FARAD Digest Extralabel use of nonsteroidal anti-inflammatory drugs Paul Damian, PhD, MPH; Arthur L. Craigmill, PhD; Jim E. Riviere, DVM, PhD I n a recent survey of food animal veterinarians, it Table 1-FARAO recommendedwithdrawal intervals was found that 93%reported using nonsteroidal anti- MIlk Melt inflammatory dmgs (NSAlD), and almost60% reported y.~,,-;-""~- using thesedrugs more than once a week.1 Dairy prac- Dr-. --- 0 IIt8V8I(hi 1ItMWIlldi titioners use NSAID more frequently than beef practi- Aspirin All food AftI11III1 doslges 24 1 Inknl" tioners, and flunixin meglumineis usedmore frequently DipyIOnI Not IPIIrOV8din than aspirin, phenylbutazone,or dipyrone. At this time, food animals no commonly used NSAID has been approved for use K8IDprofIn Caull 3.3IRA, IVor 1M, 24 7 q 24 h, for up to in food animals in the United States.The purpose of 3 days this article is to provide practitionerswith recommended GOlts 3.3malkg, IV or 1M, 24 7 milk and meat withdrawal intervals (WDI) for some q 24h, for up to 3 days uses of NSAID. Sheep 3.3mglkg. IV or 1M, 24 7 q 24 h. for up to 3 days Aspirin Flunixin Cattle 1.1-2.2mg/kg, IV or 72 10 Aspirin (acetylsalicylicacid) is commonly used in megluminl 1M,q 24h, for food animals.Available over-the-counter, it is most com- 3to5dlyl Swine 2 mg/kg.1M NA 15 monly administeredas 60- or 240..graintablets (1 grain = PlllnylbulllOnl CaIIIl 6 g/animal.IV or 1M. 12 65 mg). Aspirin formulations havenot beenapproved by 4-t g/anlmll,IV or 131 21 the FDA-Center for Veterinary Medicine (FDA-CVM); 1M,toa_d by up to 2 g/lnlml' however,the agencyconsiders use of aspirin to be of low daily regulatoryconcern. Under this policy, the FDA-CVM as- sumesthat veterinariansknow how to usethe drug prop- -Toc-.tw ~. divideby U erly and that the drug doesnot presenta substantialfood NA."~, safetyissue; therefore, formal drug approvalis not neces- sary.However, it also meansthat uniform WDI recom- the Dec 6, 1995 GYM Updateand include a lack of data mendations have not been establishedfor commercial indicating that dipyrone is safeand effective as well as aspirin products, although someproduct labelsdo con- lack of pharmacokinetic and residue infonnation that tain warnings againstuse in lactating dairy animals.De- can be used to establish a WDI. In addition, dipyrone spite the fact that aspirin is of low regulatory concern, has been associatedwith toxic effects in human be- some epidemiologicdata suggesta link betweensalicy- ings, including bone-marrow toxicosis, agranulocytic lates and Reyessyndrome in children with chickenpox anemia, and teratogenicity. or influenza} For this reason,FARAD recommends mini- mum meat and milk WDI of 24 hours for typical usesof Ketoprofen aspirin in food animals. There are few published residue or pharmacoki- netic data for ketoprofen. Available data in cattle indi- Dipyrone catea short terminal half-life of 30 minutes and a small Extralabel use of dipyrone in food animals is spe- volume of distribution (0.2 Ukg [0.09 IJ1b]). Milk cifically prohibited by the FDA-CVM; therefore,FARAD concentrations following IV administration at the rate does not offer extralabel WDI recommendations for of 3.3 mg/kg (1.5 mg/lb) of body weight to dairy cows this drug. Reasonsfor this prohibition are describedin werealways less than the limit of quantitation(27 ng/ml). Results in lactating goats also indicated a short half- Prom the Food Animal Residue Avoidance Databank (FARAD), Environmental Toxicology Extension, College or AgricultUral and life (20 minutes) and a small volume of distribution Environmental Sciences, University of CaUfomia, Davis, CA 95616- (0.23 Ukg [0.10 IJ1b]), suggesting limited distribu- 8.588 (Damian, Craigmill), and FARAD, Cutaneous Pharmacology tion in tissue. Ketoprofen was not detected in milk and Toxicology Center, College of Veterinary Medicine, North from goats treated with a single IV bolus at 2.2 mg/kg Carolina State University, Raleigh,NC 27606 (Riviere). (1 mg/ib). In France,ketoprofen is approved for use in Referencesto studies mentioned in this reP;Ortand references for FARAD determinations are available on written request. cattle, and recommendedmeat and milk WDI for this laU/8~-r,umxln vetennery proaucts approvedtor use in food animals in foreign countries Table 3-Pheny1butazone veterinary products approved .. ... for use in food animals in foreign countries ~ 0 v.-:".-11""'.'I~I II1II..I~ ~ ... ~ ..~~ ..~~ flllland c.1d8 2.2~ IV,q 24h,:' 7 ~ .. ~ .41 for up to 5 dlY' SwfIz8ftIIId CIaII W FrInc. c.1d8 2 ~, W~ 1M . '. .,..,... IIow 1a 12 WI8 2 nII/ke.1M NA . IV or 1M ~ c.1d8 2.2n'IOI'ko. IV. 1M. 72 I CaIYII 1-2 8/1'*nIUM 12 SwIne ,~ 8/1""1, 1M 12 q24h fr8IC8 c... 48/111in11.1V~. 21 1M, on die firII s.. TIbII1 for kIY. diY, 2 8/lntmll on Sla.qlJ8ntdlyl CMs 2 g/1IimII,IV or NA 21 drug given IV or 1M at 3.3 mglkg, every 24 hours, for 1M, on dIe 11m 3 days, are 4 and 0 days, respectively.On the basis of dIY, 1 g/lninli on IU.UI" dIYI this information, FARAD recommendsmeat and milk SwinI 2~ ~lnimlllV or NA Z1 WDI of 7 days and 24 hours, respectively, for use of 1M,q 24h ketoprofen in cattle, sheep,or goatsat dosagesof up to '-',., C6 W 1Iow . 11 lVorN 3.3 mg/kg, every 24 hours, for up to 3 days (Table 1). CaIve8 1~g/II8lIM NA 12 SMI8 1.W "IM NA 12 Flunlxln Mevlumine In the United States,flunixin meglumine is labeled "'TI~I_W for use in horses only. Only limited pharmacokinetic I and residue data are available in food animals. In 1 c nance dosageof 2..5to 14.0 mg/kg (1.1 to 6.4 mg/lb), study, 1 cow was given 2.2 mg of flunixin meglumin~g t every 24 or 48 hours. The potential for residues in (1 mg/lb), IV; twice, 12 hours apart. Concentrations of 1 treated animals is high becauseof its long elimination flunixin meglumine in milk 24 hours after treatment i half-life in cattle. Plasmaelimination half-lives rang- were similar to concenn-ationsin milk from untreated ~ing from 30 to 80 hours havebeen reponed, with about control animals. In a radiolabel study in which cows f 40 hours being most common. Phenylbutazoneis also received2.2 mgIkg, IV;background concentrations were ~excreted in milk. In cows. given a loading dose of reachedin milk by 72 hours. In a multiple dosing study, f 24 IngI1cg (11 mgI1b)followed by 12 mgIkg (5.5 mgAb), lactating cows received 1.1 mg/kg (0.5 mg/lb), every 8 t every 24 hours, milk residues were detected until 82 hours. Residueswere not detected in oillk at any sam- d hours after the last dose. In another study, milk resi- piing time at a detection limit of 50 ng/ml. The termi- Sdues declined to the detection limit (0.05 ~g/ml) nal elimination half-life in sheep and cattle has been cJ5 days after cows received 2.5 g, PO, every 12 hours, reported as ranging from 3 to 9 hours. In the only £ daily, for 5 days.Only 1 tissueresidue study for PBZ in tissue residue study available,liver and kidney samples r food animals could be located. In cows given a single from cattle given 2.2 mg/kg. IV; had residues of about a IV injection of 7.5 mg/kg (3.4 mg/lb; 3.75 g/animal), 0.05 ~g/mI 5 days after treatment. dabout 14 dayswere required for muscle and liver resi- Flunixin meglumine is approved for use in food Sdues to decline to < 0.1 ~g/g. The half-life of PBZ was animals in several other countries, including England. 56 days in liver and muscle. France. Switzerland, and Germany (Table 2). For the c SeveralPBZ products havebeen approved for use in same dose in cattle. foreign WDI recommendations ( cattle and swine in Germany;Switzerland, and France vary widely. For catde given the typical dosageof 1.1 I (Table 3). Meat WDI range from 3 to 21 days,wh~ to 2.2 mg/kg (0.5 to 1.0 mg/ib), IV or 1M, every 2~ J milk WDI rangefrom 48 to 120 hours. On the basisof hours, for 3 to .5days, FARAD recommendsuse of the j residueand pharmacoktneticdata mentioned,as well as milk WDI specified by the Swiss product (72 hours) , foreign withdrawal time recommendations,FARAD rec- and the meatWDI specified by the French product (10 J ommendscattle meat and Inilk WDI of 12 days and 96 days). For swine given up to 2 mw'kg (0.9 mg/ib), 1M, hours, respectively;for a single doseof up to 6g of PBZJ FARAD recommends use of the French meat WDI of animal. For a multiple doseregimen in which a loading IS days (Table 1). doseof 4 to 6 g/animal is given IV or 1M followed by up to 2 g daily,FARAD recommends meat and Inilk WDI of PhenylbUt8zone 21 daysand 120 hours, respectively(Table 1). Although not approved for use in food animals in theUnited States,phenylbutazone (PBZ) is widely used Reference. In cattle. Two types of treatment are common: a single I. KopchaM, KaneeneJB. SheaME, et II. Use of nonsteroi- lose of 4 to 6 g/animal, 1M or Iv; or a multiple dose dal Inti-inflammatory dnap In food animal practice. J Alii Vet regimenconsisting of a loading dose of 10 to 25 mg/kg Med &soc 1992;201:1868-1872. :4.5 to 11.0 mg/ib), 1M or Iv; followed by a mainte- 2.