As a practicing veterinarian, you’ve likely prescribed a drug for an extra-label use. What does that mean? What gives you the legal ability to do so? What conditions must you meet? By explaining FDA’s requirements for extra-label drug use in animals, this article answers these questions and more.
In 1994, Congress added provisions to the Federal Food, Drug, and Cosmetic Act (FD&C Act) that give veterinarians the legal ability - with certain restrictions - to use approved human and animal drugs in an extra-label manner. This means, in some cases, you can use an approved drug in a way that isn’t listed on the drug’s labeling. Extra-label drug use is sometimes called off-label because the use is “off the label.”
To prescribe drugs in an extra-label manner, you need to follow FDA’s requirements for extra-label drug use, as stated in the FD&C Act and FDA regulations. You should also educate your clients, particularly food animal producers, on these requirements and on FDA’s recommendations for the judicious use of antimicrobials.
Extra-Label Drug Use in Animals
Before Congress passed the Animal Medicinal Drug Use Clarification Act (AMDUCA) in 1994, federal law did not permit extra-label drug use in animals. The AMDUCA provisions amended the FD&C Act to allow veterinarians to prescribe approved human and animal drugs for extra-label uses in animals under specified conditions. The key points are:
- Valid Veterinarian-Client-Patient Relationship
- General Conditions for Extra-Label Drug Use
- Conditions for Extra-Label Drug Use in Food-Producing Animals
- Drugs Prohibited from Extra-Label Uses in Animals
We’ll look at each point separately as well as touch on how FDA’s judicious use recommendations affect extra-label use of antimicrobials in food-producing animals.
Valid Veterinarian-Client-Patient Relationship
The AMDUCA provisions of the FD&C Act allow extra-label drug use only on the lawful order of a licensed veterinarian in the context of a valid veterinarian-client-patient relationship. A valid veterinarian-client-patient relationship has three parts:
- You have assumed responsibility for making medical judgments about the health of an animal, or animals, and the need for medical treatment. In turn, the client (the owner or other animal caretaker) has agreed to follow your instructions;
- You have sufficient knowledge of the animal, or animals, to develop a general or preliminary diagnosis of the medical condition; and
- You are readily available for follow-up in case of adverse drug reactions or treatment failure.
Such a relationship can exist only when you have recently seen and are personally acquainted with the keeping and care of the animal or animals. This means you have recently examined the animal or animals, made “medically appropriate and timely visits” to the premises (usually the case for food-producing animals), or done both.
General Conditions for Extra-Label Drug Use
The purpose of FDA’s requirements for extra-label drug use in animals is to limit this use to situations where an animal’s health is threatened or where the animal may suffer or die without treatment. In addition, one of the following general conditions must be met before you can legally prescribe an approved human or animal drug for an extra-label use:
- There is no animal drug approved for the intended use; or
- There is an animal drug approved for the intended use, but the approved drug does not contain the active ingredient you need to use; or
- There is an animal drug approved for the intended use, but the approved drug is not in the required dosage form (for example, you need a liquid dosage form, but the approved drug is only available as a tablet dosage form); or
- There is an animal drug approved for the intended use, but the approved drug is not in the required concentration (for example, you need 5 mg, but the approved drug is only available at 50 mg); or
- You have found, in the context of a valid veterinarian-client-patient relationship, that the approved drug is clinically ineffective when used as labeled.
In companion (non-food-producing) animals, you can prescribe an approved human drug for an extra-label use even if an approved animal drug is available. This is not the case for food-producing animals. For these animals, FDA’s requirements for extra-label drug use prohibit you from prescribing an approved human drug if there’s a drug approved for food-producing animals that you can prescribe instead. For example, if a drug approved for chickens is available, you must first use that drug to treat a sick cow before reaching for a drug approved for people.
Thorough recordkeeping is vital. You must maintain records that identify the treated animal or animals. For food-producing animals, this can be done on a group, herd, flock, or per-client basis. The records must include the:
- Established name of the drug including its active ingredient, or if formulated from more than one active ingredient, the established name of each active ingredient. Ordinarily, the established name of the drug is the name listed in the United States Pharmacopeia (USP) and is made up of the active ingredient, route of administration, and dosage form (for example, “fenbendazole oral suspension”);
- Condition treated;
- Animal species treated;
- Dosage administered;
- Treatment duration; and
- Number of animals treated.
- For food-producing animals, the records must include the withdrawal, withholding, or discard period for food products, such as meat, milk, or eggs, made from treated animals.
You must keep these records for two years or as otherwise required by federal or state law, whichever is longer. The records must be made available to FDA-designated personnel, at all reasonable times, for copying and verifying.
Thorough labeling is critical. The labeling for a drug dispensed on your order for an extra-label use must state your name and address. If the drug is dispensed by a pharmacy on your order, the labeling must state your name, and the name and address of the dispensing pharmacy. The labeling must also include information similar to what is required in the record:
- Established name of the drug or, if formulated from more than one active ingredient, the established name of each active ingredient. As mentioned above, the established name of the drug typically is the name listed in the USP and is made up of the active ingredient, route of administration, and dosage form (for example, “fenbendazole oral suspension”);
- The class/species or identity of the treated animal. Animals should be identified individually (usually for companion animals) or by herd, flock, pen, or lot (usually for food-producing animals);
- Directions for use, including dosage, frequency, route of administration, and duration of therapy; and
- Any cautionary statements (for example, “Not for use in veal calves”).
- For food-producing animals, the drug labeling must also include the withdrawal, withholding, or discard period for food products, such as milk, meat, or eggs, made from treated animals.
Conditions for Extra-Label Drug Use in Food-Producing Animals
If you’re a food animal veterinarian, you should be aware of the additional requirements for extra-label drug use in food-producing animals. Before prescribing any approved human or animal drug for an extra-label use in food-producing animals, you must:
- Carefully diagnose and evaluate the condition for which you are prescribing the drug;
- Make sure procedures are in place so your client maintains the identity of the treated animal or animals;
- Establish a substantially extended withdrawal period supported by appropriate scientific information. You may get this information from such sources as scientific literature, academia, or the Food Animal Residue Avoidance Databank (FARAD); and
- Take measures to assure that no illegal drug residues occur in the treated animal or animals. Your client must follow your established withdrawal period.
If you want to use a drug approved for people or a drug approved only for companion animals in food-producing animals, you must also have an appropriate medical rationale for using the drug. In addition, if scientific information is unavailable on the safety of food products made from animals treated with the particular drug, you must take appropriate measures to assure that the animal and its food products will not enter the human food supply.
Remember, you may not prescribe an approved human drug for food-producing animals if there’s an animal drug approved for food-producing animals that you can prescribe instead.
The FD&C Act doesn’t allow the extra-label use of any drug in animal feed. However, for some minor species, you may determine that extra-label use of a drug in animal feed is needed to prevent suffering and death in these animals. (Minor species are all animals that aren’t one of the seven major species: cattle, horses, swine, chickens, turkeys, dogs, and cats.) Please refer to FDA’s Compliance Policy Guide on extra-label use of medicated feeds for minor species.
Under the FD&C Act, an animal drug that is compounded using an unapproved drug or bulk drugs as the starting material is adulterated. An animal drug that is compounded using an approved human or animal drug as the starting material is not adulterated, and using such a drug is considered a legal extra-label use as long as all other conditions required by law are met. You can find these requirements in:
- Sections 512(a)(4) and (5) of the FD&C Act [Sections 360b(a)(4) and (5) of Title 21 of the United States Code (New Animal Drugs, 2017)] and;
- Section 530.13 of Title 21 of the Code of Federal Regulations (Extra-label use from compounding of approved new animal and approved human drugs, 2017).
FDA recognizes that in some situations a drug compounded from bulk drug substances may be the only appropriate treatment option for a particular animal. On November 19, 2019, FDA issued draft Guidance for Industry #256, “Compounding Animal Drugs from Bulk Drug Substances,” which addresses situations in which, if the guidance is finalized, the FDA does not intend to take action for certain violations of the Food, Drug, & Cosmetic Act when pharmacists and veterinarians compound or oversee the compounding of animal drugs from bulk drug substances:
- to fill patient-specific prescriptions for nonfood-producing animals
- to compound “office stock” (certain drugs kept in veterinarians’ supply) for nonfood-producing animals and
- to compound antidotes for food-producing animals.
Animal drugs compounded from bulk drug substances do not undergo review by FDA, meaning that the FDA has not determined that these unapproved products are safe and effective for their intended use. Because of the safety benefits and protections of the pre-market review process and post-market monitoring of FDA-approved, conditionally approved, and indexed drugs, veterinarians should only use drugs compounded from bulk drug substances if FDA-approved, conditionally approved, or indexed drugs are not available to treat the animal.
For more information, see Animal Drug Compounding.
Drugs Prohibited from Extra-Label Uses in Animals
Under the AMDUCA provisions, FDA has the right to prohibit extra-label uses of certain drugs in animals. The following drugs (both human and animal), families of drugs, and substances are prohibited from extra-label uses in all food-producing animals, including horses intended for human food:
- Diethylstilbestrol (DES)
- Ipronidazole and other nitroimidazoles
- Furazolidone and nitrofurazone
- Sulfonamide drugs in lactating dairy cattle, except for the approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine
- Phenylbutazone in female dairy cattle 20 months of age or older
- Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys:
- For disease prevention purposes;
- At unapproved doses, frequencies, durations, or routes of administration; or
- If the drug is not approved for that species and production class.
The following drugs, or classes of drugs, that are approved for treating or preventing influenza A are prohibited from extra-label uses in chickens, turkeys, and ducks:
- Neuraminidase inhibitors
The above list can be found in Section 530.41 of Title 21 of the Code of Federal Regulations (Drugs prohibited for extra-label use in animals, 2017). Currently, no approved drugs are prohibited from extra-label uses in companion animals.
Judicious Use of Medically Important Antimicrobials and Extra-Label Drug Use in Food-Producing Animals
FDA's Guidance for Industry #209 discusses the agency’s concerns about antimicrobial resistance and recommends the following judicious use principles in food-producing animals:
- Limit medically important antimicrobials to uses that are necessary for assuring animal health (in other words, therapeutic uses to treat, control, or prevent specific diseases); and
- Limit medically important antimicrobials to uses that include veterinary oversight or consultation.
(The term “medically important antimicrobials” generally refers to antimicrobials that are important for therapeutic uses in people.)
In light of the public health risk posed by antimicrobial resistance, FDA stated in this guidance document that the agency doesn’t think using medically important antimicrobials for production purposes in food-producing animals is a judicious use of these drugs. Animal drugs currently approved for production purposes, such as increased rate of weight gain and improved feed efficiency, are typically given in feed or water on a herd- or flock-wide basis.
FDA’s Guidance for Industry #213 discusses the agency’s recommendations for drug sponsors to align with the judicious use principles outlined in Guidance for Industry #209. (A drug sponsor is the entity that owns the right to market a particular drug. Any organization, or even one person, can be a drug sponsor, but typically, the drug sponsor is a drug company.) The process of implementing Guidance for Industry #213 began in December 2013 when FDA recommended that drug sponsors voluntarily phase out the use of medically important antimicrobials for production purposes in food-producing animals. By January 2017, this phase-out was complete—the drug sponsors voluntarily removed all production claims from the approved labeling of medically important antimicrobials for use in food-producing animals in or on feed or water or the sponsors voluntarily withdrew the approvals. Continued use of such a drug in animal feed or water for a production purpose is an illegal extra-label use.
Let's say a medically important antimicrobial is approved for a therapeutic use in food-producing animals, such as to treat bovine respiratory disease in cattle. Prescribing this drug in an extra-label manner for a production purpose, such as to increase rate of weight gain in cattle, goes against FDA’s judicious use principles. It also doesn't comply with FDA’s requirements for extra-label drug use in animals. These requirements state that for extra-label drug use in food-producing animals, you must carefully diagnose and evaluate the condition for which you are prescribing the drug. This means you must diagnose a medical condition and any drug you prescribe in an extra-label manner must be for a therapeutic use, which wouldn’t include increased rate of weight gain (or any production claim).
The Animal Medicinal Drug Use Clarification Act of 1994 added provisions to the Federal Food, Drug, and Cosmetic Act legalizing the extra-label use of approved human and animal drugs in animals under certain conditions. You can ensure proper extra-label use by complying with FDA’s requirements and by understanding what’s allowed and what’s not under the law.
For more information, please call FDA’s Center for Veterinary Medicine at 240-402-7002, or email AskCVM@fda.hhs.gov.
FDA’s Guidance Documents on Judicious Use
- Guidance for Industry #209: The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals
- Guidance of Industry #213: New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with GFI #209