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Regulatory and Ethical Issues in Veterinary Pharmacy
In the United States, regulations governing veterinary drugs have much in common with the regulations that govern human drugs. For example, both human and animal drugs are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic (FDC) Act. New animal drugs must have an approved New Animal Drug Application (NADA), similar to the New Drug Application (NDA) for human drugs. Animal drugs, like human drugs, must be shown to be safe and effective for their intended uses. Generic copies of new animal drug products can be approved pursuant to submission of an Abbreviated New Animal Drug Application (ANADA).
However, regulations for human and animal drugs differ in important ways because of a critical distinction: humans are legally permitted to consume animal tissues and byproducts (with the exception of endangered species). The administration of drugs to food-producing animals—including addition of drugs to animal feed or water—has the potential to generate residues of the parent drug or its metabolites that could be consumed by (and pose health hazards to) humans. Thus, regulations governing veterinary drugs have evolved to ensure that drugs are safe and effective when used to treat animals, and also that food and other products derived from treated animals are safe for human consumption.
It is likely that most community pharmacists and pharmacy technicians will interact with animals primarily as pets or companion animals and will not be asked to fill prescriptions specifically for food-producing animals. Nonetheless, as the line between pets and food-producing animals continues to blur, it is imperative that all pharmacists who dispense drugs or compound prescriptions for animal patients have a working knowledge of veterinary drug law. Penalties for violating regulations can be steep, and lenience rarely is granted based on ignorance.
Food-Producing and Performance Animals
Pharmacists and pharmacy technicians should be familiar with two categories of animals that have important implications for veterinary drug law and pharmacy practice:
- Food-producing animals.
- Performance animals.
Many regulations specifically address the use of veterinary drugs in food-producing animals. This category traditionally encompasses livestock species such as cattle, swine, sheep, goats, chickens, turkeys, fish, and honeybees that provide food products consumed by humans—e.g., meat, milk, eggs, and honey. Food-producing animals also provide byproducts—e.g., fur, skin, bone meal, manure, hooves, horns, blood, internal organs, and beeswax—that are used extensively to create hundreds of other products used by humans (e.g., leather, wool).
The FDA considers the major food-producing animal species to be cows, pigs, chickens, and turkeys. However, because humans legally can consume any animal (except endangered species) as food—and many traditionally food-producing animals are kept as pets (e.g., chickens, pigs, goats, rabbits) or maintained as valuable breeding stock—neither the FDA nor Congress has defined a food-producing animal strictly by species. Rather, the intended use of the "target animal" is considered.1 For example, rabbits may be food-producing animals, pelt-producing animals, pets, performance animals, or laboratory animals. Pigs may be consumed as meat or kept as pets (e.g., potbellied and miniature pigs). Consequently, the intended use of any rabbit or pig must be considered carefully before drugs are administered.
The nature of the drug being administered also must be considered. As will be discussed later in the module, the FDA recently released a draft guidance on compounding animal drugs from bulk drug substances. In that guidance, the FDA proposes that all cattle, swine, chicken, turkey, sheep, goats, and non-ornamental fish always would be considered food-producing animals for the purposes of the guidance, regardless of whether the specific animal or food from the specific animal were intended to be introduced into the human or animal food chain.2 This means that pet pot-bellied pigs, pet chicks, and other animals that might be kept as pets always would be considered food-producing animals and therefore could not legally receive a compounded drug that contained a bulk drug substance.
Drug distribution into tissues is an area of extensive scientific investigation in veterinary medicine, and depletion profiles of drugs from muscle, organs, blood, milk, and eggs are characterized carefully for drugs approved for use in food-producing species. The time that must lapse after the last dose of drug is administered (either directly or in medicated feed) until the animal or food product is safe to enter the human food supply (i.e., is free of potentially harmful drug residues) is called a withdrawal time (abbreviated WDT) or withdrawal interval (WDI).3 Information about withdrawal times must be included in the product labeling of drugs approved for use in food animals.
Withdrawal times are expressed in terms of days for meat and eggs and hours for milk (in multiples of 12 because most cows are milked twice daily). For meat withdrawal times, the animal cannot be slaughtered for food prior to the date stated. For milk, the milk taken from the lactating cow must be discarded for the stated number of hours after the last dose of drug is given.
Pharmacists filling prescriptions and pharmacy technicians involved with the filling of prescriptions for animal patients must be aware of the intended use of the animal and follow all regulations and guidance when providing drugs for animals intended for use as food. This includes ensuring that the veterinarian's prescribed withdrawal time is included on the prescription label and the animal owner is aware of the need to keep the animal from entering the food supply during this time.
Animals used in competitive performance for human entertainment often are held to even more robust anti-cheating standards than human athletes are. Pharmacists are expected to exercise vigilance in preventing drug abuse by animal athletes.
Racehorses and racing greyhounds are held to an international anti-doping standard developed and enforced by members of the Association of Racing Commissioners International (ARCI). ARCI is composed of the governmental regulators of horse and greyhound racing in the United States, Canada, Mexico, Jamaica, and Trinidad-Tobago4; ARCI members are legally charged with ensuring the integrity of racing and parimutuel wagering in these jurisdictions. ARCI members conduct background investigations and license the participants in racing to safeguard the public interest and ensure the safety of animal athletes and their human riders.
ARCI has developed a set of Model Rules of Racing that include Uniform Classification Guidelines for medications and prohibited substances.5 Drugs are assigned to one of five classes (Table 1) according to the following criteria:
- Pharmacology. Drugs that are known to be potent stimulants or depressants are placed in higher classes (e.g., Class 1 or Class 2), while those that have little effect on the outcome of a race are placed in lower classes.
- Drug Use Patterns. Some consideration is given to placement of drugs based on practical experience with their use and the nature of positive tests. For example, procaine is classified as a Class 3 substance—not Class 2 like other local anesthetics—because procaine often is used in combination with penicillin, rather than as an anesthetic.
- Appropriateness of Drug Use. Drugs that clearly are intended for use in equine therapeutics are placed in lower classes. Drugs that are recognized as legitimately useful in equine therapeutics but could affect the outcome of a race are placed in the middle or higher classes.
|Table 1. Association of Racing Commissioners International Uniform Classification Guidelines
||Stimulant and depressant drugs that have the highest potential to affect performance and have no generally accepted medical use in the racing horse
Examples: opiates, amphetamines, all DEA Schedule I substances
||Drugs that have a high potential to affect performance, but less of a potential than drugs in Class 1; these drugs either are not generally accepted as therapeutic agents in racing horses, or they are therapeutic agents that have a high potential for abuse
Examples: psychotropic drugs, injectable local anesthetics
||Drugs that may or may not have generally accepted medical use in the racing horse, but the pharmacology of which suggests less potential to affect performance than drugs in Class 2
Examples: bronchodilators, anabolic steroids, high-ceiling diuretics
||Therapeutic medications that would be expected to have less potential to affect performance than those in Class 3
Examples: corticosteroids, cardiac glycosides, antidiarrheals
||Therapeutic medications for which concentration limits have been established by the racing jurisdictions as well as certain miscellaneous agents and other medications as determined by the regulatory bodies
Examples: anti-ulcer drugs, anticoagulants
|Source: Reference 5.
Four drugs are banned entirely: erythropoietin, darbepoietin, oxyglobin, and hemopure. In addition, use of any drug that has not been approved by the FDA is prohibited in the United States. Antibiotics, anthelmintics, antifungals, and vitamins are not classified and are always permitted.
Penalties for detection of classified substances are divided into four classes (A–D). Class A penalties accrue the highest penalty points, highest fines, and longest expulsions, followed by Classes B, C, and D. The drug classes generally correspond with penalty classes. For example, nearly all Class 1 and Class 2 drugs are Penalty A substances.
Pharmacists filling prescriptions and pharmacy technicians involved in the filling of prescriptions for performance animals should be familiar with drug use rules and penalties for animal athletes in their states.
The Veterinarian–Client–Patient Relationship
The veterinarian–client–patient relationship (VCPR) is the basis of providing care and medications for animals. The American Veterinary Medical Association defines a valid VCPR as meeting all of the following requirements6:
- The veterinarian has assumed responsibility for making medical judgments regarding the health of the animal patient, and the client (owner or caretaker) has agreed to follow the veterinarian's instructions.
- The veterinarian has sufficient knowledge of the patient to initiate at least a general or preliminary diagnosis of the patient's medical condition. This means that the veterinarian is personally acquainted with the keeping and care of the patient by virtue of (1) a timely examination of the patient or (2) medically appropriate and timely visits to the operation where the patient is managed.
- The veterinarian is readily available for follow-up evaluation or has arranged for veterinary emergency coverage and continuing care and treatment.
- The veterinarian provides oversight of treatment, compliance, and outcome.
- Patient records are maintained.
All states except Alaska, Connecticut, Delaware, Maine, Washington, and the District of Columbia currently have laws in place that require a VCPR before a veterinarian can prescribe a drug for use in an animal or a prescription drug can be dispensed for use in an animal.7 As will be discussed later in this module (see Evolution of Veterinary Drug Law section), even if a VCPR is not mandated at the state level, it is required by federal law when drugs are prescribed for extra-label uses in animal patients [21 CFR 530.10], when veterinary feed directive drugs are used in animal patients [21 CFR 558.6 (a)(2)], and when autologous biologics are used in animal patients [9 CFR 113.113].
Because the VCPR requires that the veterinarian is "personally acquainted with the keeping and care of the patient" by virtue of examination or visits to the operation where the patient is managed, "staff" veterinarians hired by Internet facilities cannot authorize prescriptions for animals with which they do not have a VCPR. Also, there are no specific federal statutes or regulations addressing whether an associate veterinarian in a group practice can approve a prescription refill after reviewing the patient's medical record when the attending veterinarian is away. Some state practice acts do address this situation, and it is a commonly accepted practice to honor prescriptions authorized in this manner.
Categories and Regulation of Drugs Used in Animals
Regulatory authority for products used in veterinary patients extends to a number of agencies at both the federal and state levels. These agencies include the FDA, the Drug Enforcement Administration (DEA), the U.S. Department of Agriculture (USDA), and the Environmental Protection Agency (EPA), in addition to the state boards of pharmacy and veterinary medicine.
Given the broad spectrum of stakeholder and patient needs in animal health care, a number of different categories have evolved for animal products. Major categories are described below, in the discussion of the respective regulatory agency; some newer categories are introduced and discussed in the section titled Evolution of Veterinary Drug Law.
Food and Drug Administration
The FDA is responsible for enforcing the FDC Act, which governs the safety and effectiveness of new animal drugs. The FDA's Center for Veterinary Medicine is charged with ensuring that drugs and medicated feeds are safe and effective for use in animals, and that food from treated animals is safe for humans to eat. Some products receive more attention than others, and some are governed concurrently by state laws. Adverse drug events that occur in animal patients are reported to the FDA using Form 1932a.8
Prescription and over-the-counter (OTC) drugs approved by the FDA for use in animals are listed in the "Green Book," also known as Animal Drugs@FDA (www.fda.gov/animalveterinary). All drugs in the Green Book will have an assigned NADA number for new animal drugs or an ANADA number for generic animal drugs. If a drug cannot be located in The Green Book, it is not FDA-approved for use in animals. National Drug Code (NDC) numbers for drugs only identify the manufacturer, the specific product (e.g., strength, dosage form, formulation), and package size and type: they do not confer legal approval by the FDA.
Although categories of veterinary drugs are similar to those for human drugs, there are some notable differences.
Prescription Drugs. Prescription animal drugs (also known as legend drugs) are restricted by federal law to use by or on the order of a licensed veterinarian, according to section 503(f) of the FDC Act. The law requires that such drugs be labeled with the statement "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian." Requirements exist at both the state and federal levels mandating that a VCPR be in place when these drugs are used in animals.
Over-the-Counter Drugs. The FDA is responsible for determining whether an animal drug product will be available by prescription only or sold directly to laypersons. OTC status hinges on whether it is possible to prepare "adequate directions for use" under which a layperson can use the drug safely and effectively. Safe use includes safety to the animal, safety of food products derived from the animal, safety to persons administering the drug or otherwise associated with the animal, and safety in terms of the drug's impact on the environment.
Human OTC drugs are not labeled for use in any species other than humans. Consequently, federal law prohibits the use of a human OTC drug in an animal unless such use is specifically pursuant to a prescription order by a licensed veterinarian who has a valid VCPR with that animal.
Recommending human OTCs for use in non-human patients is an illegal act. Pet owners who seek such guidance from pharmacists should be asked for written documentation (e.g., a prescription or discharge summary) establishing that a veterinarian has recommended use of a human OTC drug in their pet. Pet owners who have not sought veterinary evaluation should be encouraged to consult a licensed veterinarian and discouraged from self-medicating their pets. Many human OTC drugs are very toxic to non-human species.
Ethical Products. Ethical products are sold to veterinarians only as a condition of sale that is specified in a sales agreement or on the product label.6 There is no legal basis for restricting sales of these products to veterinarians; it is a voluntary marketing decision made by the manufacturer. Ethical products often are given a different product name and packaged differently than products that are sold directly to laypersons. For example, the same company sells omeprazole as Gastrogard to veterinarians only and Ulcergard directly to laypersons.
Compounded Preparations. Compounded preparations are treated similarly to prescription drugs: they can be prepared only on the order of a licensed veterinarian, with a VCPR in place for the patient in states that require it. At the time this module was finalized, compounding for animals is legal only if the compounder uses FDA-approved drug products as starting ingredients (see Veterinary Compounding Guidance section).
Dietary Supplements and Nutraceuticals. In contrast with the equivalent human products, dietary supplements and nutraceuticals for animals are regulated by the FDA as either foods or drugs. (Dietary supplements and nutraceuticals for humans are exempt from regulation under the Dietary Supplement and Health Education Act of 1994, known as DSHEA.) If dietary supplements for animals are marketed as foods, the products cannot contain active drug ingredients and the labeling cannot make therapeutic claims.9
Grooming Aids. Grooming aids—also known as veterinary cosmetics—typically are OTC products such as shampoos, cream rinses, and skin conditioners. They are not under the jurisdiction of the FDA, provided they do not contain any active drug ingredients and do not make therapeutic claims.
Drug Enforcement Agency
The DEA enforces provisions of the Controlled Substances Act of 1970 and subsequent amendments. Prescriptions for controlled substances for veterinary patients are handled in the same manner as prescriptions for human patients.
U.S. Department of Agriculture
By authority of the Virus-Serum-Toxin Act of 1913, the USDA is responsible for regulating all veterinary biologics, including vaccines. Within the USDA, the veterinary biologics staff at the Animal and Plant Health Inspection Service (APHIS) has jurisdiction over viruses, serums, toxins, and analogous products of natural or synthetic origin. In contrast with human medicine, the FDA has no regulatory authority over the veterinary vaccine market. Adverse events resulting from use of an animal vaccine or biologic are reported to the USDA via Adverse Event Report Worksheets that can be downloaded at the USDA website.10
Because veterinary biologics are regulated by the USDA, they technically are OTC products—the USDA cannot confer prescription drug status. Some states strictly limit possession or administration of certain biologics to licensed veterinarians or certified rabies vaccinators.
It is very important for pharmacists and in some states pharmacy technicians who are certified as immunizers to understand that they are trained and certified to immunize humans only. Certification does not extend to administering vaccines to animals.
Environmental Protection Agency
By authority of the Federal Insecticide, Fungicide and Rodenticide Act of 1947, the EPA is responsible for regulating the manufacture, sale, and use of pesticides—including rodenticides, insecticides, and germicidal preparations—used topically on animals or on inanimate objects. (Pesticides administered systemically to animals—e.g., orally administered flea control products—fall under the jurisdiction of the FDA.11) EPA-registered products must not be repackaged (i.e., must be dispensed in their original container) and must bear the original manufacturer label.12 Extra-label use of EPA-registered products is prohibited. Adverse events from use of EPA-registered products are reported using the portal at the National Pesticide Information Center.13
State Practice Acts
Practice acts for pharmacy, veterinary medicine, and other health professions originate at the state level, and laws and regulations vary significantly among professions depending on the state. It is imperative that pharmacists know all laws and regulations regarding the practice of pharmacy in the state(s) where they practice. However, it also is important for pharmacists and pharmacy technicians to be familiar with the veterinary practice act in their state(s), especially with respect to prescribing and dispensing drugs for animals. While it clearly is the jurisdiction of the Board of Pharmacy to regulate the practice of pharmacy in a particular state, and the jurisdiction of the Board of Veterinary Medicine to regulate the practice of veterinary medicine, there may be collaborative overlap.
Information regarding state boards of pharmacy can be found by visiting the National Association of Boards of Pharmacy website at www.nabp.net. Information regarding state boards of veterinary medicine can be found by visiting the American Association of Veterinary State Boards website at www.aavsb.org.
Evolution of Veterinary Drug Law
Pharmacists and pharmacy technicians will recall that the regulation of drugs intended for use in humans began in earnest when Congress passed the Federal Food and Drugs Act (also known as the Pure Food and Drug Act) of 1906.14 This legislation prohibited "misbranded" and "adulterated" foods and drugs in interstate commerce. The Food and Drugs Act was largely replaced by the FDC Act in 1938. The FDC Act required manufacturers to provide evidence that drug products were safe when used as directed, before the product would be approved for marketing. It also required that all drug products be labeled with adequate directions for safe use. In 1962, the Kefauver-Harris Amendments added a requirement that manufacturers provide substantial evidence that drug products were effective for their intended use, in the form of adequate and well-controlled studies.15
Both the Federal Food and Drugs Act and the FDC Act defined the term "drug" to include substances intended for use in the cure, mitigation, or prevention of disease in man or other animals. Thus, animal drugs were subject to the same provisions as human drugs. The Kefauver-Harris Amendments also applied to drugs intended for use in animals.
Yet as drug regulations evolved, the focus tended to be more on human use than use in animals. For example, in 1951, the Durham-Humphrey Amendment to the FDC Act defined a category of drugs that could not be used safely without medical supervision and thus could be dispensed only pursuant to a prescription from a licensed practitioner.16 The Durham-Humphrey Amendment created our current system of prescription and nonprescription medications—but it applied to human drugs only. A category of drugs that could be dispensed only on the order of a licensed veterinarian did not come about until 1988, with passage of the Generic Animal Drug and Patent Term Restoration Act (GADPTRA).17
Important differences also exist in extra-label use of drugs (i.e., use for an indication that has never received FDA approval) in humans and animals. After a drug is approved for human use, the FDA does not limit or control how physicians prescribe medications. In contrast—as will be explained in this section—extra-label use of drugs in animals is permitted only when specific conditions are met.
Food Additives Amendment of 1958
The regulation of veterinary drugs actually began unintentionally when Congress passed the Food Additives Amendment of 1958 in response to widespread public concern about the increased use of chemicals in foods.18,19 The Food Additives Amendment defined "food additive" as any substance intentionally added to food, and it made food additives subject to premarketing approval by the FDA unless they were generally recognized as safe (GRAS) for their intended use. Drugs used in food-producing animals were considered to be food additives, because the drugs were "added" to species intended to be "food" for humans. As a result, these drugs had to meet standards for both drugs (under the FDC Act) and additives (under the Food Additives Amendment). To gain FDA approval as an additive, manufacturers had to demonstrate that any drug residues present in edible products derived from treated animals—products such as meat, milk, eggs, and honey—were safe for humans.
The Food Additives Amendment also included language prohibiting the use of food additives in any manner other than the approved conditions of use. This meant that drugs used as food additives could be used only in accordance with the approved labeling.
Animal Drug Amendments of 1968
At the time the FDA established the Bureau of Veterinary Medicine (now the Center for Veterinary Medicine) in 1965, animal drugs were regulated under three different sections of the FDC Act.20 As drugs, they were subject to the provisions of section 505. If the drug was a certifiable antibiotic, it also was subject to the provisions of section 507. If the drug also qualified as a food additive, it was subject to the provisions of section 409.
Recognizing that this situation was complex and confusing, Congress passed the Animal Drug Amendments of 1968. These amendments consolidated the principal provisions relating to approval of new drugs for administration to animals into a single section (section 512).20,21 A "new animal drug" was defined as any drug intended for use in animals other than man, including any drug intended for use in animal feed. Before a new animal drug could receive FDA approval, it had to be established as both safe and effective for its intended use.
As the FDA explains on its website—by virtue of various Supreme Court interpretations, there are, for all practical purposes, no animal drugs that are not also new animal drugs.22 According to the section 512 provisions, a new animal drug is "unsafe" with respect to any particular use or intended use unless:
- There is an approved NADA for that use.
- The labeling and use of the drug conform to the approved NADA.
An unsafe new animal drug also is considered to be adulterated under section 501(a)(5) of the FDC Act.
By requiring that animal drugs be used only in the exact manner stated in the approved labeling, the section 512 provisions essentially made the extra-label use of drugs in any animal illegal. Extra-label use of animal drugs also was complicated by requirements for "adequate directions for use." Recall that a category of veterinary prescription drugs did not officially exist until 1988. According to section 502 of the FDC Act, a drug is considered to be misbranded unless its labeling bears adequate directions for use, defined elsewhere in regulations as "directions under which the layman can use a drug safely and for the purposes for which it is intended." (In the case of animal drugs, the "layman" typically might be a farmer.)
Animal Medicinal Drug Use Clarification Act of 1996
After the Animal Drug Amendments went into effect, the FDA quickly realized the difficult position that veterinarians were in. They were forced to choose between two impracticable alternatives: (1) follow the letter of the law and ignore suffering by not treating an animal patient if no appropriately labeled drug was available, or (2) break the law to uphold the veterinarian's oath (i.e., prevent and relieve animal suffering by using a drug off-label). The FDA attempted to address this dilemma by creating a set of guidelines for extra-label use of drugs in animals. These Compliance Policy Guides were internal guidance documents that specified when FDA intended to enforce regulatory action versus exercise regulatory discretion regarding extra-label drug use. But the Compliance Policy Guides did not resolve the dilemma, and veterinarians—increasingly frustrated with the choice of breaking the law or allowing animals to suffering—lobbied Congress in 1994 to pass the Animal Medicinal Drug Use Clarification Act (AMDUCA).23
AMDUCA permits extra-label uses of certain approved new animal drugs and approved human drugs, by or on the lawful order of a veterinarian within the context of a VCPR. "Extra-label use" is defined explicitly as "actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling." This includes, but is not limited to, use in species not listed in the labeling; use for indications (disease or other conditions) not listed in the labeling; use at dosage levels, frequencies, or routes of administration other than those stated in the labeling; and deviation from the labeled withdrawal time based on these different uses.
Extra-label use is limited to circumstances when the health of an animal is threatened, or suffering or death may result from failure to treat. There are additional restrictions on extra-label use in food-producing animals (see below). Some types of extra-label use are expressly prohibited:
- Use by a layperson (except when under the supervision of a licensed veterinarian).
- Use in or on animal feed.
- Use resulting in residue that may present a risk to the public health.
- Use resulting in residue above an established safe level, safe concentration, or tolerance.
AMDUCA requires that any drug dispensed for extra-label use (by a veterinarian or by a pharmacist on the order of a veterinarian) must bear or be accompanied by labeling information adequate to assure the safe and proper use of the drug. At a minimum, the labeling must include the information listed in Table 2. Note that the withdrawal time must be specified by the veterinarian, not the dispensing pharmacist; however, pharmacists who fail to include the withdrawal time on the label are in violation of federal law.
|Table 2. Labeling Requirements for Drugs Prescribed for Extra-Label Use
- Name of the prescribing veterinarian.
- Name and address of the dispensing pharmacy (if dispensed by a pharmacy); may include the address of the prescribing veterinarian.
- Established name of the drug (active ingredient), or, if formulated from more than one active ingredient, the established name of each ingredient.
- Any directions for use specified by the veterinarian, including class/species or identification of the animal(s) being treated; dosage, frequency, and route of administration; and duration of therapy.
- Any cautionary statements (for both the animal and the human caregiver).
- Veterinarian's specified withdrawal, withholding, or discard time(s) for meat, milk, eggs, or any food which might be derived from the treated animal(s).
|Source: Reference 23.
Extra-Label Use in Food-Producing Animals. AMDUCA includes very specific provisions for extra-label use of approved animal and human drugs in food-producing animals. Extra-label use is acceptable only if there is no approved animal drug that is labeled for such use in that species and that contains the same active ingredient in the required dosage form and concentration. Extra-label use of an approved human drug is not permitted in a food-producing animal if an animal drug approved for use in food-producing animals can be used in an extra-label manner for the particular use.
A drug labeled for use in humans can be administered to a non–food-producing animal even if an animal drug labeled for use in that species and medical condition exists. This means, for example, that veterinarians can prescribe human generic cefpodoxime tablets in place of veterinary-approved cefpodoxime for use in pets, but they cannot prescribe the human tablets for an animal intended to be used as food if a veterinary-approved product exists.
Veterinarians who prescribe an approved animal or human drug for extra-label use in a food-producing animal are required to establish a substantially extended withdrawal period prior to marketing of milk, meat, eggs, or other edible products, supported by appropriate scientific information. They also are required to take appropriate measures to ensure that assigned time frames for withdrawal are met and no illegal drug residues occur in any food-producing animal. If information regarding the human food safety aspect of the drug in food-producing animals is not available, veterinarians must ensure that the animal and its food products will not enter the human food supply.
It can be challenging to estimate accurate withdrawal times for drugs not specifically approved for use in food-producing animals, and penalties for illegal drug residues are severe. Veterinarians who do not wish (or are unable) to estimate an accurate withdrawal time can consult the Food Animal Drug Avoidance Databank (FARAD) at www.farad.org.24 FARAD is a risk management program supported by the USDA; FARAD scientists use their drug database and pharmacokinetic modeling to calculate accurate WDTs for drugs and pesticides. If no pharmacokinetic information is available regarding tissue depletion of a given drug, FARAD often will recommend an extremely conservative withdrawal time of 180 days. This long waiting period bypasses prime marketing ages for food animals and generally discourages continued use of the animal for food.
Pharmacists who feel a need to validate questionable withdrawal times should contact the prescribing veterinarian but also may consult FARAD for advice.
Pharmacy technicians should be aware of FARAD as a databank and resource in the pharmacy information system.
Drugs Prohibited for Use in Food-Producing Animals. Given the importance of keeping toxic drug residues out of the food supply, AMDUCA bans extra-label use of certain drugs and drug classes altogether in food-producing animals (or certain types of food animals). A current list of prohibited substances is provided in Table 3.25 Reasons for inclusion on the list range from a high incidence of non–dose-related aplastic anemia in humans (chloramphenicol) to carcinogenic potential (diethylstilbesterol, nitroimidazoles, nitrofurans) and concern about antimicrobial resistance (fluoroquinolone antibiotics, glycopeptides).
|Table 3. Drugs Prohibited for Extra-Label Use in Food-Producing Animals
- Adamantanes in chickens, turkeys, and ducks
- Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys:
- For disease prevention purposes
- At unapproved doses, frequencies, durations, or routes of administration
- If the drug is not approved for that species and production class
- Diethylstilbestrol (DES)
- Ipronidazole and other nitroimidazoles
- Neuraminidase inhibitors in chickens, turkeys, and ducks
- Phenylbutazone in female dairy cattle 20 months of age or older.
- Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine)
|Source: Reference 25.
The FDA may add drugs to this list at any time if they are shown to pose a risk to human health. Pharmacists are encouraged to consult the most up-to-date information at 21 CFR 530.41.25
Animal Drug Availability Act of 1996
After the Animal Drug Amendments were passed in 1968, the veterinary pharmaceutical industry could not possibly keep up with the need to develop, test, and label medications for all species–disease combinations in veterinary medicine (i.e., for every target species, at the required dose, by the appropriate route of administration, for the desired indication, and for the medically necessary duration of therapy). As a result, a shortage of suitably approved and labeled drug products developed quickly in the 1970s and 1980s.
Concurrent with the enacting of AMDUCA, Congress passed the Animal Drug Availability Act (ADAA) of 1996 to increase the number of approved new animal drugs on the market.26 The ADAA introduced significant changes to the animal drug approval process. Importantly, it amended the definition of "substantial evidence of effectiveness" to make the drug review and approval process more flexible; for example, it included provisions that allow approval following a single adequate and well-controlled study.
The ADAA also created a new category of drugs called veterinary feed directive (VFD) drugs.27,28 VFD drugs are intended for use in or on animal feed but are limited to use under the professional supervision of a licensed veterinarian. The VFD drug category was created largely to reduce unnecessary use of certain antimicrobial drugs in animals and slow or prevent the potential for the development of resistance to antimicrobial drugs administered through medicated feed or water.
Drugs used in animal feeds traditionally were approved as OTC drugs.28 This was done for practical purposes: if the drugs were available by prescription only, many state laws would have required feed mills to have a pharmacist onsite to dispense the drugs. When Congress passed the ADAA, it very deliberately avoided use of the term "prescription" to describe orders for VFD drugs, to avoid the need for these medicated feeds to be dispensed by state-licensed pharmacies.
Before an animal feed containing a VFD drug can be fed to animals, a licensed veterinarian must issue an order (a VFD) providing for such use, within the context of a VCPR.28 Typically, a veterinarian will direct a feed distributor to distribute (or mix and distribute) a certain medicated feed to an identified group of animals. VFDs are under the jurisdiction of the FDA; copies of VFDs must be retained by all parties for 2 years.
Recognizing the impact of VFD drugs on the food animal industry, the ADAA allowed for a 20-year implementation period. The regulations are fully enforceable as of January 1, 2017. After that date, VFD drugs may be used only exactly as described in the VFD submitted to an FDA-registered Medicated Feed Mill; they no longer will be available OTC.
Veterinary Compounding Guidance
Neither AMDUCA nor its regulations specifically permitted or prohibited the compounding of drugs for animals using bulk drug substances. A Compliance Policy Guide titled "Compounding of Drugs for Use in Animals" (CPG 608.400) was developed in 1996 and updated in 2003 to explain the FDA's current thinking and outline how it would exercise regulatory discretion regarding compounding with bulk chemicals for animals. In essence, the FDA would tolerate the use of bulk drug substances only when used to prepare antidotes for livestock poisonings.
In May 2015, reaction to the Drug Quality and Security Act (DQSA) of 2013 and its provisions regarding compounding for human use prompted the FDA to revoke CPG 608.400 rather suddenly and replace it with a proposed draft guidance (Guidance for Industry #230) that drew heavily on the compounding classes described in the DQSA.29 A Guidance for Industry differs significantly from a Compliance Policy Guide. Compliance Policy Guides advise FDA inspectors on how to apply agency standards and procedures when determining industry compliance; they do not inform stakeholders of FDA expectations for desirable practices. Guidances for Industry inform stakeholders of expected behaviors in areas unaddressed by law.
At the time this module was finalized, Guidance for Industry #230 remained a draft guidance and had not yet been implemented by the FDA. It sets forth an approach similar to the DQSA. Veterinary compounding would be divided into traditional compounders (i.e., pharmacists and veterinarians providing a compounded drug for an individual patient known at the time of compounding, pursuant to the veterinarian's prescription or order) and outsourcing facilities (i.e., FDA-registered facilities that compound drugs for distribution to veterinarians without a patient known at the time of compounding, in accordance with current good manufacturing practices).
The FDA would tolerate the use of bulk drug substances to compound drugs for individually identified animal patients that are not food-producing animals (as defined in the guidance), provided that compounding is medically necessary and the compounded drug cannot be made using an FDA-approved animal or human drug. Compounding drugs from bulk drug substances for use in food-producing animals would be subject to action for violations of the FDC Act. All cattle, swine, chicken, turkey, sheep, goats, and non-ornamental fish always would be considered food-producing animals, regardless of whether the specific animal or food from the specific animal were intended to be introduced into the human or animal food chain (e.g., pet pot-bellied pigs and pet chicks always would be food-producing animals). Prescriptions for drugs to be compounded from bulk drug substances would need to include the statement "This patient is not a food-producing animal."
Minor Use and Minor Species Act of 2004
In 2004, in an attempt to further increase the number of legally marketed new animal drugs, Congress passed the Minor Use and Minor Species Act (MUMS).30 MUMS was modeled on the Orphan Drug Act for humans. It modified provisions of the FDC Act to provide alternate drug approval pathways that help pharmaceutical companies overcome financial hurdles associated with developing limited-demand animal drugs:
- Drugs used to treat uncommon diseases in the major animal species (i.e., minor uses).
- Drugs used to treat minor animal species.
Because the markets for these drugs are so small, it is almost impossible for a company to generate sufficient revenues to offset the costs associated with the drug approval process.
For the purposes of MUMS, the major animal species are horses, dogs, cats, cattle, pigs, chickens, and turkeys. Minor species are all animals (other than humans) that are not one of the major species.
MUMS defines "minor use" as diseases that occur infrequently or in limited geographic areas, and in only a small number of animals annually. The FDA has established, and periodically reassesses, the specific number of animals that constitute the upper limit of minor use for each of the seven major animal species. Current threshold numbers are shown in Table 4.31
|Table 4. FDA Thresholds for Minor Use in Major Animal Species
||No. Animals to Determine "Minor" Use*
|*Number of animals treated must be below indicated threshold to quality as a minor use
Source: Reference 31.
MUMS also amended the FDC Act to allow for three new drug categories30:
- Conditional approval.
Conditional Approval. Conditional approval allows the sponsor of a veterinary drug to legally market the drug after proving that it is safe but before collecting all effectiveness data necessary for full approval. At the time of conditional approval, the sponsor must be able to show that there is a reasonable expectation for efficacy. The sponsor has 5 years to collect the remaining effectiveness data to prove efficacy. Conditionally approved drugs must be used exactly as labeled.
Indexing. The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index) is a list of drugs authorized by the FDA for use in minor species that are too rare or too varied to be the subject of adequate and well-controlled studies in support of drug approval. This classification is particularly helpful for treating captive and exotic wildlife and pet reptiles, fish, and birds. Indexing is possible only for minor species that are not used as food for humans or other animals.
Designation. This category provides incentives for pharmaceutical companies to develop drugs for minor use or minor species. For example, sponsors of "designated" new animal drugs can apply for grants to support safety and efficacy testing. They also are awarded 7 years of exclusive marketing rights after approval or conditional approval of the designated drug.
Filling Veterinary Prescriptions
Some states require veterinarians to write prescriptions for clients (owners or caretakers) to have filled elsewhere if requested by the client; others are less strict.32 It is important for pharmacists and pharmacy technicians (especially in the community setting) to be aware of requirements for dispensing medications for use in animals.
Elements of Veterinary Prescription Labels
Elements of the veterinary prescription label are mandated on both federal and state levels. Pharmacists are encouraged to consult local practice acts to determine state requirements for prescription labeling. As a rule, most states require the following information:
- Pharmacy name, address, and phone number.
- Prescription (serial) number.
- Date of initial dispensing.
- Name and species of the animal patient.
- Directions for use.
- Name and strength of the drug product (or active ingredients in a compounded prescription).
- Quantity or volume of drug product dispensed.
- Name of the prescribing veterinarian.
- Any withdrawal times stated for food-producing animals.
- Name of the dispensing pharmacist.
- Expiration or beyond-use date.
- Number of refills.
Many state boards of pharmacy also require the statement "For Veterinary Use Only" on the prescription label of medications to be used in animals.
When presented with a prescription, the pharmacist must verify that it represents a legitimate order from an appropriately licensed prescriber. Prescriptions for humans can be verified easily by requesting the prescriber's National Provider Identifier (NPI) number. Many software programs used in retail pharmacies require mandatory entry of the NPI number for identification of prescribers, or the DEA registration number for practitioners who are prescribing controlled substances.
Veterinarians are not eligible for NPI numbers. The DEA strongly opposes the use of DEA registration numbers for any purpose other than the intended (i.e., to provide certification of DEA registration in transactions involving controlled substances); this includes use as an identification number for non-controlled substances.33 Pharmacists therefore are encouraged to find alternative methods of verifying veterinarian prescribers, such as the state veterinary license number, office phone number, driver's license number, etc.
Veterinarians may not be aware of individual state rules regarding generic substitution of human drugs. In many states, pharmacists are obligated to substitute a generic drug in place of a brand drug unless the prescription is signed "dispense as written."
Although human generic drugs have demonstrated bioequivalence in humans, they may or may not be bioequivalent in animals. Pharmacists should contact veterinarians prior to substituting generic drugs to confirm that generic substitution is appropriate. Likewise, pharmacists should take the opportunity to educate veterinarians about use of the signature line "dispense as written" when a specific brand is required.
Information Resources for Veterinary Drug Law
Pharmacists who provide pharmaceutical care, products, and counseling for non-human patients must keep current on important statutes, regulations, rules, practice acts, and guidances for drug use in those species. Pharmacy technicians as part of their role should keep current on important statutes, regulations, rules, practice acts, and guidances for drug use in non-human patients as well. Information resources relevant to the legal and ethical use of drugs in animal species are described below.
Pharmacists and pharmacy technicians should be aware that the Model Act proposed by the National Association of Boards of Pharmacy in 2015 includes a facility requirement for pharmacies that provide care for non-human patients to have access to veterinary information resources.34
Plumb's Veterinary Drug Handbook
Plumb's Veterinary Drug Handbook is a comprehensive monograph reference of drugs used in non-human species. Most pertinent to this activity, Plumb's describes relevant food animal and performance animal prohibitions for use of each drug in non-human species.
Plumb's also is available as a subscription online database and app for desktop, smartphone, and tablet use (www.plumbsveterinarydrugs.com).
Regulatory agencies responsible for the oversight of drug use in veterinary patients provide news and event updates for their respective regulatory jurisdictions. Websites with updates that would be of particular use to pharmacists are listed in Table 5.
The FDA Center for Veterinary Medicine also offers a number of free subscription services:
Veterinary Pharmacy Professional Organizations
Some professional pharmacy organizations are dedicated to the advancement of veterinary pharmacy and patient care. These organizations offer multiple hours of ACPE-accredited continuing education as well as informative resource, critical regulatory updates, and interactive member listserves.
The Society of Veterinary Hospital Pharmacists (SVHP; http://www.svhp.org) is an international organization comprised of pharmacists working exclusively in the veterinary field, primarily at veterinary teaching hospitals in colleges of veterinary medicine. Associate membership is open to pharmacists, veterinarians, or other associated animal health professionals who have an interest in veterinary pharmacy. The Society meets annually for continuing education and exchange of ideas and information concerning veterinary pharmacy practice.
The American College of Veterinary Pharmacists (ACVP; http://www.vetmeds.org) was established to support the efforts of independent pharmacists in developing and strengthening the services they provide for animals as well as strengthening the support services they provide for veterinarians. ACVP encourages interaction and exchange of ideas among pharmacists and provides networking opportunities and specialty services for Members. ACVP is committed to providing support to develop a successful veterinary compounding practice.
Case Study 1: Dog Owner Requests Recommendation for OTC Antihistamine Product
A customer approaches you and asks for assistance in selecting an antihistamine for his dog.
You ask the pet owner why he thinks the dog needs an antihistamine. The pet owner replies that he just returned from a visit to the veterinarian; his dog had been scratching a lot, and licking and chewing at his feet. The veterinarian diagnosed seasonal allergies and recommended diphenhydramine 25 mg orally every 8 hours for 1 week. The veterinarian suggested that the dog owner purchase OTC diphenhydramine at a pharmacy because it would be less expensive.
The pharmacy technician should have the pet owner consult with the pharmacist.
The pharmacist then asks the pet owner to show the instructions from the veterinarian. The dog owner shares the visit summary with the treatment recommendation. The pharmacist helps the dog owner locate and purchase a box of 24 store-brand diphenhydramine 25-mg tablets.
Case Study 2: Prescription for Doxycycline in a Pet Chicken
You receive a prescription for "Thelma," a 1-year-old, 2-kg, intact female Rhode Island Red laying hen that is kept as a pet. Thelma is recovering from wounds suffered during a predator attack. The prescription is for doxycycline 100 mg tablets, #10. Directions for administration are 1 tablet orally every 12 hours for 5 days. Amount to dispense is 10 tablets; no refills are authorized.
Although Thelma is a pet, she still is potentially a food-producing animal because she is a laying hen. Her eggs should not be consumed by humans for an appropriate interval that should be determined by the veterinarian.
The pharmacy technicians consults the pharmacist.
The pharmacist calls the veterinarian and asks for an egg withdrawal time for the doxycycline. The veterinarian can consult FARAD; alternatively, the pharmacist can assist the veterinarian by locating any pharmacokinetic data on doxycycline disposition in eggs.
Once the veterinarian assigns a withdrawal time (e.g., 28 days), add the following information to the prescription label and include in verbal counseling: "Eggs from this animal should be discarded during administration of this drug and for 28 days after administering the last dose."
- Food and Drug Administration. Guidance for industry: changes to approved NADAs—new NADAs vs. Category II supplemental NADAs (May 2015). http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052460.pdf. Accessed October 1, 2016.
- Food and Drug Administration. Draft guidance for industry: compounding animal drugs from bulk drug substances (May 2015). http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM446862.pdf. Accessed October 1, 2016.
- Friedlander LG, Brynes SD, Fernández AH. The human food safety evaluation of new animal drugs. Vet Clin North Am Food Anim Pract. 1999;15(1):1-11.
- Racing Commissioners International website. http://www.arci.com/about-rci.html. Accessed October 1, 2016.
- Association of Racing Commissioners International. Uniform classification guidelines for foreign substances and recommended penalties and model rule. https://drive.google.com/file/d/0B2HwTiDKu_FHZmNVNFM1SHVVYXc/view. Accessed October 1, 2016.
- American Veterinary Medical Association. Principles of veterinary medical ethics of the AVMA. April 2016. https://www.avma.org/KB/Policies/Pages/Principles-of-Veterinary-Medical-Ethics-of-the-AVMA.aspx. Accessed October 1, 2016.
- American Veterinary Medical Association. Does every state require a valid VCPR to exist before a veterinarian can write a prescription? (table). https://www.avma.org/Advocacy/StateAndLocal/Documents/VCPR_state_chart.pdf. Updated June 2015. Accessed October 1, 2016.
- Food and Drug Administration. How to report animal drug side effects and product problems. http://www.fda.gov/AnimalVeterinary/SafetyHealth/ReportaProblem/ucm055305.htm. Updated February 22, 2016. Accessed October 1, 2016.
- Food and Drug Administration. Product regulation. http://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/ucm050223.htm. Updated February 23, 2015. Accessed October 1, 2016.
- U.S. Department of Agriculture. Adverse event reporting worksheets. https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/veterinary-biologics/adverse-event-reporting/ct_vb_adverse_event_forms. Updated July 17, 2015. Accessed Octoer 1, 2016.
- Food and Drug Administration. Is FDA responsible for regulating pesticides that are used in animal products? http://www.fda.gov/AboutFDA/Transparency/Basics/ucm217977.htm. Updated March 5, 2016. Accessed October 1, 2016.
- Environmental Protection Agency. Pesticide container and containment standards. http://www.epa.gov/sites/production/files/2015-06/documents/container_scope_flowchart_sr.pdf. Accessed October 1, 2016.
- National Pesticide Information Center. Veterinary pesticide incident reporting. http://pi.ace.orst.edu/vetrep/. Viewed September 29, 2016.
- Food and Drug Administration. Federal Food and Drugs Act of 1906. http://www.fda.gov/RegulatoryInformation/Legislation/ucm148690.htm. Updated May 20, 2009. Accessed October 1, 2016.
- Food and Drug Administration. Promoting safe and effective drugs for 100 years. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/PromotingSafeandEffectiveDrugsfor100Years/. Updated June 18, 2009. Accessed October 1, 2016.
- Food and Drug Administration. A history of the FDA and drug regulation in the United States. http://www.fda.gov/downloads/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandingover-the-countermedicines/ucm093550.pdf. Accessed October 1, 2016.
- Food and Drug Administration. Generic Animal Drug and Patent Term Restoration Act of 1988 (summary). http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/ucm147135.htm. Updated May 20, 2009. Accessed October 1, 2016.
- Food Additives Amendment of 1958. http://uscode.house.gov/statutes/pl/85/929.pdf. Accessed October 1, 2016.
- Sundlof SF. Legal control of veterinary drugs. In: Riviere JE, Papich MG, eds. Veterinary Pharmacology and Therapeutics. 9th ed. Ames, IA: Wiley-Blackwell; 2009:1355-64.
- Kingma FJ. New animal drug amendments and implementing regulations—FDA's view on their effect on sponsors. Food Drug Cosmet Law J. 1971;26:56-60.
- Food and Drug Administration. Chronological history of the Center for Veterinary Medicine. http://www.fda.gov/AboutFDA/WhatWeDo/History/FOrgsHistory/CVM/ucm142587.htm. Updated April 27, 2009. Accessed October 1, 2016.
- Food and Drug Administration. Animal drugs. http://www.fda.gov/AnimalVeterinary/ResourcesforYou/ucm268128.htm#A_Brief_Overview_of_CVM_s_Drug_Approval_Process. Updated June 16, 2015. Accessed October 1, 2016.
- Food and Drug Administration. Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/ActsRulesRegulations/ucm085377.htm. Updated December 9, 2014. Accessed October 1, 2016.
- Food Animal Residue Avoidance Databank. Withdrawal interval (WDI) recommendations. http://www.farad.org/wdilookup/. Accessed October 1, 2016.
- Code of Federal Regulations. Extralabel drug use in animals: drugs prohibited for extralabel use in animals. 21 CFR §530.41. http://www.ecfr.gov/cgi-bin/text-idx?SID=3666b3b4970c744d80966328dd4184f2&mc=true&node=pt21.6.530&rgn=div5#se21.6.530_141. Accessed October 1, 2016.
- Food and Drug Administration. Animal Drug Availability Act of 1996. http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/ActsRulesRegulations/ucm105940.htm. Updated July 27, 206. Accessed October 1, 2016.
- Food and Drug Administration. Veterinary feed directive (VFD). http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/ucm071807.htm. Updated October 11, 2016. Accessed October 13, 2013.
- Veterinary feed directive. Fed Regist. 2015;80:31707-35. To be codified at 21 CFR §514 and 21 CFR §558. https://www.federalregister.gov/documents/2015/06/03/2015-13393/veterinary-feed-directive. Accessed October 1, 2016.
- Food and Drug Administration. Draft guidance for industry: compounding animal drugs from bulk drug substances. http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM446862.pdf.
- Food and Drug Administration. Minor use/minor species. http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/MinorUseMinorSpecies/. Updated June 14, 2016. Accessed October 1, 2016.
- Food and Drug Administration. FDA to retain current small numbers of animals for minor use in major species. http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm397488.htm. Published May 19, 2014. Updated June 5, 2014. Accessed October 1, 2016.
- American Veterinary Medical Association. Prescriptions and pharmacies: for veterinarians (FAQ). https://www.avma.org/KB/Resources/FAQs/Pages/Prescriptions-and-Pharmacies-Veterinarian-FAQs.aspx. Accessed October 1, 2016.
- U.S. Department of Justice Drug Enforcement Administration Diversion Control Division. Prescriptions: questions & answers. http://www.deadiversion.usdoj.gov/faq/prescriptions.htm. Accessed October 1, 2016.
- National Association of Boards of Pharmacy. Model pharmacy act/rules. https://nabp.pharmacy/publications-reports/resource-documents/model-pharmacy-act-rules/. Accessed October 1, 2016.
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