Prohibited Drugs and Drug Classes Prohibited From Extralabel Drug Use in Food Animals
Certain drugs may not be prescribed or used even under the auspices of AMDUCA.6 Under statutory authority provided in AMDUCA, the FDA-CVM has prohibited approximately a dozen drugs or drug classes, making their extralabel use in food animals illegal.
Other compounds not specifically listed in AMDUCA are prohibited because no approved animal or human products are commercially available. Last, extralabel use of treatments is also regulated by the Pasteurized Milk Ordinance (PMO). The extralabel use in food animals of the compounds listed in Box 45.5 represents one of the FDA's highest priorities for regulatory attention. It is advised that the FDA-prohibited drug list be checked on a regular basis for updates, as it is subject to change. FARAD and AVMA websites both list prohibited drugs.7,8 Alternatively,■ BOX 45.4
■ BOX 45.5
Conditions Necessary for Extralabel Use of Medicated Feed in Minor Species
1. Extralabel use of medicated feed is only for treatment of minor species, defined by exclusion as animals other than cattle, horses, swine, chickens, turkeys, dogs, and cats.
2. Extralabel use of medicated feed is limited to farmed or confined minor species but not unconfined wildlife.
3. Extralabel use of medicated feed is limited to situations in which the health of an animal is threatened and suffering or death may result from failure to treat.
4. There is no alternative therapeutic dosage form (besides feed) that can be practically used under legal extralabel use.
5. Only feeds formulated and labeled for use in a major species animal are used.
6. Extralabel use of medicated feed in aquaculture is limited to medicated feed products approved for use in aquatic species.
7. The medicated feed is used within 3 months of a veterinarian's written recommendation. Recommendations, feed labels, and invoices are kept for at least 1 year.
Adverse reactions are reported to the U.S. Food and Drug Administration within 10 days.8. All other AnimalMedicinalDrug Use Clarification Act requirements are complied with, including a valid veterinarian-client-patient relationship, lack of label alternatives, treatment records, animal identification, and extended withdrawal times (see Box 45.3).
9. The medicated feed is used in accordance with federal, state, and local environmental regulations and approval. This is particularly important for aquaculture uses.
10. The producer has followed worker safety provisions in the approved product labeling.
21CFR530, the section of the CFR pertaining to ELDU, may be accessed directly.9
If any of these prohibited drugs are mistakenly used in a food-producing animal, that animal and its by-products should never be allowed to enter the human food chain and ideally that animal should be isolated from other food animals.
Drugs Prohibited From Use in Food Animals
1. Diethylstilbestrol: From the 1940s to the 1970s, U.S. physicians prescribed diethylstilbestrol (DES, a potent nonsteroidal synthetic estrogen) to pregnant women to prevent miscarriage and other reproductive diseases. In 1971 a link between in utero exposure to DES and a rare vaginal cancer (clear cell adenocarcinoma) was established. In the same year the FDA published an alert advising doctors against the use of DES during pregnancy. The USDA banned the use of DES in food animals in 1979.
2. Chloramphenicol: An estimated 1 in 10,000 to 50,000 people exposed to chloramphenicol will develop a non-dose-related aplastic anemia. Because of concerns that this idiosyncratic and frequently fatal complication could be triggered by residues, chloramphenicol use in food animals was prohibited in 1984. The prohibition extends to all formulations of chloramphenicol, including ophthalmic ointments. Florfenicol, a synthetic member of the chloramphenicol family, lacks the p-NO2 group thought to be responsible for inducing the aplastic anemia.
Florfenicol may be used extralabel in food-producing species. However, veterinarians should be aware that extralabel use of florfenicol in dairy cattle older than 20 months of age requires extended withdrawals to allow depletion of drug residues in the liver to a level below detection by the Food Safety and Inspection Service (FSIS).Drugs or Drug Classes Prohibited From Extralabel Drug Usea
Diethylstilbestrol (DES)
Chloramphenicol
Nitroimidazoles (including dimetridazole, metronidazole, and
i pronidazole)
Sulfonamide (other than sulfadimethoxine) in adult dairy cattleb Clenbuterol
Fluoroquinolones (e.g., enrofloxacin, danofloxacin) Glycopeptides (e.g., vancomycin)
Nitrofurans (including nitrofurazone, furazolidone; topical use prohibited as well)
Phenylbutazone in adult dairy cattleb
Adamantane and neuraminidase inhibitors in poultry
Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys:
(i) For disease prevention purposes
(ii) At unapproved doses, frequencies, durations, or routes of administration
(iii) If the drug is not approved for that species and production class
aExtralabel use of some drugs or drug classes (not specifically addressed in the Animal Medicinal Drug Use Clarification Act) are prohibited because these drugs are not available as approved animal or human products, by U.S. Food and Drug Administration (FDA) policy or in the Pasteurized Milk Ordinance (see chapter text).
bDefined by the FDA as dairy cattle (lactating or dry) older than 20 months of age.
3. Nitroimidazoles: Historically, dimetridazole and ipronida- zole have been approved for the treatment of histomoniasis (infectious enterohepatitis, blackhead) in turkeys. Iproni- dazole and the human drug metronidazole have been used off-label to eliminate the carrier state of trichomoniasis in bulls. Laboratory studies of members of this drug class demonstrated mutagenicity and carcinogenicity, leading to the prohibition of their use in food animals.
Because there are no approved veterinary nitroimidazole labels, the use of any member of this drug class in food animals is illegal.4. Nitrofurans: In the past, nitrofurazone and furazolidone were approved for a variety of protozoal and bacterial infections in poultry and swine. Tapical formulations (sprays and “puffer” products) have also historically been marketed for wounds and ocular infections in livestock (“pinkeye”). Based on laboratory evidence of carcinogenicity and the absence of a reliable detection method, the FDA withdrew approval for systemic animal nitrofuran products in 1991 and prohibited all extralabel treatment (including topical use) in 2002. Because nitrofurans have no approved food animal uses, the use of any member of this drug class in food animals is illegal.
5. Clenbuterol: Marketed in the United States as an equine bronchodilator, this synthetic sympathomimetic has been used illicitly to increase weight gain and lean body mass in food animals, particularly show animals. Because muscle depletion and fat redeposition commences after drug withdrawal, producers may be tempted to market animals with little or no withdrawal interval. Cooking temperature only minimally denatures the compound, and toxicity from residues has resulted in hundreds of emergency hospitalizations in consumers of tainted beef in Spain and Italy.10,11
6. Glycopeptides: Vancomycin, the only glycopeptide antibiotic available in the United States, is often the therapy of last resort for methicillin-resistant Staphylococcus aureus (MRSA) infections in humans. Demonstration of vancomycin-resistant Enterococcus in the feces of poultry and swine fed the glycopeptide avoparcin led the CVM to prohibit extralabel use of glycopeptides in food animals in 1997.
7. Phenylbutazone in adult dairy cattle: The use of phenylbutazone, a nonsteroidal antiinflammatory drug, in humans has been associated with various adverse drug reactions, including fatal blood dyscrasias.
After USDA reports of a high incidence of phenylbutazone tissue residues in cull dairy cows, the CVM prohibited its use in female dairy cattle older than 20 months of age. Anti-inflammatory therapy for lactating dairy cattle is available as flunixin meglumine. Flunixin should be used only on-label (intravenously) because intramuscular or subcutaneous administration can greatly extend withdrawal times.128. Antiviral drugs in poultry: Concern exists that use of antiviral drugs in poultry could promote drug resistance in zoonotic pathogens, particularly avian influenza H5N1 (“bird flu”). These concerns led the CVM to prohibit extralabel use of two drug classes used in treating human influenza in 2006. Adamantanes and neuraminidase inhibitors may not be used in chickens, turkeys, and ducks. Aside from compounds specifically prohibited through AMDUCA, there are several compounds that the CVM has reminded veterinarians cannot be legally obtained as finished animal or human products and therefore have no legal extralabel uses.
9. Dipyrone: At one time approved for humans and animals, dipyrone was withdrawn from the market because of concerns of adverse events in humans associated with its use, including teratogenicity, prolonged bleeding times, and agranulocytosis.
10. Estradiol cypionate: Before 2003, estradiol cypionate (ECP; a synthetic estrogen) was commercially marketed as reproductive therapy in food animals. ECP had not undergone a formal approval process, however, and discretionary marketing was discontinued for lack of food safety and efficacy data. Use in or compounding of ECP for food animals remains illegal.
11. Gentian violet: Gentian violet was originally used as an additive to poultry feed as a mold inhibitor. However, the FDA has never approved the use of this product as a feed additive or as an animal drug, and the impact of any residues on human health is unknown. Therefore any use in feeds constitutes extralabel use of a medicated feed and unapproved animal drug.
In addition to medicated feeds, topical formulations containing gentian violet are currently being marketed. However, in 2007, the FDA issued a warning advising veterinarians of the illegal nature of using topical products containing gentian violet in foodproducing animals.12. Hormone implants in veal calves: Although growth-promoting hormone implants have been marketed for ruminating cattle, these products never underwent regulatory approval for nonruminating veal calves. Concern existed in the CVM that nonruminating calves may eliminate the hormone contained in the implants differently than ruminants. In 2005 a new warning statement was added to the label of all growth-promoting hormone implants, reminding producers and veterinarians that their use in veal calves is illegal.
13. Dimethyl sulfoxide and colloidal silver: Besides AMDUCA, the Grade A PMO also directs how drugs will be used and stored on dairy farms. Dimethyl sulfoxide (DMSO) and colloidal silver may not be used in or on dairy animals and, if found during a dairy inspection, can result in “debits.”
Drug Classes Prohibited From Extralabel
Drug Use in Food Animal Species
In addition to the aforementioned specific drugs that the FDA has prohibited, there are drug classes for which some drugs may have FDA approval for use in food-producing animals, but these drug classes are prohibited from any ELDU. Drug classes with an ELDU prohibition include the following:
1. Cephalosporin-class antibiotics: On April 5, 2012, in hopes of preserving their effectiveness for human populations and decreasing the likelihood of the emergence of cephalosporin- resistant strains of foodborne bacterial pathogens, the extralabel use of cephalosporins in cattle, swine, chickens, and turkeys was prohibited. This prohibition does not include (1) the extralabel use of cephapirin in food-producing animals; (2) use of a cephalosporin to treat an extralabel indication, provided that all other label directions are followed, including species, dose, route, duration, and frequency; and (3) extralabel use in minor food-producing animal species (i.e., species that do not include cattle, swine, chickens, or turkeys).
2. Sulfonamides in adult dairy cattle: The observed carcinogenicity of sulfonamides in laboratory animals, coupled with the frequent finding of sulfonamide residues in milk, led to the prohibition of extralabel use of these compounds in adult dairy cattle. The FDA defines a lactating cow as any dairy cow (milking or dry) older than 20 months of age. The use of any sulfonamide in adult dairy cattle other than approved uses of sulfadimethoxine (SDM), sulfabromethazine, and sulfamethoxypyridazine is illegal. This would include using a higher dose of SDM or slow-release formulation SDM boluses.
3. Fluoroquinolones: Uncertainty exists related to the magnitude and significance of human pathogen resistance resulting from antibiotic use in animals. Fluoroquinolones are mainstay treatments of antibiotic-resistant Salmonella and anthrax infections in humans. Concern that fluoroquinolone use in food animals was promoting human pathogen resistance prompted the CVM to prohibit extralabel use of these compounds in 1997. Any deviation from a fluoroquinolone product label (altering species use, dosage, route of administration, or disease indication) is illegal. In the case of the approved beef cattle formulation of danofloxacin, this prohibition extends to use in all non-beef-production animals, including lactating and nonlactating dairy cows, heifer replacements, bulls, and veal calves. The same applies to enrofloxacin, with the exception of nonlactating dairy cattle, defined by the FDA as dairy cows younger than 20 months of age, for which there is a label indication.