FARAD Digest Drugs prohibited from extralabel use in food animals Michael A. Payne, DVM,PhD; Ronald E. Baynes, DVM,PhD; Stephen E Sundlof, DVM,PhD, DA8V'r; Anhur Craigmill, PhD;Alistair I. Webb, BVSC,PhD; Jim E. Riviere, DVM,PbD T he Animal Medidnal Drug Use Clarification Act Diethylstilbestrol (DES}-From 1941 to 1971,US (AMDUCA), signed into law in 1994, amended the physiciansprescribed this potent nonsteroidalsynthetic Food Drug and Cosmetic Act to decriminalize most estrogento between0.3 and 3 million pregnantwomen instancesof ExtralabelDrug Use by veterinarians.I to prevent miscarriageor other reproductive diseases.' This privilege, however, is not can~ blanche; specific The drug continued to be useddespite considerable evi- conditions must be met btIore a veterinarian may dence,collected during the 19505,that raisedquestions legally use or prescribe drugs in an extraIabel fashion regardingefficacy for its label claims.' In 1971 a link for food-producing animals. These requirementsl-4 between in utero exposureto DES and a rare vaginal include a valid veterinarian-clIent-patient relationship cancer (clear cell adenocarcinoma)was estab)jshed.' and appropriate drug labeling and record keeping. Between35 and ~ of fetal~ femaleo&prlng Certain ~gs may not be prescribed or used even will develop precancerous lesions,' which undergo under AMDUCA auspices.Section 530.21 of the act clear- malignanttransformation in approximately1 in 1,000of ly states that the FDA CenteI' for Veterinary MedidDe those exposed,'In 1971, the FDA pub)jshed an alm (CVM) may prohiliit the extI2label use of approved new advising doctors against the use of DES in pregnant animal or human drugs for a number of reasons.Thus far, WOlDen.The FDA banned the use of DES in food ani- FDA-CVM has prohibited 8 drugs or drug classes,mak- malsin 1979.\0The 'drug hasapplications in human and ing their extI2label use in food animals illegal companionanimal medicine,but DES-containingprod- Veterinarians violating state or federal laws regu- ucts ale not currently being marketed. lating the transpon, sale, or use of drugs may face var- ious sanctions, includl,ng warning letters, fines, tempo- Chloramphenicol-Reversible, dose-relatedbone rary or pennanent revocation of their state veterinary marrow suppression resulting from treatment with license, or incarceration. Extralabel use of any of the chloramphenicol has been detected in numerous prohibited drugs in food animals represents one of the species including humans. Of more concern is a FDA's highest priorities for regulatory attention. human-specific aplastic anemia, estimated to affect Because of the potential adverse human health between 1 in 10,000 to 50,000 exposed people. effects resulting from the use of these drugs in food Because this idiosyncratic toxicosis is often fatal, animals, FARAD will decline to routinely provide appearsto be non-doserelated, and could presumably withdrawal intervals for them. However, in the event of be triggered by residues, use of chloramphenicol in accidental exposure, FARAD bas consulted with veteri- food animals was prohibittd in 1984. Severalreports narians and regulatory officials to deterDline periods document human fatalities resulting from ophthalmic after which tissue and milk might be safely marketed. preparations containing chloramphenicol, with total This FARAD Digest provides background infor- exposure doses that could be achieved from food mation to more clearly define the regulatory require- residues.11Several veterinarians have been fined or ments regarding these compounds. The drugs are list- imprisoned for distributing or misbranding chloram- ed in the order in which they were prohibited. Except phenicol for use in food animals.11.UA number of onl, as described, these drugs should not be used in food injectable, and topical products containing chlonm- animals. phenicol are approved and available for use in small animals. The prohibition againstthe drug's use in food Prom the Food Animal Residue Avo~ Databank (FARAD), animals extends to all formulations of chlonmpheni- Environmental Toxicology Extension, College or AgricultUral and col including ophthalmic ointments. Florfenicol EDviroDmenta1Sd~, Unive:rStyof CaJifom1a,Davis, CA 95616 (Nuflor), a synthttic member of the chlonmphenicol (Payne.Cftigm111); FARAD, Center ror CutaDeOUSToxicolosy and family, is approvedfor use in beef cattlt in the United Residue Pharmacology,College or Veterinary Med1clne, NoM States.This compound lacks the p-NO2 group thought Carolina State University, Raleigh. NC 27606 (Baynes,Riviere); to be responsiblefor inducing aplastic anemia and has FARAD, Depanment or PbysioiOltcal Sciences, College or Veterinary Medtctne, University or Florida, Gainesville,PL 32610 not been associatedwith the syndromt.14Florfenicol (Webb); and the Center ror Veterinary Medtctne, Food and Drug may be usedin an extnl.bel fashion in food-producing Administntion, RockviDe,MD ~55 (SundJoC). species. 28 Vet Med Today:FARAD Digest JAVMA, \101215. No.1, July 1,1999 Nitroimidamles--Laboratory studies of members than 20 months. Currently, use of any sulfonamide of this drug class (which include dimetrtdazole, other than SDM in dairy cattle older then 20 months is metronidazole, and ipronidazole) have demonstrated illegal Additionally. exttaJabeluse of SDM in lactating mutAgenicity and carcinogenicity.I' After undergoing dairy cattle is prohibited (for example,use of a higher reductive activation in vivo, metabolites from these doseor slow-releaseSDM bolusesin dairy cattle is not compounds attAck DNA basepairs resulting in loss of permitted). helical structure, strand breakage,and possible inhibi- tion of DNA repair mechanisms. Oral exposure to Nitrofurans-As with the nitroimidazolesand sul- nitroimidazole compounds has causedcarcinogenesis fonamides, the can:tnogenicity and mutagenicity of in rodents and mutagenic urinary metabolites in nitrofurans bas been documented in laboratory stud- humans. D1metrldazole was approved in the mid- ies. Feedingtrials with nitrofurazone havedemonsttat- 19605 for the treatment of histomoniasis (infectious ed the development of fibroadenomasin mammary enterohepatitis, blackhead) in turkeys. Despite avail- glands of rats and benign mixed tumors and granulosa able label alternatives, the FDA-CVM documented cell tumors in ovariesof mice.DFurazolidone has been widespreadextralabel use of the drug to treat and pre- shown to causebronchial adenocarcinomasin mice fed vent swine dysentery Food safety concernsled to with- the compound for life.H Thesedrugs are also believed drawal of its approval in 1987,1' to cause occupational allergic contact dermatitis in Metronidazoleis approvedin humansfor the treat- humans.JSOn the basis of concernsrelated to caIctno- ment of trichomoniasis, amebiasis, giardiasis.. and genicity, approval for all human nitrofurazone prod- anaerobicbacterial infections. Shon-tenn exposure in ucts, except for dermatologic preparations,were with- human patients does not appear to increase risk of drawn in 1974.» Nitrofurazone and furazolidone had developing cancer.IT The drug has found extensive been approved for a variety of protozoal and other extralabelveterinary use for indications similar to those infections in poultry and swine. On the basis of car- in humans,particularly in the treatmentof giardiasisin cinogenicity and the absenceof a reliable detection companion animals. Metronidazole and ipronidazole method, the FDA withdrew approval for systemic ani- (the latter also once labeled for histomoniasis) have mal nitrofuran products in 1991.17A number of nitro- beenused to eliminate the bull carrier-stateof the vene- furan-containing products are still availablefor topical real diseasetrichomoniasis. With no approved veteri- use in dogs,cats, and horses.A limited number of top- nary nitroimidazole labels, the use of any member of ical nitrofurazone products Jabe.edfor .pinkeye in cat- this drug classin food animals is illegal. tle, sheep and goats",and "surface wounds, cuts and abrasionson all1ivestockwwere recently available.As a Sulfonamide use in dairy cattle-As with the result of a FDA-CVM sponsoredstudy demonstrating nitroimidazoles, concerns about suHonamideresidues meat and milk residuesfollowing label use,. manufac- have arisen as a result of observedcarcinogenicity in turers of these products a~ to remove their food laboratory animals. In 1988, the FDA National Center animal indications. The parenthetic reference to for Toxicologic Resean:hreponed an in~ in thy- "approved topicalWnitrofurans in AMDUCA will be roid follicular cell carcinomasand hepatocellular ade- omitted in the near future. Product with .oldw Jabels, nomas in rodents given large dosesof sulfamethazine already in distribution, may be depleted through nor- (SMZ),18.l9These studies were of panicular concern to mal sale channeJs.Following this, with no approved regulatory agencies,as they coincided with reports of food animal labels,the use of any member of this drug sulfonamide residuesin up to 13% of swine carcasses classin food animalswill be illegal and up to 73% of retail milk samples,30.1lIn swine tis- sue and milk, SMZ was by far the most common sul- Clenbuterol- This synthetic sympathomimetic is fonamide detected, becauseof the compounds wide- approved in a number of foreign countries and is spreaduse, high oral bioavailability, long half-life, and administeredas either a bronchodilator in horsesor as stability in the environmenL a uterine relaxant in cattle and sheep.A ~2 adrenergic A