Off-Label Drug Use for Horses
Off-label drug use, which technically was illegal until recently, might be one of the most beneficial things we as veterinarians do in the treatment of disease in animals. The technically illegal part was a result of the way a drug was licensed by the Food & Drug Administration (FDA) for use. For example, Drug X is licensed for the treatment of Disease Y, in a specific species, at a specific dosage, and at a specific frequency of administration. If there was deviation from that protocol (unless under special circumstances), then use of the drug technically was illegal.
This is an area not only where there have been changes in regulations over the past few years, but one that now can be influenced by clinical research. For example, the plain white penicillin (which is still a very good drug in the horse) is licensed for the use of treating infection at the dose of 3,000 International Units (IU) per pound of body weight. Clinical experience has shown that this "labeled" dose is too low to be effective in curing many infections and that the dose of 10,000 IU per pound is much more effective. The label still says 3,000, but most veterinarians use 10,000 because that''s what works. For a drug company to go back and complete all of the research necessary to put 10,000 IU on the label could cost several million dollars, so the drug is used in an off-label way most of the time.
This example carries through for many available drugs whose dose and frequency of administration are modified based on years of clinical research. That information is disseminated in veterinary journals, textbooks, at universities and conferences, and by word of mouth. The bottom line is that the little label on the bottle represents, at times, more than $10-$15 million and five to eight years worth of research (or more) to support the specific usage of a drug. After the research is completed, the drug''s performance must be evaluated on clinical cases.
Unfortunately, many of the decisions made by the pharmaceutical industry are based on financial considerations. This is in part due to the system of FDA checks and balances that is in place to ensure that a marketed drug does in fact do what it is claimed to do and is safe to use; the potential benefits of a drug must outweigh the potential side effects. One such factor is called the "therapeutic index." This is a value that approximates the "closeness" between a drug''s effective dosage and its toxic dosage--the greater the therapeutic index, the safer the drug.
As I said before, the drug approval process is a lengthy and costly one. If a company gets the patent rights to a particular drug, they have a relatively short period of time (seven years, depending on the patent) to recover all of the research costs and the production costs and to make some degree of profit before the drug becomes available in generic forms.
Some drugs are extremely expensive to develop and produce, so despite our complaints about the price of pharmaceuticals, the company might not be making a profit. In addition, for every successful drug developed there might be a hundred "duds" that sucked up a company''s resources and are losses. In some cases, a drug will make it all the way through the approval process, then when it finally starts being used in millions of animals or people, side effects are noted that take it off the shelf.
Finding New Drugs
The process starts with the discovery of a compound that might have a potential use as a drug. Many drugs have very novel beginnings. For example, many of the antibiotics come from different fungal species that produce chemicals as a natural defense in their environment. Drug companies have collected dirt and fungus samples (millions of them) from all over the world and tested them one by one for the presence of an antibacterial agent--after all, penicillin was found in a mold growing on a loaf of bread. (Just think, that mold growing in the coffee cup you left on your desk might contain the next multi-million-dollar antibiotic.)
In fact, research is quite a lottery. The chances of finding a useful drug in that manner is about the same as winning the Lotto. For the billions of compounds tested, there is a relative handful of useful drugs developed.
The plant world is a source for many drugs. For example, the heart drug digitalis comes from the foxglove plant, and aspirin comes from the bark of the willow tree. Pharmaceutical companies have sampled plants from the most remote rain forests in the world looking for the next anti-cancer drug.
With more modern technology, drugs can be engineered for the diseases at hand. For example, a new anti-viral drug that might defeat the common cold recently was engineered to fit into a microscopic cleft on the virus surface and prevent it from even attaching to our cells, let alone causing a cold.
After the painstaking process of identifying a potential new drug and all the preliminary chemical analyses, the drug enters the first of the three-phase FDA approval process. The first phase describes how the drug distributes and works within the body--pharmacokinetics and pharmacodynamics, respectively. The initial evaluation for toxicity and side effects is underway at this point.
After a year or two of those tests, the drug enters phase two of the process. Now, it is used on a small number of clinical cases of the disease it is being developed to treat. The questions that must be answered are: What is the effective dose (if there is one)? What is the correct frequency and route of administration (oral, in the muscle, in the vein, or other)? What are the side effects, and are they greater than the benefits?
After another year or two of those tests, the drug enters phase three and begins a large-scale clinical evaluation. All of the aforementioned parameters must be fine-tuned.
If the drug makes it through that process, there is more work to be done to evaluate shelf life and stability. In addition, questions must be answered such as whether there are any interactions with other common drugs used in the treatment of the disease in question. Also, does it affect the pregnant, the young, or the old differently?
The bottom line is that there is an enormous amount of effort undertaken to get that drug in the prescription bottle.
As I mentioned before, a drug is licensed for the treatment of a specific disease, at a certain dosage and route of administration. Any deviation from that label is considered off-label use. A question at this point is why is there a need to use a drug "off-label"? The bottom line is that unless a drug can at least pay for its own development (and potentially generate a profit), it is very unlikely that this whole process outlined above will be undertaken. If it is developed for use in people, there might not be enough demand to do all the research needed to develop it for the horse.
It should be noted that even though the whole process has been completed for a specific drug for use in people or a small animal species, the entire process would need to be repeated using the horse as a target species to get the drug labeled for use in the horse.
Recent FDA legislation now allows veterinarians to use a drug in an off-label fashion for a specific disease if there is no other drug licensed for use in treating that disease, or if that treatment is not working. In equine practice, this is a very important factor since as many as 50% of the drugs we use in daily practice are used in an off-label way. This practice has broadened our disease-fighting capabilities tremendously.
One of the down sides of off-label use is that many of the drugs licensed for humans are expensive for the average 150-pound person; when the dose is scaled up for use in the horse, the expense can be quite shocking.
Another factor is that there are many older formulations of drugs that are no longer available from a commercial source. In such cases, we can have a pharmacist "compound" a suitable formulation on a case-by-case basis, which further broadens our treatment options. There are a number of examples of this type of drug usage in the horse.
Many of the antibiotics we use have not been licensed for use in the horse, especially some of the more exotic ones used for very resistant infections. Many of the ophthalmic (eye) drugs are from human medicine, particularly ones such as miconazole, natamycin, and itraconazole used for treating fungal infections. The drugs used to treat heart conditions in the horse are all licensed for human use. Quinidine, used in the treatment of atrial fibrillation, is an example.
If we look to the lungs in horses, the drug clenbuterol (Ventipulmin) recently was licensed for use in the horse as a bronchodilator for aiding in the treatment of allergic airway disease. Until that drug cleared FDA approval, we used human license drugs such as albuterol, theophylline, and the steroid inhalants beclomethasone and fluticisone.
In the gastrointestinal system, we recently saw the human drug omeprazole licensed for use in the horse for the treatment of gastric ulcers (GastroGard). That drug as well as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and sucralfate (Cara-fate) were (and in the case of all but Gastro-Gard still are) used off-label for the treatment of gastric ulcers.
These are just a few examples of the plethora of drugs used off label in the horse.
Picking The Medication
So, if these drugs were not licensed for use in the horse, how do we know that they will work and in fact not be harmful to the horse? In addition, how do we know how much to give and in what method to administer it?
Clinical pharmacology research in the horse is extremely active and is performed by universities and private clinics and practitioners all over the world. There is a journal (Journal of Veterinary Clinical Pharmacology and Chemotherapeutics) devoted to the subject. In addition, of the five major journals containing equine veterinary topics, clinical pharmacology is no stranger.
This clinical research is a vital component of the off-label drug use practice because the horse is a very unique species. There are things that are toxic to the horse that are not harmful to other species. In fact, there are drugs that have the exact opposite effect on the horse as they do on other species of animals.
Another much more important factor is that many of these drugs were originally studied on a simple stomached being (people, dog, cat), but the horse has a very different gastrointestinal system. The horse is a "post gastric fermenter," meaning that behind the stomach is a large fermentation vat. The horse derives much of its daily nutrition from the fermentation of fiber (hay). This poses a problem for many orally administered drugs as they have to survive this unique gastrointestinal system in order to be absorbed and go to work.
In addition, we know that some drugs bind to the hay particles and have very poor or delayed absorption. For example, the systemic anti-fungal drug ketoconazole was used in the horse to treat a variety of fungal infections (there is no systemic antifungal drug for use in the horse available commercially); it was also very expensive (about $100 per day). Use of the drug came before any research was performed. It was a relatively safe drug, and the dose was just increased extrapolating from the human dose. It was a good thought until subsequent research demonstrated that it was not absorbed at all in the horse; absolutely no ketoconazole could be found in the blood after weeks of administration.
Several other drugs have followed a similar trail. With the increase in technology and the heightened interest (and need) to use drugs in an off-label fashion in the horse, there are studies being performed every day all over the world to help guide the practitioner to the most effective usage of other medications in the horse.
In summary, the off-label use of pharmaceuticals in the horse is an important and vital part of equine practice and tremendously improves our ability to effectively treat equine disease.
About the Author
Michael A. Ball, DVM, completed an internship in medicine and surgery and an internship in anesthesia at the University of Georgia in 1994, a residency in internal medicine, and graduate work in pharmacology at Cornell University in 1997, and was on staff at Cornell before starting Early Winter Equine Medicine & Surgery located in Ithaca, N.Y. He is also an FEI veterinarian and works internationally with the United States Equestrian Team.
Ball authored Understanding The Equine Eye, Understanding Basic Horse Care, and Understanding Equine First Aid, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.