Q: What is compounding?
A: Compounding is any manipulation of a drug beyond that stipulated on the drug label. Veterinary drugs should only be compounded based on a licensed veterinarian's prescription, and to meet the medical needs of a specific patient. Manipulation might include mixing, diluting, concentrating, flavoring, or changing a drug's dosage form.
Examples of compounding include:
- Mixing two injectable drugs in the same syringe
- Creating an oral suspension from crushed tablets or an injectable solution
- Adding flavoring to a commercially available drug
- Creating a transdermal gel for a drug typically taken through other routes
- Mixing two solutions for instilling into the ear
Q: How is compounding regulated?
A: It's regulated by both the U.S. Food and Drug Administration and state governments. The FDA regulates compounding for animal patients as a subpart of its Extralabel Drug Use (ELDU) rules. The FDA says it generally defers day-to-day regulation of compounding by veterinarians and pharmacists to state authorities. The state boards of pharmacy oversee pharmacy practices within the states, while the state veterinary medical boards oversee the practice of veterinary medicine, including prescribing.
Q: Are pharmacists trained to compound for animals?
A: Many pharmacy schools have not traditionally included significant veterinary pharmacotherapy in their curricula although there have been recent efforts to incorporate more veterinary-specific training. However, most veterinary-specific pharmacy training (including compounding) is obtained through independent continuing education on the part of the pharmacist. Because drugs and compounded preparations may behave differently in animals than in humans, veterinarians should ask compounding pharmacists if they have specialized training or credentials in veterinary compounding, and veterinarians should specifically seek the compounding services of pharmacists who have specialized knowledge of veterinary compounding.
In addition to information on the active ingredient(s), veterinarians should convey to pharmacists any restrictions on inactive ingredients for the compounded preparation, such as “NO XYLITOL” for your canine patients.
Q: What is a bulk substance?
A: A ‘bulk drug substance’ (BDS) is any substance incorporated into a finished drug product that furnishes its pharmacological activity. In other words, a bulk drug substance is an active pharmaceutical ingredient (API) or chemical ingredient used to produce a drug.
Q: How do compounded medications differ from the ones I or my clients can get from a store or regular pharmacy?
A: The medications bought at a store are either brand name drugs or generic drugs. A generic drug is a non-brand name version of a drug: for example, Tylenol® is a brand name for a drug used in human medicine, but acetaminophen is the generic name. In general, buying a generic drug with the same ingredient and same strength as the brand name is equivalent to (but may be cheaper than) buying the brand name version. Both brand name and generic drugs are approved by the FDA. Therefore, they have to be shown to be safe and effective; their label has to be approved by FDA; their manufacturing facilities have to meet certain FDA specifications; and the manufacturer is required to continually ensure the shelf stability of the product. FDA assigns an equivalency rating to human generic drugs, which states whether the generics are therapeutically equivalent (achieve the same therapeutic goal) as compared to the branded product.
Veterinary extralabel use of human generic drugs in animals is allowed under specific conditions within federal law, under AMDUCA and regulations at 21 CFR Part 530.
Compounded medications are modified versions of the FDA-approved brand name or generic medications you would otherwise buy at the store or pharmacy. Per FDA, they should be altered formulations of FDA-approved drugs (i.e. ones that have been crushed, have had a flavor added, or otherwise tweaked). FDA says they should not be brand new medications such as those compounded from bulk drug substances (BDS), or FDA asserts they are legally "new animal drugs" and are required to have FDA approval in order to be legally marketed. Animal drugs compounded from BDS that have the same active ingredient as an approved generic drug or an approved brand name drug may no longer perform in the same manner as the approved drug. Yes, the compound still incorporates the same drug ingredient, but the composition of the dosage form has been changed, and it will not be identical in every way to the original drug. Compounding may cause changes in stability, bioavailability, metabolism, and elimination of the drug.
Q: When is compounding necessary?
A: Compounding for non-food animals may be necessary when approved drugs need to be modified to sufficiently treat the patient (e.g., through flavoring, diluting, or changing the form of medications from tablet to suspension). For example, if you need to prescribe methimazole (Felimazole®) for a hyperthyroid cat, but the owner tells you the cat will not allow the owner to “pill” it, you might need to have the product compounded into a liquid form so the cat can be adequately treated.
Compounding for non-food animals might also be necessary when no approved drug exists, or if the approved drug isn’t commercially available to treat a pet’s diagnosed condition. There are three general sets of circumstances in which the AVMA believes compounding from bulk ingredients (i.e., “raw” active ingredients) may be necessary:
- The approved drug is not commercially available.
- The needed compounded preparation cannot be made from the approved drug.
- There is no approved product from which to compound the needed preparation.
For food animals, the AVMA recognizes specific circumstances wherein bulk compounds might be medically necessary, specifically poison antidotes and compounds for euthanasia or depopulation that are not approved or commercially available.
Otherwise the AVMA believes drugs should be compounded only from FDA-approved drugs to fulfill the regulations written to implement the Animal Medicinal Drug Use Clarification Act (AMDUCA).
The status of drug shortages can be checked on the FDA website.
Q: When is compounding legal? What criteria must be met?
A: Compounding is considered legal when federal and state rules are followed. Veterinarians can inquire about state requirements from the relevant state boards of pharmacy and veterinary medicine. Federal extralabel drug use regulations specifically permit compounding from FDA-approved drugs when a veterinarian believes there is a need to alter the approved drug to adequately medicate a non-food animal with a diagnosed medical condition. This means that there is an established veterinarian-client-patient relationship (VCPR); the individual patient has a medical condition for which a prescribed medication is needed; and the veterinarian determines that a compounded drug is needed for the animal. To be in line with FDA’s extralabel drug use rules, compounding should be performed using the FDA-approved drug.
For example, let’s say you need to prescribe a particular FDA-approved antimicrobial for an ear infection in a dog, but the antimicrobial only comes in an injectable form. Following the FDA’s rules, you could mix the FDA-approved product – for example, amikacin – with normal saline for instilling into the ear.
Q: What are FDA’s enforcement priorities regarding animal drugs compounded from BDS?
A: FDA's priorities, found here, include:
- Compounded drugs that present human or animal health concerns, for instance, because of contamination or formulation errors.
- Drugs compounded for food-producing animals, because of the risk of drug residues in the meat, milk, or eggs consumed by people. When FDA approves a drug for a food-producing animal, the agency evaluates human food safety data to establish residue tolerance levels, withdrawal times, and other conditions of use to prevent violative drug residues in the edible products from those animals. Drugs compounded for food-producing animals have not been evaluated by FDA for human food safety.
- Compounded drugs that are copies of approved or indexed products, because they undermine incentives for firms to invest in getting drugs approved or indexed, which can reduce the availability of animal drugs for which safety and effectiveness has been established through the FDA review process.
- Drugs compounded as office stock without a patient-specific prescription, because office stock exposes larger numbers of animals to drugs of unproven quality and undermines incentives to seek approval by distributing large quantities of unapproved animal drugs.
Q: Are there different compounding rules/regulations applied to products for use in food-producing animals?
A: Yes, and those rules are much more stringent. For example, compounding from a human drug for use in food-producing animals is not be permitted if an approved animal drug can be used for compounding. Using a compounded drug in food animals is reserved only for when no approved new animal drug is labeled for such use and contains the same active ingredient and when safe use of that animal for human food purposes can be predicted following discontinuation of the drug. All federal requirements for use of drugs in food-producing animals still apply, including that the veterinarian must specify a substantially extended withdrawal interval for the compounded preparation supported by appropriate scientific information, and the compound must be prescribed within the veterinarian-client-patient relationship. For further information veterinarians should refer to Title 21 CFR Sec. 530.13 of the Code of Federal Regulation: Extralabel use from compounding of approved new animal and approved human drugs.
Q: What is a mimic drug?
A: A mimic is a compounded drug that is produced to copy an FDA-approved human or animal drug, but avoids the drug approval process and is usually compounded for economic reasons and not medically necessary therapeutic reasons. Such compounding is outside the bounds of traditional compounding, and the production and prescribing of compounded mimic drugs is illegal. Although these mimic drugs may appear identical to the FDA-approved product, there may be differences that affect the product's efficacy or safety.
Use of a mimic drug is detrimental for several reasons:
- It denies the patient treatment with an approved drug proven to be safe, effective, pure, potent, stable and made under FDA-mandated "good manufacturing practices."
- It exposes the patient to products that have not been proven safe and effective and could be contaminated, sub- or super-potent, or unstable.
- It exposes parties involved in mimicry to unnecessary liability.
- It undermines the incentive for research and development-oriented animal pharmaceutical companies to market new animal drugs. Without a healthy animal pharmaceutical industry, veterinarians will have fewer approved therapies.
Q: How can I find a reputable compounding pharmacy?
A: Check your state board of pharmacy for information on which pharmacies are licensed to do business within your state. In addition, there are independent, third-parties (for example – the Pharmacy Compounding Accreditation Board) that accredit pharmacies meeting certain criteria. Veterinarians also should consider whether the pharmacy is compliant with the United States Pharmacopeial Convention (USP) standards, such as General Chapters <795> and <797> for non-sterile and sterile compounding, respectively, for both humans and animals.
Q: Can vaccines be compounded?
A: Unlike FDA’s rules, there is no term analogous to “compounding” when it comes to USDA’s rules (USDA’s Center for Veterinary Biologics is the federal regulatory authority governing animal vaccines/biologics).
When you’re reconstituting a vaccine to administer to a patient, be sure you are doing so according to the manufacturer’s directions. Mixing multiple vaccines in one syringe for administration is illegal, could be a liability issue, and could render the vaccines useless or even harmful, especially if they are adjuvanted vaccines.
Q: How can I know that the compounded medication prescribed and dispensed for my patient is safe and effective?
A: You don’t have the assurances with a compounded drug that you would have with an FDA-approved drug that the drug will effectively and safely treat your patient. Ways you can help to ensure therapeutic success in this scenario include:
- Determine if a compounded drug is really necessary.
- Prescribe from a reputable and trustworthy compounding pharmacy.
- Ask the pharmacist to provide evidence to support the stability and assigned “beyond-use date” (BUD).
- Ask the compounding pharmacist for evidence that the compounded drug is safe and effective.
- Inquire with the state board of pharmacy to ascertain the status of a pharmacy’s license and to gain valuable information including the pharmacy permit number. Recognize that most state boards of pharmacy require that an out-of-state pharmacy register with their state prior to filling prescriptions to be mailed into their state.
- Consider whether the pharmacy is certified by an independent body.
If you observe unanticipated drug precipitation, visible flocculant material, color change, or separation of liquid phases with a compounded preparation, these changes may indicate improper storage, transport, or an unexpected chemical/physical drug interaction. If you have questions about the efficacy or safety of the preparation, consult with the compounding pharmacist.
Q: What is the expiration date for compounded drugs?A:
Compounded preparations have beyond-use dates; FDA-approved products have expiration dates. Beyond-use dates and expiration dates are not the same. Expiration dates for the chemical and physical stability of manufactured products are determined from results of rigorous analytical and performance testing, and they are specific for a particular formulation in its container and at stated exposure conditions. According to the United States Pharmacopeial Convention (USP)
beyond-use dates (BUDs) are the date or time after which a compounded sterile preparation or compounded nonsterile preparation may not be stored or transported and are calculated from the date or time of compounding. Veterinarians should inquire with the pharmacist as to how the beyond-use date for a particular preparation was established.
Q: What is the difference between “potency” and “stability” testing in determining the beyond-use date (BUD) of a compound?
A: Potency testing measures the concentration of drug in a compound at a given point in time. Stability testing measures the amount of active drug remaining AND measures the amount of degraded drug byproducts present at a given time. Stability testing allows determination of a true beyond-use date (BUD).
Q: How do I know if the compound is bioavailable (e.g., being absorbed and reaching desired blood levels)?
A: You don’t. Veterinarians should seek results from scientifically designed studies demonstrating the efficacy and safety of a particular preparation, including drug delivery systems in the target species. These study results showing suitable stability, relative efficacy, and safety in the target species can be considered in the benefit-risk analysis a veterinarian performs when deciding whether to use the particular preparation in the patient. For example, some drugs are specially formulated by their manufacturers with various chemical complexes that allow them to be absorbed from animal gastrointestinal tracts. The bulk chemical for these drugs might not be absorbed appreciably from the animal’s gastrointestinal tract and blood levels cannot be assured from compounds of these drugs. Therefore, objective therapeutic monitoring is critical when using compounds in your patients.
Q: What's my liability if there's a problem with a compounded medication?
A: If you have a potential claim, you should always contact your liability carrier. Insurance carriers are unable to provide an unequivocal statement on the potential liability and related insurance coverage associated with compounding because the subject is a complex mix of state and federal regulations, with many situational variables, and a history of varying and unpredictable degrees of enforcement.
Q: How many refills can be ordered on a compounded prescription?
A: We are unaware of any differences between refilling compounded preparation prescriptions versus other refills. However, to be certain you are following the applicable rules for your state, check your state’s veterinary medical and pharmacy rules. Due to the short beyond-use dates (BUDs) on some compounds, more frequent refills may be indicated.
Q: Can controlled substances be compounded? And if so, how does the process differ from compounding non-controlled substances?
A: Yes, but remember you will need to follow the Food and Drug Administration’s (FDA) rules, the state’s rules, and the Drug Enforcement Administration’s (DEA) rules. When you prescribe a compounded controlled substance, be sure that the compounding pharmacy is dispensing the product directly to your client/patient. If you do this, you’re maintaining what federal authorities refer to as a “closed distribution system.”
However, if you allow the compounding pharmacy to deliver the controlled substance product to your clinic for your client to pick up, you’ll need to enter that delivery into your controlled substance records because you’ve received controlled substance inventory that must, by law, be tracked through recordkeeping. This may be necessary if the drug needs to be compounded for use within your clinic (for example, if the drug is needed for your patient who is being hospitalized), but recognize that receipt of the drug from the pharmacy is a registrant-to-registrant transfer of controlled substances for which DEA has very specific rules. In this case, your records need to show the flow through the clinic at a high level of detail, like any other shipment of controlled substances you receive.
Q: Can a client use a compounded medication for another pet/animal they own? A:
Check your state's pharmacy rules to be sure but, in general, if you are treating animals as a group, herd, or flock and you have an established veterinarian-client-patient relationship (VCPR)
, it would be acceptable to provide one prescription or dispensed product with directions for treating the group. However, you must have determined that the compounded drug is necessary for those animals, you are following FDA’s extralabel drug use rules, and the patients are to be treated as a group (e.g. a litter of puppies being treated for coccidia). If the animals are to be treated as individuals, separate prescriptions are advised to ensure client compliance and effective treatment. Be sure you keep accurate records and label the drug accordingly.
Regardless of the number of animals for which the prescription is filled, the AVMA recommends the following information be clearly included on the label.
- Name, address, and telephone number of veterinarian
- Name of clients
- Identification of animal(s) treated, species and number of animals treated, when possible
- Date of treatment, prescribing, or dispensing of drug
- Name, active ingredient, and quantity of the drug (or drug preparation) to be prescribed or dispensed
- Drug strength (if more than one strength available)
- Dosage and duration
- Route of administration
- Number of refills
- Cautionary statements, as needed
- Beyond-use date (BUD)
- Slaughter withdrawal and/or milk withholding times, if applicable
The actual container must bear the veterinarian's name, address, name of the drug (active ingredient), identification of the animal(s) to be treated, adequate directions for proper use, and cautions/precautions including milk and meat withdrawal times. This information may be on the label applied by the manufacturer, or on a label attached to the product by the veterinarian or compounding pharmacist.
Q: How do I register a possible adverse event or complaint about a compounded medication or a compounding pharmacy?A:
Veterinarians should report suspected adverse events or product failures involving compounded preparations to the compounding pharmacist, the state board of pharmacy, and the FDA Center for Veterinary Medicine. Instructions for reporting adverse events to FDA can be found on the FDA website
Pharmacists should instruct pet owners to contact both the prescribing veterinarian and pharmacist immediately if a compounded preparation has caused an adverse event.
If an unlawful pharmacy practice is suspected, a complaint should be filed with the respective state board of pharmacy, the state board where the pharmacy is located (if different), and the FDA.
Q: Is it legal to compound from bulk chemicals?
A: The FDA contends that compounding from bulk drug substances for animals has been illegal for many years and continues to be illegal.
That said, the FDA recognizes the medical need for compounding from bulk ingredients within certain areas of veterinary practice and under very specific circumstances. In November 2019 FDA released Guidance for Industry (GFI) # 256 “Compounding Animal Drugs from Bulk Drug Substances” which describes those conditions or situations under which the FDA does not intend
to take enforcement action against entities compounding animal drugs from BDS. Please see AVMA's FAQ regarding GFI #256