Off-Label Drug Use

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Off-Label Drug Use

by: Ball, DVM

April 2000 Article # 225

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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.

FDA Approval

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.

Off-Label Use

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.