Photo of Deerhounds on a dune by Jan Enlund.

We take for granted that medicines will be safe and effective if we use them as prescribed or as the package label instructs. This month I want to explore that subject.

by John Dillberger, DVM, PhD

Reprinted from the November/December 2008 Claymore

Medicines are wonderful things—miracles, really, that conquer illness or let us live with it on terms we can accept. Dogs and people both have benefited from the discovery and development of new medicines in the 20th century. We take these medicines for granted most of the time; specifically, we take for granted that they will be safe and effective if we use them as prescribed or as the package label instructs. Have you ever thought about why that is so? This month I want to explore that subject.

History in a Nutshell

Today’s abundance of medicines can be traced to breakthroughs in chemistry made in the 18th and 19th centuries. Not that there weren’t medicines before then. There always have been, and always will be, medicines derived from plants and animals, such as willow bark and opium for pain. Chemistry’s contribution was to extract the pain-relieving substances in willow bark and poppy sap, deduce their molecular structures, and figure out how to make them in a laboratory and then in factories. Suddenly, we could have an endless supply of aspirin or morphine instead of being limited to what we could get from willow trees or poppies.

But that was just the beginning. Once we had the blueprint for a medical molecule, we could tweak its structure in a hundred different ways to see if we could come up with an even better version—one with longer-lasting activity, or that was stronger, or non-addictive, or more stable. This is the history of the medicines that fill today’s pharmacy shelves. And the process is still going on today in pharmaceutical companies and university research labs around the world.

Drugs for Dogs and People

Most readers will know that the same medicine often can be used in dogs and their owners. That is so because we and our dogs get many of the same illnesses and respond to them in similar ways. These similarities work in the favor of both species. For us, they mean that we can use dogs to test potential new medicines for safety and effectiveness before we test them in human volunteers. Many new human drugs would not be available if not for the knowledge gained from testing in dogs.

For dogs, the benefits may be just as great. Many of the medicines we now use in dogs would never have been developed for dogs alone because it would not be profitable to do so. Companies cannot develop new drugs that lose money, or they won’t be in business for long. So, companies develop many more drugs for humans than for animals. But once a new human drug is available, veterinary researchers can try it in dogs to see if it works as well as it does in human beings. Because of the similarities between dogs and humans, many human drugs turn out to be safe and effective in dogs.

The end result of using dogs to discover and test new human drugs is that we have pharmacies full of safe, effective medicines to treat and manage our own illnesses. And because many of these new drugs turn out to work well in dogs, too, we also have dozens of new medicines for our dogs.

Off-Label Use

A medicine may be marketed for both veterinary and human use, although under different names and at different strengths. Alternatively, the medicine may be marketed only for humans, but be used in dogs either because a veterinarian prescribes it or because an owner buys it directly.

Medicines are developed, approved for sale, and labeled to treat specific illnesses, and the instructions for how to use the drug for a particular illness are in the label. But medicines frequently are prescribed and used to treat illnesses other than those listed on the label, or are used at doses or for durations that are not described in the label. This so-called “off-label” use is perfectly ethical and legal. Indeed, the use of a human drug to treat an illness in a dog is simply another example of “off-label” use.

In the USA, a veterinarian is free to prescribe any drug, whether approved for use in humans or in animals, to treat any illness, and is not confined to using the drug only as the label directs. There is a catch, however. When a drug is prescribed and used as the label says, the manufacturer of the drug can be held liable for any harm that results. When a drug is prescribed for an off-label use, then the manufacturer is off the hook, and it is the veterinarian who is liable for any harm.

Approved versus Unapproved Use

Instead of the term “off-label use,” you will often hear the term “unapproved use.” Any off-label use is an “unapproved use.” This term reflects the fact that, in most countries, drugs must be approved by a government regulatory agency before they can be sold legally. Selling an unapproved drug is illegal. (Notice that it is illegal to sell an unapproved drug, but that it is not illegal to prescribe an approved drug for an off-label use.) As part of the approval process, the regulatory agency reviews the information from tests done in animals and humans to decide if there is sufficient evidence that the drug is safe and effective when used in a specific way to treat a specific illness. The agency also carefully reviews the proposed label to make sure it accurately and completely describes how to use the drug—what disease(s) it should be used for, what dose should be given, how long one should take the drug, potential side effects, and a lot more.

As you can see, every approved drug has its approved use. Using the drug in any other way is considered an “unapproved use.” Clearly, using a human drug to treat an illness in a dog is an unapproved use. Such unapproved use goes on every day. Many of the drugs routinely used to treat and manage cancer and cardiomyopathy in Deerhounds are being used in unapproved ways.

Is Off-Label, Unapproved Use Safe?

Should it concern us if drugs are used in unapproved ways to treat our dogs? Does it matter? Well, maybe—after all, dogs and humans are similar, not identical.

Veterinary drugs that are approved to treat a disease in dogs have been tested for safety and effectiveness against that disease in dogs, and the results have been reviewed and found acceptable by a government regulatory agency. In the USA, that agency is the Food and Drug Administration (FDA); specifically, the Center for Veterinary Medicine. Human drugs that are approved for use also have been tested for safety and effectiveness, but in humans, not in dogs. Human drugs are approved by a different branch of the FDA, called the Center for Drug Evaluation and Research.

So, one consequence of using a human drug in your dog is that the drug has not been tested in dogs. Sometimes there are published reports by veterinary researchers of studies done in dogs with the human drug, which give information on its effectiveness and safety. But otherwise you and your veterinarian are on your own.

But in truth, that is not always so. As I mentioned at the beginning of this article, many approved human drugs have been tested in dogs—some for effectiveness, and many more for safety. This is so because dogs (almost exclusively Beagles) are regularly used to test new human drugs before those drugs are tested in human volunteers. A new human drug may have been tested in dogs for many reasons:

• To see if the drug is effective, and what doses and dose regimens work best

• To identify potential side effects, understand at what doses the effects might occur, and learn if the effects will go away if one stops taking the drug.

Testing in animals for effectiveness is optional but widely done. Testing in animals for safety is required by law in most countries. In the USA, the test results must be reviewed and found acceptable by the FDA before a company can give a new drug to any human volunteer. And dogs rank right behind rats as the most commonly used species for testing the safety of human drugs.

Obviously if one is contemplating an off-label, unapproved use of a human drug in a dog, it would be useful to know if the drug was tested for safety in dogs and to see the reports from those studies. However, the reports for animal tests done by companies in the process of developing new human drugs are confidential. Unless published in a scientific journal (which is rare), the reports stay in company files.

But there is an indirect way to get at the animal testing information, at least in summary form, for human drugs approved for sale in the USA. That’s because the FDA produces a formal review document, called a Summary Basis of Approval (SBA), for every drug it approves. The SBA is a public document, which is available to any citizen. For newer drugs, the SBA can be had via the USFDA website.

For older drugs, one must make a written request. The SBA contains a detailed summary of each animal study done with the drug to investigate potential side effects. If the drug was tested for effectiveness or safety in dogs, then the SBA will summarize the studies that were done and the results, often in great detail.

An Example

Some drugs are available in approved versions for use in both dogs and humans. Even in those situations, it can be useful to review the animal testing done to support the approval of the human version of the drug, especially if that testing was done partly in dogs. Let me give you an example from my own experience.

There is a group of antibiotics called trimethoprim-sulfa drugs, which combine a drug called trimethoprim with any one of a number of different sulfa drugs. Several brands of trimethoprim- sulfa antibiotics are approved for use in humans and dogs. Years ago I was researching these antibiotics because the Deerhound Health Survey and anecdotal reports from owners suggested that these drugs sometimes led to bone marrow suppression in Deerhounds. As part of my research, I got hold of a summary of the testing done in Beagles back in the 1950s with the first one of these products: Tribrissen®, developed by Burroughs Wellcome Company (BW).

BW invented trimethoprim as an anti-malarial drug. It proved only modestly effective against malaria parasites, but when given together with one of the anti-bacterial sulfa drugs then available, the combination was very effective as an antibiotic. BW tested the combination product for safety in rats and dogs and then in human volunteers, and eventually received approval to market it as Tribrissen®.

From the testing reports, I learned that Tribrissen® had caused bone marrow suppression in dogs when given at relatively low doses—doses very close to those used to treat infection. BW had discovered that this toxicity was due to folic acid deficiency. This was not surprising, because the company knew that Tribrissen® killed bacteria by blocking their ability to make folic acid, and it was well known that bone marrow needed plenty of folic acid to make red blood cells, white blood cells, and platelets. The company assumed that dogs (and people) would have enough folic acid in reserve, or would absorb enough folic acid from their diet, to prevent them from being harmed by the product. Yet when the drug was given at doses only slightly higher than were effective in killing bacteria, some dogs developed bone marrow suppression. The company figured out how to “rescue” dogs that experienced bone marrow suppression, using an earlier drug they had developed called leucovorin.

Because the dog test results showed a risk of bone marrow suppression, BW carefully monitored human subjects in clinical trials with Tribrissen® for evidence of bone marrow suppression. Bone marrow suppression did not occur in humans. The product proved very safe and was eventually approved for sale.

Two decades later Tribrissen® was developed for use in animals, including dogs. Testing in dogs at that time did not reveal any risk of bone marrow suppression, probably because only a few dogs were tested and because the toxicity is sporadic and uncommon. No one remembered the earlier results, because they were filed away, and the people who did the testing were gone. Tribrissen® was approved for use in dogs, and approvals for other trimethoprim-sulfa combination products followed soon after. These products have been, and still are, widely used.

With time, it became apparent that some dogs developed bone marrow suppression when taking these products, although it took many years for veterinary researchers to come to that conclusion. Had the researchers been aware of the results of the first tests done in dogs, it might not have taken so long to realize that trimethoprim-sulfa drugs carry this potential risk.

Another Example

Let me give a different sort of example, with an over-the-counter product instead of a prescription drug. This time, I want to illustrate that it isn’t dog testing results that can alert one to the potential side effects of using a human drug in dogs. The results of safety tests in humans also can be useful. We use dogs to test potential new human drugs because the similarities in dogs and humans make dogs good predictors for what might happen in us. But by the same token, that makes us humans good predictors for what might happen in dogs.

One of my mother’s friends had a dog that developed an itchy scrotum. Based on recommendations from me, other owners, and websites, she started using Gold Bond® medicated powder, which worked like a charm, soothing the itch within seconds. Trouble was, after a few applications, it didn’t seem to be working as well. While the itching was soothed, the redness persisted. The owner did what most of us would do: she started putting the powder on more often. But the more she put on, the redder the dog’s scrotum became. Finally, she realized that the powder was making things worse, and stopped. When she called me, I suggested she put some hydrocortisone ointment on the scrotum to ease things. The dog made a fine recovery, although the skin on his scrotum peeled like it had been badly sunburned.

Out of curiosity, I did some web sleuthing to see if anyone else had ever experienced something like this with Gold Bond® medicated powder. I didn’t find anything similar described in dogs, but—surprise, surprise!—there was an email to a dermatologist from a man who had used the product on this particular part of his anatomy with exactly the same results as occurred in the unfortunate dog. The poor guy asked the dermatologist if the product could be responsible for the burning he experienced. The reply? “No, I don’t think so. Probably you have a secondary bacterial or yeast infection.” I am not saying that the dermatologist was wrong in his reply— simply that he did not have the benefit of knowing what I knew.

I tell this story not to malign Gold Bond® medicated powder, but simply to illustrate that what we learn about the side effects of a product in humans can be useful for predicting what might happen in dogs. In this case, it seems that the more tender skin of the scrotum does not always tolerate the Gold Bond® medicated powder.

Veterinary drugs approved for use in dogs must be tested in dogs for safety and effectiveness. Human drugs used in dogs need not be tested in dogs; however, some human drugs are tested for effectiveness in dogs, and many more are tested for safety, as part of the process of developing them for use in human patients. For human drugs, the results of safety testing in dogs (when available) and in humans can help guide safe use in dogs. For drugs approved in the

USA, information on testing in dogs is confidential and rarely published, but a summary can be gotten from the FDA.