another purpose or must be on the list of substances generally recognized as safe (GRAS). Extralabel drug use in food animals has additional restrictions:

  • Permitted only for therapeutic purposes (ie, the animal’s health is suffering or threatened)

  • Not allowed when the drug is administered in water or feed

  • Not permitted if it results in violative food residues or any residues that may present a risk to public health

  • Not allowed if specifically prohibited by the FDA

Drugs specifically prohibited for extralabel use in food animals by the FDA as of April 2019 include chloramphenicol; clenbuterol; diethylstilbestrol; dimetridazole; ipronidazole; other nitroimidazoles; furazolidone; nitrofurazone; sulfonamide drugs in lactating dairy cattle (dairy cattle ≥ 20 months); fluoroquinolones; glycopeptides (eg, vancomycin); phenylbutazone in female dairy cattle ≥20 months old; cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys for disease prevention and treatment; and adamantanes (eg, amantadine) or neuraminidase inhibitors in chickens, turkeys, and ducks. There are approved uses for some of these drugs (eg, sulfonamides, fluoroquinolones, cephalosporins) in food animals, and veterinarians are permitted to prescribe these only as specified on the approved label. See 21 CFR §530.41. Use of a compounded preparation also constitutes extralabel drug use. Compounding includes any manipulation of a drug beyond that stipulated on the label. A major distinction is that a compounded preparation undergoes no regulatory assessment or approval. The Drug Quality and Security Act of 2013, among other things, increases the regulation of compounding in human medicine. However, this act does not cover the compounding of products used in animals. Conditions under which compounding is legal for veterinary medicine are specified in AMDUCA, but they do not apply to compounding from bulk drug substances. Guidelines regarding compounding from bulk drug substances under the direction of a veterinarian are being modified and are delineated in draft form in CVM GFI #256 - Compounding Animal Drugs From Bulk Drug Substances. In addition, two chapters in the United States Pharmacopeia (Chapter 795: Pharmaceutical Compounding - Nonsterile Preparations, and Chapter 797: Pharmaceutical Compounding - Sterile Preparations) describe the recommendations for both human and veterinary compounding. Among the FDA's greatest concerns regarding compounded products is compounding intended to circumvent the drug approval process, resulting in the mass marketing of products that have had little or no quality control to ensure purity, potency, and stability. The FDA considers a compounded product to be an adulterated—ie, unapproved—new animal drug, and thus a violation. Compounding is not subject to regulatory actions if the following conditions are met:

  • It is done within a legitimate practice (pharmacy or veterinary with licensure).

  • It conforms to state law.

  • For pharmacists, it is done only to fill a prescription requesting a compounded product.

  • For veterinarians, a valid VCPR exists.

Compounding of human drugs and, very occasionally, bulk drugs into appropriate dosage forms may be acceptable in certain circumstances. A legitimate medical need must be identified (eg, the health or life of the animal is threatened, or suffering may occur). In addition, there must be no marketed, approved animal or human drug—whether used as labeled or in an extralabel fashion—that may be substituted for the compounded agent. Rarely, other circumstances may be considered. Pharmacists often can dispense an equivalent, less expensive, nonproprietary (generic) drug without prescriber approval Some states have mandatory substitution laws, requiring pharmacists to use the generic by default. Prescribers can request the brand-name product with a dispensed as written (DAW) order. Generic products must contain the same active ingredient as the proprietary drug, are subject to regulatory approval, and must meet bioequivalence standards (ie, total amount of drug absorbed, peak plasma concentration, and time to peak plasma concentration must match those for the proprietary product in the species for which it is labeled). A formulation containing the same active ingredient as the proprietary product may not be therapeutically equivalent. Human drugs tested by the FDA and found to be therapeutically equivalent are listed in Approved Drug Products With Therapeutic Equivalence Evaluations (known as the “Orange Book”). However, the status of a generic drug is relevant only for the approved species; therefore, therapeutic equivalence of a human generic drug may not apply to extralabel use of that drug in an animal. Although AMDUCA legalizes extralabel drug use in the US, selected states or other countries may have additional or complementary regulatory or legal restrictions. In all instances, it is important to read the label instructions carefully for the administration of specific drugs.

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