Have you ever wondered how medications go from the lab to your dog?
Chances are, when you pick up your prescription drug or give your dog their heartworm medication, you don’t think about how that drug got from the drug company laboratory to your home. We are going to dive into that and talk about prescription drugs – from the lab to your dog. What are the laws and regulations about approval, dispensing, and prescribing medicines? We won’t cover OTC (over-the-counter) medications, those that anyone can pick up off the shelf (a), and we aren’t going to talk about supplements or herbal medicines. As with most government laws, regulations, and rules – approval of and prescribing medications is a bit confusing, nuanced, and filled with abbreviations. A similar process is used to approve drugs for both humans and animals.
THE FDA
The FDA (Food & Drug Administration) is responsible for the approval of both human (1) and animal medications (2). The approval process starts with the drug company having an idea, developing a new drug, testing it, and providing data to the FDA showing that the drug is “safe and effective for its intended use.” Data is obtained from laboratory and animal testing. For human medicines, scientists and physicians from the FDAs Center for Drug Evaluation and Research (CDER) evaluate the data, determine if the potential health benefits outweigh the known risks, and review the proposed labeling. Following CDER evaluation, the drug company performs clinical trials on human subjects to determine safety and efficacy. If the drug is found to be safe and effective in humans, it is approved.
Animal drugs are approved by another FDA division, the Center for Veterinary Medicine (CVM). The approval process is similar to that described for human drugs, BUT for drugs designed to treat animals raised for food, “the sponsor must also prove that it’s safe for people to eat food from treated animals (2).” In addition, a “pilot study” is required. This is a little “off-topic,” but drugs used to treat food-producing animals have a meat and milk withdrawal (with-hold) time that has been scientifically determined using available or extrapolated data based on drug, species, age of the animal, route of administration, dose, and duration of treatment, and the withdrawal is listed on the label (3). Meat and milk are routinely tested for drug residue way before they are processed for consumers, and there is a list published monthly of violators. Product with residue does not enter the human food supply. Any drug approved for use in animals must include the following information: “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.”
THE LABEL
So when a drug is approved for use, the approval also includes “the label.” The label describes what the drug has been approved to treat, including species, dose, administration route, and treatment duration. Any use of the drug that varies from the label use is considered “off-label” or “extra-label” (ELDU = extra-label drug use). In 1994 congress passed the Animal Medicinal Drug Use Clarification Act (AMDUCA). This act made “ELDU an FDA-regulated veterinary medical activity.” It allowed veterinarians to prescribe approved animal and human drugs ELDU “only when the health of an animal is threatened, or when suffering or death may result from failure to treat animals.” Before the passage of the AMDUCA, ELDU of animal drugs was “illegal” (4, 5). For example, very few drugs have been approved for use in “minor species” (sheep, goats), and before AMDUCA, it would have been illegal to treat a goat with pneumonia with a drug approved for use in cattle. The prescribing veterinarian determines if the “health of an animal is threatened, or when suffering or death may result from failure to treat animals.” If this statement appears particularly vague, it is, current FDA rules, regulations, and laws are open to broad interpretation. Today, with few exceptions primarily related to drug use in animals raised for food, it is not illegal to use most drugs extra-label in our dogs (or other companion species), but it is incumbent on the veterinarian to provide the client the information that the medication prescribed is ELDU.
THE GRAY ZONE
But of course, it isn’t quite that simple; for example, Previcox® (firocoxib) is a nonsteroidal anti-inflammatory drug labeled for use in dogs. Equioxx®, the same drug labeled for horses, is considerably more expensive (on a mg/mg basis) than the canine drug. However, according to the FDA, “selecting a canine product over an equine product for any nonmedical reason, including economics, is not acceptable.” (4) Economic concerns are a valid reason for ELDU only when the veterinarian can select an approved human drug to relieve pain and suffering in a non-food producing animal, even when an identical approved animal drug is available.
So basically, if your dog is prescribed fluoxetine, and the branded approved for dogs fluoxetine Reconcile® costs the client $2.00 per day, it is legal for the veterinarian to prescribe generic fluoxetine at a cost to the client 25 cents per day. However, if your arthritic mini horse needs firocoxib, it is not legal because of the cost of using the dog-approved drug.
If this all seems “a little gray,” it is a little gray, and veterinarians have had many discussions among themselves, with professional organizations, and with the FDA to determine what is and is not considered “legal.” The primary reason for regulatory oversight is to protect the US food supply from violative residues from drugs used to treat disease in food animals.
FLUOXETINE
So, let’s look at the label for Reconcile® (6), a branded fluoxetine hydrochloride product labeled for dogs. Most veterinarians, trainers, and behaviorists are familiar with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) that increases the concentration of serotonin (aka 5-hydroxytryptamine = 5-HT) in the synaptic cleft (space between neurons). In the early 1970s Eli Lilly began developing drugs that would inhibit the reuptake of 5-HT (7), thereby increasing 5-HT in the synaptic cleft. They based their drug search on the monoamine hypothesis that depression in humans resulted from a deficiency of monoamine function (in this context, monoamines are neurotransmitters, including 5-HT). Fluoxetine was first described as an SSRI in the scientific literature in 1974, and 16 years later, 1987, Prozac® was approved for use for humans with depression.
Today we have Prozac® and generic fluoxetine available for human use and Reconcile® specifically labeled for veterinary use. What exactly is on the Reconcile label? It starts with the notation, “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.” This is followed by a chemical description and molecular weight. Next are the “indications” – indications are basically “label-use” – in this instance, “Reconcile chewable tablets are indicated for the treatment of canine separation anxiety in conjunction with a behavior modification plan.” Following this is dosage (1-2 mg/kg once daily), administration (orally), and a behavior modification plan. Contraindications, precautions, warnings, after-approval side effects, and references are also listed.
So if Reconcile® is labeled for dogs with separation anxiety, how is it that we can use it for canine anxiety, fear, and aggression? We depend on the human, animal, and canine scientific literature (more on this to come!). The behavior drugs we use in veterinary medicine were originally developed for people. This means there is a body of scientific literature involving humans and animals that can be used when creating a behavior medication plan for a dog. It is worth mentioning that drugs labeled for use in dogs have been formulated for dogs and, therefore, may be better absorbed and or provide a more consistent response than branded or generic human drugs. That is not to say that Prozac or human generic medicines cannot be used in dogs, but it is something veterinarians consider when prescribing behavioral medications.
THE DEA
Other aspects of prescribing drugs for dogs are the Drug Enforcement Agency (DEA) and the Controlled Substance Act (CSA), which were signed into law by Richard Nixon in his “War on Drugs” initiative. Controlled drugs are in five schedules from schedule 1 (no medical use, high addiction/ abuse potential) to schedule 5 (medical use, lesser abuse /addiction potential) (8). To prescribe controlled drugs a veterinarian or human health care provider needs a DEA license. Practitioners cannot prescribe drugs from Schedule 1. Federal law requires meticulous records for prescribing and dispensing controlled substances and limits the amount of drugs dispensed. Members of the benzodiazepine group (alprazolam (Xanax®), carisoprodol (Soma®), clonazepam (Klonopin®), clorazepate (Tranxene®), diazepam (Valium®), lorazepam (Ativan®)) are schedule IV. When prescribing schedule IV drugs for canine behavior problems, the veterinarian must be cognizant of the human addiction/abuse potential, and if there is a concern, choose a different class of drug for the dog. Because it “enhances the high” from opioids, some states have “added” gabapentin to their controlled drug list. This is just an additional regulatory complication in the veterinarian’s ability to prescribe behavior medications to dogs.
PRESCRIBING A MEDICATION
Well, now we know how drugs for humans and animals are developed and approved. In the US, what happens next? In most states, the ability of a veterinarian to prescribe a drug for your dog requires a VCPR (veterinary client-patient relationship) (9). The requirements to establish a VCPR vary by state; some states require an in-person physical examination within a specified time, and in some states, telemedicine can be used to establish a VCPR. The VCPR established that the veterinarian is familiar with your dog and is assuming care for your dog. The VCPR doesn’t mean that your veterinarian is available 24/7/365 but requires that when the clinic is closed, you are provided information to other clinics or emergency facilities that can provide care. The veterinarian examines your dog, identifies abnormalities, and develops a plan. The plan can include laboratory work and radiographs (x-rays). Once all the data from the physical exam and testing is complied with, the veterinarian develops a differential list, which is a list of conditions that could cause the signs, physical exam findings, and test abnormalities. Based on the most likely diagnosis, medications are prescribed.
For example, a 2-year-old spayed Great Pyrenees presents to the veterinarian with recent onset abnormal head movements and seizure-like activity. The first differential may be idiopathic epilepsy, not uncommon in a young dog, and anti-seizure medication might be prescribed. However, the veterinarian wanted to do lab work in this case, and the client agreed. The lab work showed that the dog had mild anemia, slightly decreased kidney function, and significantly elevated serum potassium. This information rapidly changed the differential diagnosis from idiopathic epilepsy to acute renal failure or Addison’s disease (hypoadrenocorticism = the adrenal glands are not producing glucocorticoids or mineralocorticoids). Initial treatment for both conditions is the same (intravenous fluids and lowering the potassium), the dog was treated, clinical and laboratory signs stabilized, and the diagnosis of Addison’s disease was confirmed based on additional testing. The veterinarian prescribed Percorten V® (10) and prednisone to treat Addison’s disease. Percorten V (desoxycorticosterone pivalate injectable suspension) was the first drug approved to treat canine Addison’s disease in 1998. The label for Percorten V® states: “Dosage requirements are variable and must be individualized based on the patient’s response to therapy. Begin treatment with Percorten V® at a dose of 1.0 mg per pound of body weight every 25 days. In some patients, the dose may be reduced. Serum sodium and potassium levels should be monitored to ensure the animal is properly compensated. Most patients are well controlled with a dose range of 0.75 to 1.0 mg per pound of body weight, given every 21 to 30 days.” The label for Percorten V® provides guidance and a wide range of doses and duration based on the veterinarian’s assessment of the response to treatment. The label also states that treatment includes a glucocorticoid – in the case of our dog, prednisone. Meticortin® (prednisone) was patented in 1954 and approved by the FDA in 1955 for use in humans for a very wide range of conditions. Generic prednisone can be used ELDU in dogs. In this case, we have a prescription drug developed and approved for use in dogs with Addison’s disease with a lot of flexibility in dosage and interval between doses and a generic human drug with a wide range of label uses that can be used in dogs. Treatment is life-long, and the veterinarian modifies prescription drug doses over time based on clinical and laboratory findings and side effects.
The veterinarian is ultimately responsible for diagnosing and assessing the risks and benefits of a specific medication for the specific patient. There are medical, legal, and ethical considerations when a veterinarian prescribes a drug for your dog, and picking the right prescription for the dog is both an art and a science.
Thanks to Rene Smith CCBC-KA and Dr E’Lise Christensen for helpful comments and thoughtful review of this article, as well as Beth Kaiser for the wonderful graphic on “How an idea becomes your dog’s drug.”
(a) There are exceptions to this – for example pseudoephedrine [a cold and allergy medication] can be used to make methamphetamine, so as of 2005 the FDA requires that it is behind the pharmacy counter and requires ID to purchase. Phenylpropanolamine, known in the veterinary world as Prion: is used for urinary incontinence, and distributors require a DEA license for veterinarians to purchase it.
https://www.fda.gov/drugs/information-drug-class/legal-requirements-sale-and-purchase-drug-products-containing-pseudoephedrine-ephedrine-and phenylpropanolamine
(b) With the pandemic many states changed the requirements on how a veterinary client patient relationship can be established. Some states have returned to their pre pandemic “rules,” some follow the federal guidelines, and some states allow telemedicine. With the push toward telemedicine in veterinary medicine this is an ever changing situation.
(1) https://www.fda.gov/drugs/development-approval-process-drugs
(2) https://www.fda.gov/animal-veterinary/resources-you/fda-regulation-animal-drugs
(3) http://www.farad.org/eldu-resources.html
(4) https://www.avma.org/extralabel-drug-use-and-amduca-faq
(6) https://www.reconcile.com/wp-content/uploads/2021/02/prescribing-information-9-2020.pdf
(7) https://www.nature.com/articles/nrd1821
(8) https://www.deadiversion.usdoj.gov/schedules/
(10) https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5e9f71f1-09d4-4313-ad66-5cfffe428ba8
