Extralabel drug use definitions and background
Q: What is extralabel drug use (ELDU)?
A: ELDU describes the use of an approved drug in a manner that deviates in any way from the drug’s approved labeling, yet meets the conditions set forth by the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) and U.S. Food and Drug Administration (FDA) regulations. Deviations from FDA-approved labeling include use in another species, use for a different indication, use at a different dose or frequency, and use via a different route of administration.
Note that ELDU covers not just FDA-approved animal drugs and human prescription drugs but also FDA-approved human over-the-counter products and compounded products. The specific conditions under which extralabel use is permitted from compounding of approved animal or human drugs are found here.
Q: Is "off-label" use the same as “extralabel”?
A: “Off-label" is a term commonly used in foreign countries, and by physicians in the U.S. It also is sometimes used in veterinary medicine in the U.S., but the term has no legal or regulatory definition. In the U.S., “extralabel” is the appropriate term.
Q: Why is ELDU necessary?
A: The need to use approved drugs in an extralabel manner is common in veterinary medicine. This is because, compared with the situation in human medicine, fewer drugs have been approved by the FDA for use in animals for the myriad species and medical conditions we need them for. Approved animal drugs are particularly limited in number when it comes to minor species, which include all animals other than humans that are not a major species (i.e., horses, dogs, cats, cattle, pigs, turkeys, and chickens). The AMDUCA allows veterinarians the flexibility we need to adequately treat animals of any species when their health is threatened, and more readily relieve them of suffering.
One of the main reasons for the fewer approved drugs in veterinary medicine is that FDA's new drug approval process is relatively costly and time consuming for pharmaceutical companies. This can mean little return on investment for animal drug products versus human drug products, creating a relative disincentive for companies to put resources toward creating new veterinary drugs.
Q: What are the criteria for ELDU?
A: ELDU requires that you meet certain criteria:
- A valid veterinarian-client-patient relationship (VCPR) is a prerequisite.
- Only a veterinarian can determine that ELDU is needed, and only a veterinarian can administer, prescribe, or dispense a medication in an extralabel manner. The veterinarian must direct or supervise ELDU in an animal.
- ELDU rules only apply to FDA-approved animal and human drugs.
- ELDU is not permitted if it results in an illegal food residue, or any residue that may present a risk to public health.
- Certain drugs are prohibited by the FDA for use in food-producing animals.
Q: Who regulates ELDU and enforces the regulations?
A: The FDA Center for Veterinary Medicine regulates ELDU and enforces the regulations found in the AMDUCA. In cases of AMDUCA violations, FDA regulatory actions may include warning letters, product seizure, misdemeanor fines, injunction, or criminal prosecution.
Q: How does the FDA decide which drugs are prohibited from extralabel use in animals?
A: The FDA may prohibit the extralabel use of an approved new animal or human drug or class of drugs in animals if the agency determines that either of the following is true:
- An acceptable analytical method for residue detection needs to be established, and such method has not been established or cannot be established.
- The extralabel use of the drug or class of drugs presents a risk to public health.
A prohibition may involve a general ban on the extralabel use of the drug or class of drugs or may be limited to a specific species, indication, dosage form, route of administration, or combination of factors. Many of the drugs currently prohibited from extralabel use in food-producing animals are antimicrobials.
Applying ELDU regulations in practice
Q: To which species do ELDU regulations apply?
A: ELDU regulations apply to all animal species, not just food-producing animals.
Q: When is ELDU appropriate/necessary?
A: Extralabel use of an FDA-approved drug may be considered if:
- There is no approved animal drug that is labeled for such use, or that contains the same active ingredient in the required dosage form and concentration.
- Alternatively, an approved animal drug for that species and condition exists, but you find, within the context of a valid VCPR, that the approved drug is clinically ineffective for its labeled use.
ELDU is limited to circumstances when the health of an animal is threatened, or failure to treat may result in the animal’s suffering or death. This means that extralabel use to enhance production (e.g., to improve rate of weight gain or feed efficiency) is not permitted.
The following are some examples of clinical circumstances in which ELDU may be appropriate/necessary:
Q: How do ELDU regulations impact what I do in practice?
A: ELDU is common in everyday veterinary practice, so it’s important to ensure you understand the regulations that govern this use. Keep in mind that the AMDUCA does not allow veterinarians unlimited extralabel use of medications. There are certain guidelines to follow. This means you must do the following before you may consider ELDU in any animal:
- Make a careful diagnosis and evaluation of the conditions for which the drug is to be used.
- Ensure at least one of these is true:
- No approved animal drug is available for the intended use.
- An approved animal drug is available for the intended use, but:
- That drug does not contain the needed active ingredient.
- That drug is unavailable in the needed dosage form
- That drug is unavailable in the required concentration.
- You have found, within the context of a valid VCPR, that the drug is clinically ineffective when used as labeled.
For food-producing animals, you also must do all of the following:
- Ensure that the drug considered for extralabel use is not included on the FDA’s list of drugs prohibited from extralabel use in food-producing animals.
- Institute procedures to assure that the identity of the treated animal(s) is carefully maintained.
- Establish a substantially extended withdrawal period supported by appropriate scientific information prior to marketing milk, meat, eggs, or other edible products from the treated animals(s).
- Take appropriate measures to assure that assigned timeframes for drug withdrawal are met so that no illegal drug residues occur in any food-producing animal receiving extralabel treatment or that animal’s food products.
And, if the drug considered for use in food-producing animals is an approved human drug—or an animal drug approved only for use in nonfood-producing animals—both of these requirements also apply:
- Such use must be supported by an appropriate medical rationale.
- If no scientific information is available on the human food safety aspect of the use of the drug in food-producing animals, you must take appropriate measures to assure that the animal and its food products will not enter the human food supply.
Another important consideration pertains specifically to drugs approved for use in humans. Although the rules are more lenient for nonfood-producing animals, for food-producing animals, extralabel use of an approved human drug is prohibited if there’s a drug approved for use in food-producing animals that could be used instead.
Q: What else do I need to know about ELDU in nonfood-producing animals?
A: There are few restrictions on extralabel use in nonfood-producing animals, compared with the situation for food-producing animals. If the intended ELDU is for a nonfood-producing animal, then an approved human drug may be considered, although, when available, an approved animal drug for that species and condition is preferred.
Keep in mind that human-labeled drugs are approved based on studies in people and their effects in animals could vary. In addition, minor differences in the formulation between human and animal drugs may yield different pharmacokinetics and biological availability in the intended animal species versus in people. Something else to consider is that consistent use of human-labeled drugs when approved animal-labeled drugs are available could create relative disincentives for the animal health industry to pursue new animal drug approvals and could further limit the availability of veterinary drugs.
Q: What else do I need to know about ELDU in food-producing animals?
A: Both of the following additional conditions must be met for ELDU in food-producing animals:
- Such use must be accomplished in accordance with an appropriate medical rationale.
- If no scientific information is available on the human food safety aspect of the use of the drug in food producing animals, you must take appropriate measures to assure that the animal and its food products will not enter the human food supply.
If you determine that a food-producing animal needs a drug administered in an extralabel manner, you must first consider an approved animal drug for the particular use before considering a drug labeled for humans. The prescribed or dispensed extralabel drug—whether available by prescription only or over-the counter—must bear sufficient labeling information to assure the safe and proper use of the product.
Note that “food-producing animals” refers to all food-producing species and not to the intended purpose of individual animals. Therefore, ELDU regulations for food-producing animals apply to all animals of those species, even those not intended to enter the human food supply.
Q: Which FDA-approved drugs do or do not qualify for extralabel use in animals?
A: The answer depends on the species for which they’re intended. In nonfood-producing animals, any drug approved by the FDA—whether for humans or animals—qualifies for ELDU, provided a valid VCPR exists and FDA-delineated conditions are met. An exception would be when certain ELDU may threaten public health. If the FDA identifies such a threat, the prohibited drug will be codified in section 530.41 of Title 21 of the Code of Federal Regulations (21 CFR 530.41), in the subsection reserved for nonfood-producing animals.
In food-producing animals, the extralabel use of certain drugs is prohibited. A list of those drugs can be found in 21 CFR 530.41 and here.
Q: Some ELDU documentation requires listing a withdrawal time. What is that and why is it necessary?
A: Any time a drug is used in animals, the potential exists for drug residue to be present in edible tissues and other food products (e.g., milk or eggs) consumed by people. A withdrawal time is the period between when a drug was last administered to when the drug concentration in edible tissues of the treated animal falls to below the level deemed to be safe for human consumption (i.e., below the “tolerance”). If a planned ELDU involves food-producing animals, you must ensure that the specified withdrawal/discard time(s) are listed on the label for meat, milk, eggs, or any other food that might be derived from the treated animal(s).
Q: Where do I find information about withdrawal times for ELDU in food-producing animals?
A: Scientifically based information on safe withdrawal times for drugs and chemicals in food-producing animals is available from the Food Animal Residue Avoidance Databank (FARAD). FARAD is a National Food Safety Project of the U.S. Department of Agriculture National Institute of Food and Agriculture. Visit the FARAD website for various resources or call (888) USFARAD. Other resources that may be used to determine a scientifically based withdrawal time may include scientific literature or other academic sources.
It is important to understand that the withdrawal time given on the label does not apply when an approved drug for food-producing animals is used in an extralabel manner.
Q: Who is responsible for ensuring that no illegal drug residues result from ELDU?
A: Both the veterinarian and the animal owner are responsible.
Q: Does ELDU require any special documentation?
A: Yes. Thorough record keeping and labeling are critical when drugs are used in an extralabel manner.
The following must be documented in the medical records:
- Identity of the animal(s), either as individuals or a group
- Species of animal(s) treated
- Number of animals treated
- Medical conditions being treated
- Established name of the drug and active ingredient*
- Dosage prescribed or used
- Duration of treatment
- Specified withdrawal, withholding, or discard time(s), if applicable, for meat, milk, eggs, or other animal-derived food products
*Typically, the established name of the drug is the name listed in the United States Pharmacopoeia (USP) and comprises the active ingredient, administration route, and dosage form (e.g., “fenbendazole oral suspension”).
Further, these records must be kept for a minimum of two years after treatment. If requested, the FDA must be allowed access to these records to estimate risk to public health.
The product label must include the following:
- Name and address of the prescribing veterinarian
- Established name of the drug
- Any specified directions for use, including the class/species or identity of the animal or herd, flock, pen, lot, or other group; the frequency and route of administration; and the duration of therapy
- Any cautionary statements restricting use to a licensed veterinarian (e.g., "CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian")
- Your specified withdrawal, withholding, or discard time for meat, milk, eggs, or any other food product originating from the treated animal(s).
Q: Do generic drugs qualify for ELDU?
A: Yes. The same ELDU rules apply to both brand-name and generic drugs.
Q: Can clients themselves decide to administer drugs in an extralabel manner to their animals?
A: No. The AMDUCA does not allow clients to decide to administer drugs in an extralabel manner. However, if a VCPR exists, and you decide that ELDU is a valid option, your client may administer the drug extralabelly provided this is under your supervision or direction.
Q: Do I need to list a withdrawal time if the ELDU is for a nonfood-producing animal?
A: No. Withdrawal times of drugs prescribed for ELDU are not necessary for nonfood-producing animals.
Q: Can I treat my patient with a drug labeled for use in a different animal species?
A: For both food-producing and nonfood-producing animals, extralabel use of a drug labeled for a different animal species is allowed in either of the following circumstances:
- No approved, appropriate drug is available that is labeled for use in the patient's species.
- An approved drug exists for the patient's species, but you’ve found it to be clinically ineffective.
However, if the patient is a food-producing animal, you also must have adequate scientific information to allow you to determine a withdrawal time. Otherwise, you must take measures to ensure that animal never enters the human food supply.
Appropriate labeling and record maintenance is of utmost importance when ELDU is prescribed. The AMDUCA does not permit extralabel use of any drug if public health may be threatened.
Q: Can I treat my patient with a drug labeled for use in people?
A: If the patient is a nonfood-producing animal, a human drug may be considered if there is no approved, appropriate animal drug that is labeled for use in the patient’s species or if the approved drug exists but you’ve found it to be clinically ineffective.
If the patient is a food-producing animal, a human drug may be considered if the same criteria as for nonfood-producing animals apply, if the drug is not prohibited from use in food-producing animals, if there is no drug approved for use in animals, AND if there is adequate scientific information to determine a withdrawal time.
Q: Do I need to tell my client when I've prescribed an extralabel treatment?
A: Yes, it’s important to discuss the available treatment options with your clients, especially when extralabel use of a drug is indicated. It’s important for the client to understand that you’re prescribing a drug in a manner that differs from the label and there may be risks associated with this use.
Your state veterinary practice act also may include regulations regarding client consent in ELDU. However, the AMDUCA is generally sufficient to protect patients and public health from inappropriate ELDU.
Q: What is my liability if I prescribe or administer a drug in an extralabel manner and there's a problem?
A: When you administer or prescribe a drug extralabelly, doing so within the confines of the law will help you minimize your risk of liability in the case of an adverse event. The overarching premise of the AMDUCA is that extralabel use is acceptable when filling a medical need for an animal whose health is threatened. Veterinarians who deviate from ELDU guidelines set out in the AMDUCA risk becoming the target of unfavorable actions by the FDA. Such actions range from warning letters and regulatory meetings to product seizures, injunctions, and prosecution. Failure to follow the AMDUCA/ELDU regulations could potentially make you liable if an adverse event occurs, opening you up to the risk of a lawsuit and/or potential disciplinary action by your state's veterinary medical board. If you have questions regarding coverage for liability associated with specific extralabel uses of drugs, check with your liability insurance carrier for terms of your coverage.
Q: What about ELDU in feed?
A: The AMDUCA does not permit extralabel use of medicated feeds. However, there are some minor species that cannot practically be medicated in any way other than through the use of medicated feeds. See the FDA’s Compliance Policy Guide Section 615.115 for the agency’s current thinking on extralabel use of animal drugs approved for use in or on animal feed (medicated feeds) (as defined in 21 CFR 558.3(b)(8)) for minor species.
Q: Are vaccines subject to ELDU?
A: Vaccines are considered "veterinary biologics" and fall under regulation by the U.S. Department of Agriculture’s Center for Veterinary Biologics. Veterinarians are allowed discretionary use of vaccines. For example, if a minor species requires a vaccine not labeled for that species, you can exercise your discretion and use the particular vaccine that you see fit. Veterinarians should check state rules to discern whether it’s acceptable to vaccinate animals with vaccines labeled for another animal species.
Q: Whom should I contact if I have specific questions about ELDU?
A: If you have specific questions about ELDU regulations, the FDA and FARAD are valuable resources. Contact information is available on their websites.