But a high-profile case has brought the safety of this practice under scrutiny.
When 21 polo horses died suddenly in Florida this April, an investigation revealed a fatal error in the amount of selenium contained in a compounded vitamin-mineral supplement. Many similar mishaps have occurred, including a situation in Louisiana in 2008, when several horses died after receiving a compounded clenbuterol product.
So what is a compounded drug and how can a trainer be sure to avoid a potential error in compounding?
The U.S. Food and Drug Administration regulates medications for humans and animals. Specific laws governing drug products, their manufacturing and use include the Food Drug and Cosmetic Act, the Animal Medical Drug Use Clarification Act, and the State Pharmacy Board Regulations in each individual state. The state boards have the authority to monitor within their state, but they answer to the FDA. There might be slight differences in interpretation of the rules, and the FDA may act on things it considers to be out of bounds.
Every new drug must go through rigorous testing before it can be approved for commercial use. It must be tested in and approved for the target species. A drug that is legal and labeled for use in dogs, for instance, might not be labeled for use in horses. And there are numerous drugs approved for horses or dogs that are not labeled for use in food animals.
According to James P. Morehead, DVM, drug manufacturing comes under the authority of the FDA and includes strict requirements related to Good Laboratory Practices, Good Manufacturing Practices, data demonstrating safety, efficacy and other parameters.
“Under strict interpretation of the law, all compounding is illegal,” said Morehead, of Equine Medical Associates in Lexington, Ky., and a member of the American Association of Equine Practitioners Professional Conduct and Ethics Committee.
Yet veterinarians have been compounding for a long time. Years ago, before the advent of drug manufacturers, medications were always compounded. Even today, there are not always appropriate approved, manufactured products to meet every medical need, and certain medications must be compounded.
Veterinarians often compound their own medications and mix their own formulas, their own oral and topical treatments. In the equine market especially, there are a limited number of approved drugs commercially available. Also, some medications that veterinarians relied upon in the past have been dropped by the manufacturer, perhaps due to profitability issues.
“Therefore the FDA recognizes the need for compounded products in specific situations, in both human and animal medicine, and has published some guidelines for compounding,” said Morehead.
The AAEP also recognizes the importance of drug compounding.
Hoyt Cheramie, DVM, MS, was a practicing equine surgeon before going to work as the manager of large animal veterinary services at Merial. He said that in certain instances it is necessary to compound medications to effectively treat horses.
Take for instance the use of a human drug, pergolide, to treat horses with metabolic syndrome, or Cushings disease. This medication has prolonged the lives of many horses. Yet the FDA was considering a ban on compounding it for horses because it’s been pulled from the human market. Thanks to the efforts of several determined equine veterinarians and the AAEP, the FDA reversed its opinion about banning this drug.
Legal And Illegal Uses
“The way the FDA regulates compounding is to say it is all illegal, but that they will allow certain things,” said Morehead. “There are basic principles, in their guidelines for veterinarians, that tell us how and when to use compounded drugs and how not to.”
The criteria for legal compounding, as set forth by the FDA, include several important factors. Compounding can only be done by a licensed veterinarian or by a pharmacist upon the order of a veterinarian’s prescription for a particular patient. There must be a veterinarian-client-patient relationship.
As explained by Morehead, “A veterinarian should only order the specific amount of product needed for that particular animal, at the time it is needed. You cannot order compounded drugs for owners living elsewhere unless their horses are under your care, in your practice.”
Additionally, there must be a true need for it. The health of the animal must be threatened, or the animal must be at risk for death if there’s a failure to treat. In other words, compounded drugs are supposed to only be used when it’s a matter of life or death; it is not legal to compound a product that is merely used to enhance reproduction or athletic performance. If the health of the animal is not threatened, you should not have a product compounded for that animal.
To legally compound a certain drug, there must be no FDA-approved, commercially available animal or human drug already in existence that will appropriately treat the patient when used as labeled (or in an extra-label fashion in its current dosage form and concentration).
“If an approved product is available and appropriate for that specific condition, then we are required to use it,” said Morehead.
A case in point is oral altrenogest (known as Regu-Mate, to suppress estrus in mares), which is commercially available; it’s an FDA-approved product, to be administered daily.
“Even though a client may consider daily dosing inconvenient, this does not count as a reason to compound a long-acting injectable product,” he explained.
Another example: it’s not legal to compound phenylbutazone paste “to make it apple flavored or twice the concentration of the commercial paste, because it’s already available as an FDA-approved product,” said Morehead.
To be legal, a compounded product must be made from an FDA-approved, commercially available animal or human drug.
“If you do decide to compound your own phenylbutazone paste, then you are required to make it from the FDA-approved powder or tabs on the market. The FDA allows compounding when the approved product is not in the required concentration. It would be difficult, however, to convince the FDA that your apple-flavored compounded phenylbutazone paste at two times the normal concentration is needed for the health of the animal,” he said.
Sometimes, however, it may be necessary for a veterinarian to compound or write a prescription (for a pharmacist to compound) from non-approved substances. In these instances, the veterinarian is then responsible for the safety and efficacy of the compounded drug, and assumes liability when using the drug.
The FDA states that pharmacists and veterinarians should report (to the FDA) any adverse reactions associated with any drug. The veterinarian and pharmacist must carefully assess whether the use of the unapproved substance is consistent with state law and FDA policy.
“A big concern is when we batch compound, taking a base drug to create a different preparation that’s an unapproved new drug,” said Cheramie. “This becomes a legal and ethical question. Sometimes we need to do this for the benefit of the horse because there is no labeled product available for treating our cases. So we make medical decisions based on these factors. When we make this type of medical decision, most veterinarians would say this is probably an appropriate use of compounding, because there is no other formulation available.”
If there is a problem with a compounded drug, “the liability falls solely on the prescribing veterinarian,” said Morehead. “We must remember that the pharmacist is only following our direction. Should an adverse reaction occur and you are found negligent, then ‘standard of practice’ claims for your defense may not be admissible. The fact that use of compounded drugs and off-label use of medical devices is common practice will not constitute a viable defense in a malpractice suit.
“Supplying an illegally compounded medication, because the client requests it, is no excuse,” he added. “The veterinarian is the responsible and liable party.”
The compounded product must be safe and effective. “There are no requirements for stability or potency testing of compounded products,” said Morehead.
Therefore the AAEP suggests that veterinarians contact their state pharmacy board for advice on reputable compounding pharmacies and to verify that they are licensed. Morehead recommends that veterinarians develop a good relationship with an ethical, professional compounding pharmacist, and the FDA recommends asking the pharmacist which approved drugs will be used to compound the prescribed product.
The amount of product compounded must be commensurate with the need of the individual animal identified in the veterinarian-patient-client relationship-based prescription.
“The use of compounded medications should be on an as-needed basis, keeping on hand only what is needed now, or what you would normally expect to be needed in the short-term care for your patients,” said Morehead.
Keeping It Safe
Veterinarians must comply with all aspects of the federal extra-label drug use regulations, including accurate recordkeeping and labeling requirements. By strict definition, FDA does not allow bulk compounding of medications for use in horses.
As Cheramie explained, “bulk compounding would be taking the base drug and creating a formulation to produce a useable product and prepare it for administration. This would be considered creating a new, pioneer drug, which is illegal. To do that legally, you’d have to go through the FDA process of approval for that drug—to prove efficacy, safety, and appropriate dosing.”
It is not legal to produce a compounded drug in batch form, using commercial scale manufacturing, or to create the compounded drug for general resale.
“This is a real concern, when compounding pharmacies begin creating medications in the same formulation as an existing approved product, specifically to make a cheaper product,” said Cheramie. “One of the reasons it’s cheaper is because there’s been no research—no safety studies, no dosing studies, no trials to test the efficacy. It may not be absorbed the same, or be as effective as the approved drug. There are numerous studies that show compounded products are sometimes not as effective as those they intend to duplicate, and they may not even contain what’s on the label. The product may degrade because of how the pharmacist mixed it up.”
The expiration date of a compounded drug cannot be determined accurately, so it should only be used for the duration of the therapy for that particular horse.
“In other words, if you have a compounded product that is to be used on a horse for 30 days, at the conclusion of those 30 days the product has expired,” said Morehead.
“The common practice of saving whatever prescription is left over is not a good practice. We know the expiration dates of drugs that have gone through the FDA approval process, but we don’t have any idea on the compounded drugs,” Morehead added. “We don’t know what kind of shelf life they have; we don’t know their potency for sure, or concentration, or the active ingredients for sure. After a compounded drug sits awhile it may be ineffective, or it may become too potent. It could be one extreme or the other. That’s why it’s not a good idea to keep it around longer than for a one-point-in-time use for one patient.”
Some states require that a compounded medication be prepared only at the time of prescription and only in the amount needed by the individual patient. Other states permit compounding a certain medication in larger quantities in anticipation of historical need—for a product that will be necessary for a number of patients for which there is no FDA-approved treatment.
Morehead believes it is not a good idea, however, for pharmacies to compound a product and keep it on their shelves before sending it out as a prescription.
“FDA does not allow compounding of drugs to make money, or to substitute a compounded product at a cheaper price than an approved drug. Veterinarians cannot use compounded drugs to merely save money over FDA-approved available products,” said Morehead.
Presenting The Whole Picture
Since compounded drugs do not go through evaluation by the FDA, it can never be assumed that they are consistent from one batch to another or contain the stated amount of active ingredient(s), or are safe and efficacious for the intended use.
The practice of compounding is regulated, but the final products produced are not. There is no oversight regarding whether the product contains what the label says it contains.
The prescribing veterinarian should consider the legal, ethical and clinical ramifications concerning the use of compounded medications for patients and should always relate the benefits and risks of compounded drugs to the horse owner. The veterinarian should also understand that his or her professional liability insurance may not respond to allegations of negligence arising from the use of compounded drugs.
“As veterinarians we often think we are doing something good for the clients by getting them something cheaper,” said Cheramie. “But without giving them the whole story and allowing them to make that decision—to choose what they want to administer, knowing the potential safety issues if a product has not been tested—is not ethical. Some medications are safe even if the horse gets too much, but the margins of safety for others may be very small.”
Use of compounded “look-alike” drugs because they are cheaper than brand name drugs could ultimately reduce the number of approved drugs available. The process of bringing an approved product to market, including the necessary research and testing, is expensive. If a pharmaceutical company comes out with a new drug, and within a year it is being compounded illegally and sold for a cheaper price, the company may not be able to recoup the cost of the research that was necessary to bring the drug to market.
What Is A Compounded Drug?
Compounding is the manipulation of an existing, approved drug to make a different drug or dosage to meet the needs of a particular patient.
This may be done by mixing two drugs together, creating an oral suspension by crushing tablets and mixing the powder with fluid, adding flavoring or a palatable carrier to a commercially available drug to make it easier to administer orally, or any other manipulation—not specified on the label—that changes the form or dosage of the approved drug.
Legal compounding, in its strictest sense, would be to take an FDA-approved drug and change its formulation to make it more easily administered to a certain animal.
“For instance, before antibiotic powders were available, people used to crush up the tablets to mix with syrup to give to the horse,” said Hoyt Cheramie, DVM. “This is compounding, because it creates a significantly different formulation. We considered the crushed material equal in dosage to the antibiotic tablets. But there’s a possibility that mixing it with the syrup made it less (or more) bio-available. Maybe the horse absorbed less, or maybe it absorbed more; we really don’t know. We don’t think there was much change in this instance. When we compound something, we change the original form and nature of a product that was proven safe through the FDA-approval process.”
Not Generic Drugs
Since compounded drugs and generic drugs are both cheaper than brand-name drugs, some people have the misconception that they are the same thing.
Generic drugs, however, have been through the FDA-approval process and demonstrated their bio-equivalence to the “pioneer brand-name” drug they are duplicating. The pioneer drug has undergone the research necessary to bring it to market and has undergone the scrutiny of blinded controlled studies to demonstrate safety and efficacy in accordance with federal laws. Therapeutic consistency, product quality, accurate shelf life and scientifically substantiated labeling are federally mandated on these pioneer products.
The generics are the same as the brand-name pioneer drug in dosage form, efficacy, safety, strength, route of administration, quality, and intended use, and are brought to market after the patent on the pioneer drug expires. Generic drugs and their ingredients must be manufactured under Good Manufacturing Practices in federally inspected plants, just like the pioneer approved drugs. Generic drugs can always be identified by the ANADA (abbreviated new animal drug application) number on their label.