FARAD Digest

1 JAVMA, Vol 223, No. 9, November 1, 2003 Vet Med Today: FARAD Digest1277 Recently published pharmacokinetic studies andnew drug approvals have made it possible and nec-essary to update the previously published FoodAnimal Residue Avoidance Databank ( FARAD )extralabel withdrawal interval (WDI)recommenda-tions for pharmaceuticals administered to food-pro-ducing animals. A label withdrawal time (WDT)isestablished by the FDA Center for Veterinary Medicinewhen a drug is approved for use in a food to the label WDT ensures that tissues orproducts taken from the treated animal will not con-tain residues in excess of the official WDIs are a specific FARAD recommenda-tion delineating the withholding time necessary toensure that violative residues of a drug will not bedetectable in tissues or products following extralabeluse.

2 FARAD recommendations for WDIs are based onpharmacokinetic data analysis, foreign and domesticlabel WDTs, and maximum residue limits (MRLs). Apatented algorithm for calculating WDIs (theExtrapolated Withdrawal Estimator) is also beingimplemented and validated. The purpose of thisFARAD Digest is to update the FARAD WDIs so thatpractitioners may have the most current informationon which to base extralabel drug use in food animals. Acepromazine MaleateAcepromazine maleate is not labeled for use in anyfood animal in the United States, but is labeled in Canadaand Australia. Previously, the FARAD extralabel WDI rec-ommendations for acepromazine in swine were derivedexclusively from foreign approvals.

3 The most conserva-tive of these foreign labels is the one Canada has for cat-tle, goats, sheep, pigs, and horses, where it may be admin-istered at a dose up to mg/kg ( mg/lb), IV, orup to mg/kg ( mg/lb), IM, with 7-day slaughterand 48-hour milk WDTs. Neither Canada nor Australiahas established an MRL (similar to a tolerance in theUnited States) for the drug despite its approved food ani-mal uses in those countries. However, one residue deple-tion study2supports the Canadian label slaughter WDT of7 days for swine when acepromazine is administered at upto mg/kg ( mg/lb), IM. Because of the completeabsence of residue and pharmacokinetic data for otherfood animal species, FARAD cannot make WDI recom-mendations for other species at this MeglumineFlunixin meglumine is not labeled for use in lac-tating dairy cattle in the United States.

4 On the basis ofpublished milk residue depletion studies,3 FARAD rec-ommends an extralabel milk WDI of 72 hours and aslaughter extralabel WDI of 4 days following doses ofup to mg/kg (1 mg/lb), should not begiven IM or SC because of excessive injection sitelesions and the prolonged tissue Effective May 7, 2002, the FDA prohibited use ofall nitrofuran-containing drugs in food-producing ani-mals. This prohibition includes topical applications ofnitrofuran puffer and wound spray in Lactating CattlePreviously, FARAD recommended extralabel milkWDI of 196 hours for dairy cattle receiving a sustainedrelease oxytetracycline product at a dose of 20 mg/kg (9 mg/lb).

5 In 1998, 1 product received a label addition forlactating dairy cattle that permits milk from treated cowsto be marketed 96 hours after a single IM or SC this approval, the US FDA Center for VeterinaryMedicine (USFDA/CVM)concurrently established thefirst US tolerance for tetracyclines in milk. The cow-milktolerance of ppm is based on the sum of all tetracy-cline family residues detected in a extralabel use of oxytetracycline by intrauter-ine administration, FARAD has recommended a 168-hour milk WDI after doses up to 2 g. Several studies4-6have been published on intrauterine use of tetracyclinein cattle, and these studies suggest that after adminis-tration of up to 2 g of oxytetracycline, a 72-hour extral-abel withdrawal period will allow milk residues todeplete to less than the newly established DigestFrom FARAD , Department of Environmental Toxicology, College ofAgricultural and Environmental Sciences, University of California,Davis, CA 95616 (Haskell, Payne, Craigmill); FARAD , Center forChemical Toxicology Research and Pharmacokinetics, College ofVeterinary Medicine, North Carolina State University, Raleigh, NC27606 (Gehring, Baynes, Riviere).

6 And FARAD , College ofVeterinary Medicine, University of Florida, Gainesville, FL 32610-0136 (Webb).Address correspondence to Dr. on FARAD food animal drug withholdingrecommendationsScott R. R. Haskell, DVM, MPVM; Ronette Gehring, BVSc, MMedVet; Michael A. Payne, DVM, PhD; Arthur L. Craigmill, PhD; Alistair I. Webb, BVSc, PhD, DACVA; Ronald E. Baynes, DVM, PhD; Jim E. Riviere, DVM, 10/9/2003 3:18 PM Page 12771278 Vet Med Today: FARAD Digest JAVMA, Vol 223, No. 9, November 1, 2003 These milk WDIs apply only to aqueous formulationsof oxytetracycline. FARAD recommends testing milkafter extralabel intrauterine administration, as there isinterindividual variability in the residue eliminationprofiles in milk.

7 On the basis of US and foreign labelWDTs, FARAD recommends an extralabel slaughterWDI of 28 days for such intrauterine treatment. Oxytetracycline in Other SpeciesThere are no USFDA/CVM-approved injectableoxytetracycline products for use in sheep or goats. TheAnimal Medical Drug Use Clarification Act of 1994(AMDUCA)authorizes veterinarians to use veterinaryor human pharmaceuticals in an extralabel prescribing extralabel treatment arerequired to establish an extralabel WDI sufficient toensure that harmful residues do not develop in foodproducts. Published pharmacokinetic and residue stud-ies7,8of oxytetracycline funded by the USDA s Minor UseAnimal Drug Program (National Research SupportProgram #7)

8 Have examined tissue depletion of oxyte-tracycline in sheep and goats following a single IM injec-tion of a sustained release product at a dose of 20 studies confirm that the slaughter WDT of 28days for cattle will be adequate as a FARAD -recom-mended extralabel WDI for slaughtered sheep and milk WDI of 96 hours will be adequate for a 20-mg/kgdose administered IM or SC to lactating swine, it is noteworthy that in August 1996,the National Pork Producers Council called for pro-ducers supplying packers for international markets tovoluntarily extend the label WDT from 7 days to 14days following the administration of tetracycline prod-ucts in feed or water to swine.

9 This extension in thelabel WDT was recommended to ensure the residueconcentrations will be below the MRLs of other coun-tries, which may be lower than the US tolerance. PhenylbutazoneOn May 29, 2003, the FDA began prohibitingextralabel use of phenylbutazone in female dairy cattle 20 months of age. FARAD discourages the use ofphenylbutazone in any food-producing animal becauseof its prolonged and TolazolineThe previous FARAD slaughter WDI recommen-dation for use of xylazine in cattle (10 days) was basedon foreign approvals and supported by serum pharma-cokinetic data indicating a similar half-life and volumeof distribution in all species studied.

10 New Zealandrecently approved use of xylazine in cattle, and thedata acquired for this approval has provided moreexacting milk and tissue depletion data. On the basis ofthese data, FARAD recommends a slaughter WDI of 4days and milk WDI of 24 hours after IM administrationof xylazine at to mg/kg ( to mg/lb)to cattle. Concurrently, New Zealand approved tolazo-line as a xylazine reversal agent in cattle. Based on theproduct approval data, FARAD recommends WDIs of48 hours for milk and 8 days for tissue when tolazolineis given IV at a dosage of to mg/kg ( to ) in cattle. References1. US FDA Center for Veterinary Medicine. Guideline forestablishing a withdrawal period.