Extralabel drug use in cattle (Proceedings)

Veterinarians have been a privilege to use and prescribe FDA approved drugs in an extra label manner and to compound drugs to meet the specific health care needs of the diverse patients. Veterinarians that work with livestock species need to be sure that the drug regime that they prescribe is not only safe for their patients but also for the end consumer that will utilize the meat, milk and eggs for nourishment. It is important that food veterinarians understand not only the pharmacokinetics of their treatment regimes but also the rules and regulations concerning extra label drug use (ELDU) and compounding.

Extra label drug use

The Animal Medicinal Drug Uses Clarification Act (AMDUCA) of 1994 as described in the code of federal regulations (21 CFR Part 530) gave veterinarians the legal right to use FDA approved drugs in an extra label manner within a valid veterinary-client-patient relationship. With this privilege came added responsibility for veterinarians. Specific label requirements include Name and Address of veterinarian, Name of drug, Directions for use, Cautionary statements, and specified withdrawal for food animals. Additionally, FDA requires that records of ELDU be maintained for 2 years. Record requirements include Identifying animal or group, Species, Number treated, Condition being treated, Name of drug, Dosage prescribed, Duration of treatment, and the Specified Withdrawal. Any drug that has been prohibited for use in food animals is also prohibited from extra-label usage in food animals. Currently, there are 10 drugs or drug classes that are either prohibited or prohibited from ELDU in food animals. These prohibited drugs are Diethylstilbestrol, Chloramphenicol, Nitromimidazoles, Nitrofurans, Clenbuterol, Sulfonamide use in lactating dairy cattle, Dipyrone, Fluoroquinolones, Glycopeptides, and Phenylbutazone in lactating dairy cattle. Additional restrictions include all medicated feed is restricted from ELDU and that ELDU is for treatment for health reasons not for production enhancement. The AVMA developed an algorithm to assist veterinarians in making proper ELDU decisions (Figure 1).

Figure 1. Extra Label Drug Use Algorithm

Extra label usage applies to any use of a drug that is not in accordance with the approved label. This uses could include species not listed in the labeling, use for indications not in the labeling, and use at dosages, frequencies or route of administration not listed in the labeling. Whenever drugs are used extra label the veterinarian must establish an extended withdrawal supported by appropriate scientific information.

Compounding update

Compounding is defined as the manipulation of a drug to produce a different product other than what is specified in the directions. Compounding can include altering FDA approved drugs or making products from bulk compounds. However, particularly for food animals compounding from bulk drugs or chemicals is prohibited by the Federal Food, Drug and Cosmetic Act as well as AMCUCA.

For food animals compounding of FDA approved drugs can only occur under the Extra Label Drug Use (ELDU) guidelines of the Animal Medicinal Drug Use Clarification Act (AMDUCA). These guidelines establish the following criteria: 1) a valid Veterinary Client Patient Relationship (VCPR) exists, 2) therapeutic need exists for the prevention of pain or suffering, 3) no approved drugs exist or are clinically effective, 4) compounding is performed by a licensed veterinarian or a pharmacist with a valid prescription, 5) the compounded product will be safe and efficacious, and 6) an appropriate extended withdrawal time is established and observed. An approved drug will have a NADA (animal), ANADA (generic) or NDA (human) number on the label. Examples of permissible compounding of FDA approved drugs into a new formulation include "spiking" IV solutions with dextrose or electrolytes, xylazine/lidocaine epidural, "triple drip" anesthesia solution, and other legitimate therapies.

However, the use of bulk drugs or chemicals to manufacture compounded products is prohibited by the Federal Food, Drug and Cosmetic Act as well as AMDUCA. Bulk drugs/chemicals by definition are not approved by the FDA and cannot be used for compounding. Furthermore, many of the compounded products currently available to veterinarians and producers are copies of approved products even though they may be advertised as generics. It is important to note that a generic drug is approved by the FDA as being an equivalent product and has an ANADA number on the label.

The FDA has specified what compounding practices would be considered "high regulatory priorities". These practices include preparation for sale of large quantities of unapproved drugs, compounding medications that are copies of FDA approved products, compounding from bulk drugs for use in food animals, and fanciful or trade names, advertising, promotion or display of an unapproved new animal drug.

Much of the bulk material for these pirated products is smuggled into the country from China, Pakistan or India. The use of these illegally compounded products poses a serious food safety risk for the following reasons. The manufacturing facilities for the bulk product and the illegally compounded product are not FDA inspected and may not meet good manufacturing practices for the production of safe substance. Potential for residues because the pharmacokinetics of the active ingredient, carriers and/or excipients may be different from FDA approved drugs and contaminants can be present. Additionally, the bio-security of the nation is at risk as there is the potential for the smuggled bulk product to carry a foreign animal disease such as foot-and-mouth disease virus or the nipah virus. Furthermore, since these products are illegal their usage in food animals would lead to an adulterated product and all animals that were administered the product would be condemned. Additionally, illegal activities performed or condoned by a veterinarian may void or invalidate some malpractice policies.

The FDA has provided a list of drugs which may be compounded from bulk under regulatory discretion to be used as antidotes when there is no approved product available. This list includes Ammonium molybdate, Ammonium tetrathiomolybdate, Ferric ferrocyanide, Methylene blue, Picrotoxin, Pilocarpine, Sodium nitrite, Sodium thiosulfate, and Tannic acid.

Food veterinarians should use approved labeled drugs when ever possible. If necessary approved products may be used in an extra label manner according to AMDUCA regulations. When no approved drug (label use or ELDU under AMDUCA) is judged to be clinically effective, the veterinarian can elect to compound using FDA approved drugs to provide therapy for patients.