THE MERCK VETERINARY MANUAL
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Extra-Label Drug Use, Compounded Drugs, and Generic Drugs

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A new animal drug (NAD) is “any drug intended for use in animals other than man...not generally recognized as safe and effective for the use under the conditions prescribed, recommended, or suggested in the labeling of the drug.” A drug's label includes the label on the product itself as well as any accompanying material in or on the package, including the package insert.

To use an NAD in a legal manner, veterinarians must adhere to the specifications noted on the label. Otherwise, the drug is being used in an extra-label manner. Extra-label drug use, whether actual or intended, occurs when the drug is used in a manner not in accordance with approved label directions. This includes but is not limited to a different dosage, interval, route, indication, or species.

In 1994, Congress passed the Animal Medicinal Drug Use Clarification Act (AMDUCA), which legalized extra-label drug use by veterinarians as long as specific criteria or restrictions are met. Most restrictions are largely applicable to extra-label drug use in food animals. For both food and nonfood animals, a valid veterinary-client-patient relationship must exist. For food animals, in the absence of a drug labeled for the intended use, extra-label drug use might involve drugs approved for use in other food animals, approved for use in nonfood animals, or approved for use in people. Restrictions regarding extra-label drug use of nonfood animal and human drugs are progressively restrictive. Extra-label drug use in food animals is permitted only by or under the supervision of a veterinarian; is allowed only for therapeutic purposes (ie, the animal's health is suffering or threatened); is not allowed when the drug is administered in feed; is not permitted if it results in violative food residues or any residues that may present a risk to public health; and is not allowed if specifically prohibited by the FDA.

Drugs specifically prohibited in food animals by the FDA as of May 2015 include chloramphenicol, clenbuterol, diethylstilbestrol, dimetridazole, ipronidazole, other nitroimadazoles, furazolidone, nitrofurazone, sulfonamide drugs in lactating dairy cattle (except for those specifically approved), fluoroquinolones, aglycopeptides (eg, vancomycin), phenylbutazone in female dairy cattle ≥20 mo old, cephalosporins (except cephapirin) in cattle, swine, chickens, or turkeys for disease prevention, and amantadine or neuraminidase inhibitor classes of drugs used to treat influenza A in poultry and ducks.

Use of a compounded preparation also constitutes extra-label drug use. However, a major distinction is that a compounded preparation undergoes no regulatory assessment or approval. Conditions under which compounding is legal also are specified in the AMDUCA. Compounding includes any manipulation of the drug beyond that stipulated on the label. Guidelines regarding the compounding of pharmaceuticals under the direction of a veterinarian are delineated in Compliance Policy Guideline 7125.40. Among the greatest concerns of the FDA regarding compounded products is compounding intended to circumvent the drug approval process, resulting in 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. Conditions under which compounding is not subject to regulatory actions include a legitimate practice (pharmacy or veterinary; includes licensure), operation within the conformity of state law, for pharmacists in response to a prescription, and for veterinarians operating within a valid veterinary-client-patient relationship. 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, health or life of the animal is threatened or suffering may occur). Additionally, there must be no marketed, approved animal or human drug, regardless of whether it is used as labeled or in an extra-label fashion, that may be substituted for the compounded agent. Occasionally, other rare circumstances may be considered. In 2013, Congress passed the Drug Quality and Security Act that, among other things, increases regulation of compounding in human medicine. However, this Act does not cover compounding of animal products, and Congress is examining further actions to more effectively regulate such compounding.

Pharmacists often can dispense an equivalent, less expensive, nonproprietary (generic) drug without prescriber approval. An exception occurs if a state has a mandatory substitution law or if the brand name product is dispensed along with a “dispensed as written” order. Generic products must not only contain the same active ingredient as the proprietary drug but also meet bioequivalence standards. Generics may be pharmaceutically equivalent but may not be therapeutically equivalent. Substitutions of generic drugs for proprietary drugs are recommended only for those drugs shown to be therapeutically equivalent. Those human drugs tested by the FDA and found to be therapeutically equivalent are listed in Approved Drug Products with Therapeutic Equivalence Evaluations, otherwise known as the “Orange Book.” However, status of a generic drug is relevant only for the approved species and, as such, therapeutic equivalence of a human generic drug does not apply to extra-label use of that drug in an animal.

Although AMDUCA legalizes extra-label drug use in the USA, selected states or other countries may have additional or complementary regulatory or legal restrictions. In all instances, it is important to read carefully the label instructions for use of specific drugs.

Last full review/revision November 2015 by Dawn Merton Boothe, DVM, PhD

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