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Extralabel use of ivermectin and moxidectin
in food animals
Ronald E. Baynes, DVM, PhD; Michael Payne, DVM, PhD; Tomas Martin-Jimenez, DVM, PhD, DACVCP; Ahmed-Rufai Abdullah, DVM; Kevin L. Anderson, DVM, PhD, DABVP; Alistair I. Webb, DVM, PhD, DACVA; Arthur Craigmill, PhD; Jim E. Riviere, DVM, PhD The Food Animal Residue Avoidance Databank use of ivermectin and moxidectin and the process
(FARAD) access centers in the United States have
involved in deriving recommended withdrawal inter-
been contacted in recent months about the extralabel vals (WDI). The FARAD-derived WDI are based on
use of several macrolide endectocides. The focus of this pharmacokinetic data summarized in the FARAD data- article is to provide an update on approved use of these base, which were published in peer-reviewed journals, drugs. Caution should be exercised with extralabel use FDA freedom of information summaries, and Food and of this class of drugs, particularly with moxidectin and Agriculture Organization monographs (Table 2). With ivermectin used in dairy animals. Macrolide endecto- complete data sets, the WDI are extrapolated from tis- cides are popular in livestock operations, because they sue kinetic information and the approved WDT. The are generally efficacious against most important inter- latter are calculated by statistical analysis of tolerance nal and external parasites, and approved topical for- limits containing the 99th percentile of the test animal mulations can improve producer compliance. population with 95% confidence. The FARAD has des- ignated these extrapolated withholding times as WDI lipophilic, substantial concentrations will be found in to differentiate them from WDT, which are approved edible tissues. As much as 5% of the administered drug by the US FDA. The WDI estimates are based on the can be secreted in milk.1 Only eprinomectin and mox- effective residue half-life (ERH) derived from tissue
idectin pour-on formulations are approved for use in dairy cattle. This is because of the intrinsic chemicalbehavior and unique formulation chemistry of these 2 Extralabel Use of Ivermectin
drugs. Ivermectin and doramectin are not approved for Oral route in goats—Ivermectin is not approved
dairy animals, and their meat withdrawal times are for use in goats in the United States. However, the long, compared with other less lipophilic parasiticides.
labeled drench dose for sheep (0.2 mg/kg of body Parallel disposition data of milk and plasma ivermectin weight [0.09mg/lb]) has an 11-day meat WDT. This is indicates a milk:plasma area under the curve (AUC)
supported by an observed fat and liver depletion half- ratio of 1.08 for goats.2 Compared with approved oral life of 1.1 days for the intraruminal route in sheep,5 and subcutaneous routes of administration, approved recalling that it generally requires about 10 half-lives to topical application can result in less absorption but eliminate 99% of the drug. Several studies further extended meat withdrawal times, because the dermal demonstrated that following intraruminal administra- absorption process is rate limiting, and depletion of tion in goats,6 bioavailability was 2.5 times lower and residues to established tolerances is prolonged. These the plasma half-life was 2.3 times shorter than in pharmaceutical and pharmacokinetic differences are sheep.7 These pharmacokinetic differences were not reflected in the approved withdrawal times (WDT;
observed with doses administered SC.2 On the basis of Table 1).
these supporting data, FARAD estimates that if the oraldrench approved for sheep is administered to goats at Extrapolated Withdrawal-interval
the labeled dose for sheep, then a meat WDI of 11 days Estimation Methods
should prevent meat residues in goats. If ivermectin is This article will focus briefly on specific FARAD administered at up to 1.5 to 2.0 times the labeled dose cases or requests for information regarding extralabel for sheep, as is the common practice, then the WDIneeds to be extended by at least 1 extra ERH. Based on From the Food Animal Residue Avoidance Databank (FARAD), the WDT for sheep, and in the absence of tissue deple- Department of Farm Animal Health and Resource Management, tion data for goats, FARAD assumes an ERH of 2.2 days College of Veterinary Medicine, North Carolina State University, obtained by dividing the WDT by a half-life multiplier
Raleigh, NC 27606 (Baynes, Martin-Jimenez, Abdullah, Anderson, (HLM) value of 5.3,4 The HLM represents the number of
Riviere); the Department of Environmental Toxicology, University ERH needed for the concentration in tissue to reach of California, Davis, CA 95616 (Payne, Craigmill); and theDepartment of Physiological Sciences, College of Veterinary the tolerance level. In summary, FARAD recommends a Medicine, University of Florida, Gainesville, FL 32610 (Webb).
meat WDI of 14 days for up to 0.4 mg/kg (0.18 mg/lb) Table 1—List of approved macrolide endectocides for specific species and routes andapproved withdrawal times (WDT) Dose (mg/kg of
body weight)
Table 2—Food Animal Residue Avoidance Databank recommended withdrawal inter-vals (WDI) for ivermectin and moxidectin in dairy species Dose (mg/kg of
body weight)
*FDA approved withdrawal times. NA ϭ Not available. per os. These calculations assume that the kinetics of servative for oral administration, as the WDI was based ivermectin are linear. The milk WDI would be 6 days on intraruminal administration of a 3H-labeled drug and based on a study by Scott et al,8 that demonstrated that a dose greater than the approved label.
at 6 days, goats’ milk was clear of the drug after an oraldose of 0.2 mg/kg. Based on this information, oral Subcutaneous route in goats—Ivermectin was
administration up to 0.4 mg/kg will require a milk detected up to 25 days in milk from lactating goats given 0.2 mg/kg SC.2 There were no differences between plas-ma and milk pharmacokinetic variables, and the Oral route in cattle—Ivermectin has the same half-
milk:plasma AUC ratio was 1.08, as stated earlier. The life in cattle as it does in sheep; however, because of a elimination half-life was 4 days for plasma and milk, and larger volume of distribution, plasma clearance is more it would take 40 days (10 half-lives) to eliminate 99% of rapid in sheep.9 For these reasons, WDT and WDI will the drug via milk when administered by this route.
be shorter in sheep and goats than in cattle. Surprisingly, Limited tissue residue data from an NRSP-7 study10 pro- there is limited depletion data for oral administration of vided an ERH of 4.34 days (ke = 0.1594 days-1) in fat, ivermectin in cattle. Following intraruminal administra- which is the slowest depleting tissue. Application of our tion in cattle, depletion half-lives for 3H-ivermectin in fat algorithm resulted in a WDI of 22 days. As this FARAD and the liver were 4.2 and 5.9 days, respectively.5 This estimate is less than the cattle WDT, and there were lim- suggests a longer meat WDI (42 days) for the intraru- ited available data, we recommend the cattle WDT of 35 minal route than the approved meat WDT (24 days) with the approved oral paste. Plasma data from thatstudy demonstrated a plasma concentration of 1.0 ng/ml Subcutaneous route in cattle—Ivermectin was
of total residues at 21 days and undetectable at 28 days detected in milk at 17.8 days and even beyond 29 days after a 0.3 mg/kg dose. In the absence of milk residue when lactating cows were given 0.2 mg/kg SC.1 The data, it is possible to estimate a conservative milk WDI mean milk depletion half-life was 4.72 days, which of 28 days if we assume parallel depletion for plasma suggests that it would take at least 47 days to eliminate and milk and use published data in which the milk:plas- 99% of the drug via the milk. As seen with goats, a par- ma AUC ratio is 0.766 in cattle.1 This WDI will be con- allel disposition in milk and plasma was observed, and the milk-plasma AUC ratio was 0.766. These data and This may be related to its greater persistence once WDI estimates are further supported by the observed absorbed systemically and, therefore, caution should plasma half-life of 4.32 days in another study of sub- be exercised when using this drug in an extralabel manner, especially when administering the pour-onformulation orally to goats. Topical route in goats—Topical application of
ivermectin (0.5 mg/kg [0.23 mg/lb]) to dairy goats Subcutaneous route—There are limited pharma-
resulted in about 0.5 ng/ml of milk at 6 days.8 Because cokinetic data available in the literature for subcuta- milk residues were not detected at 7 days, this time can neous administration in goats,6 which makes estima- be used as a milk WDI for goats given ivermectin top- tion of meat or milk WDI difficult. In cattle, the half- ically. Tissues were not assayed, but plasma concentra- lives for total residue of moxidectin in fat, liver, kidney, tions were less than 1.0 ng/ml at 6 days, supporting the and muscle ranged from 9.0 to 12.2 days after SC administration (0.2 mg/kg).17 At 49 days, injection sitesand back fat concentrations were 1,178 and 141 µg/kg, Topical route in cattle—There are no available
respectively, and liver and kidney concentrations were studies on topical application of ivermectin in dairy less than 11 µg/kg. As European maximum residue cattle. However, plasma concentrations were less than concentrations for fat, kidney, and liver are 200, 20, 0.1 ng/ml at 42 days, and terminal half-life in plasma and 20 µg/kg, respectively,18 then 49 days would be a was 5.3 days in steers treated topically at the label conservative WDI for moxidectin given by the subcu- dose.12 Assuming that milk-plasma ratios were 0.776, taneous route to cattle. The FDA has also established as described earlier, milk concentrations at 42 days tolerances of 50 µg/kg and 200 µg/kg for parent mox- should be 0.0776 ng/ml, and it would take at least 2 idectin in muscle and liver, respectively, in cattle.19 more half-lives (11 days) to arrive at a milk concentra- Unfortunately, FARAD has no milk residue information tion of approximately 0.02 ng/ml. This milk concen- or milk-plasma AUC relationship from which to base tration is equivalent to a safe concentration or a provi- milk WDI for this drug if given subcutaneously to sional acceptable residue for ivermectin in milk recent- ly described in the literature.13 Based on these data andassumptions, a milk WDI of 53 days would be a con- Topical route—Moxidectin is approved as a pour-
servative estimate for dairy cattle exposed to iver- on only (0.5mg/kg) in cattle with zero meat and milk WDT, and it is possible that increasing the dose sub-stantially by this route will most likely require estima- Extralabel Use of Moxidectin
tion of meat and milk WDI (Table 1). In the absence of Oral route—Moxidectin is not approved for use in
data for goats, FARAD assumes that plasma and tissue goats. Several goat farmers have been administering clearance would be greater in goats than in cattle, as moxidectin to goats orally at the labeled pour-on dose described for ivermectin. However, FARAD would err (0.5 mg/kg) for cattle. It should be stressed that on the side of caution and recommend a milk and meat although the cattle label states that this drug has a zero WDI of 1 day if this drug was applied topically to goats.
meat and milk WDT by the topical route, it does not The calculated WDI in this article were based on imply that the meat and milk WDI will be zero if given limited available pharmacokinetic data. Updated WDI orally. Until FARAD obtains sufficient pharmacokinet- ic data for the topical formulation given orally at 0.5 (www.farad.org) as more relevant data become avail- mg/kg in goats, FARAD has based its WDI recommen- able. It should also be noted that the recommended dation on European Union approvals in sheep and WDI are case specific and are not applicable for other published studies on oral administration. It should be doses or routes of administration, nor should they be noted that oral bioavailability of moxidectin is 2.7 extrapolated to other food animal species. If veterinar- times lower in goats than in sheep,6,11 and the half-life ians are interested in obtaining such information, in goats is 1.8 times shorter in sheep. This suggests please contact us at 1-888-USFARAD, farad@ncus.edu, that European Union WDI for moxidectin in sheep will be more than adequate for estimation of WDI for mox-idectin drench in goats. In France and the United References
Kingdom, the oral formulation for sheep at a dose of 1. Toutain PL, Campan M, Galtier P, et al. Kinetic and insecti- 0.2 mg/kg [0.09 mg/lb] has a 14-day meat WDT.14,15 On cidal properties of ivermectin residues in the milk of dairy cows. J Vet the basis of these data, FARAD estimates an ERH of 3 Pharmacol Ther 1988;11:288–291.
days for this dose and, therefore, includes an addition- 2. Alvinerie M, Sutra JF, Galtier P. Ivermectin in goat plasma and al 3 ERH (9 days; WDI, 23 days) for goats given of a milk after subcutaneous injection. Ann Rech Vet 1993;24:417–421.
3. Riviere JE, Webb AI, Craigmill AL. Primer on estimating moxidectin pour-on formulation (0.8 to 1.6 mg/kg withdrawal times after extralabel drug use. J Am Vet Med Assoc [0.36 to 0.73 mg/lb]) orally. It must be recognized that there are pharmaceutical differences between the der- 4. Martin T, Baynes RE, Craigmill AL, et al. Extrapolated with- mal formulations being used in goats and the European drawal-interval estimator (EWE) algorithm. A quantitative approach approved drench, and these differences may influence to establishing extralabel withdrawal times. Pharm Res 2000;(in press).
tissue depletion. It is also important to stress that, irre- 5. Chiu S-Hl, Green ML, Bayliss FP, et al. Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, spective of the route of administration, moxidectin has sheep, and rat. J Agric Food Chem 1990;38:2072–2078.
a longer mean residence time than ivermectin in sheep 6. Escudero E, Carceles CM, Diaz MS, et al. Pharmacokinetics and cattle when given orally or by the SC route.7,11,16 of moxidectin and doramectin in goats. Res Vet Sci 1999;67:177–181.
7. Marriner SE, McKinnon I, Bogan JA. The pharmacokinetics 14. Alvinerie M, Escudero E, Sutra JF, et al. The pharmacoki- of ivermectin after oral and subcutaneous administration to sheep netics of moxidectin after oral and subcutaneous administration to and horses. J Vet Pharmacol Ther 1987;10:175–179.
sheep. Vet Res 1998;29:113–118.
8. Scott EW, Kinabo LD, McKellar QA. Pharmacokinetics of 15. DMV. Dictionnaire des medicaments veterinaires et des pro- ivermectin after oral or percutaneous administration to adult milk- duits de sante animale diagnostic, dietetique, hygiene, petit materiel.
ing goats. J Vet Pharmacol Ther 1990;13:432–435.
Cedex, France: Editions du Point Veterinaire, 1997;459–461.
9. Lo P-KA, Fink DW, Williams JB, et al. Pharmacokinetic 16. NOAH. Compendium of data sheets for veterinary products studies of ivermectin: effects of formulation. Vet Res Commun 1985;9: 1999–2000. Enfield, England: National Office of Animal Health Ltd, 10. NRSP-7 animal drug request number 17. NRSP-7 studies of 17. Lanusse C, Lifschitz A, Virkel G, et al. Comparative plasma ivermectin in goats (SQ Administration). Public Master File (PMF disposition kinetics of ivermectin, moxidectin, and doramectin in cattle. J Vet Pharmacol Ther 1997;20:91–99.
11. Toutain PL, Upson DW, Terhune TN, et al. Comparative 18. FAO. Moxidectin: residues of some veterinary drugs in ani- pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol mals and foods. Monographs prepared by the forty-eighth meeting of the Joint FAO/WHO Expert Committee on food additives. Geneva, 12. Gayrard V, Alvinerie M, Toutain PL. Comparison of phar- macokinetic profiles of doramectin and ivermectin pour-on formula- 19. EMEA. Moxidectin summary report. European agency for tions in cattle. Vet Parasitol 1999;81:47–55.
the evaluation of medicinal products. London, England: EMEA, 13. Baynes RE, Martin T, Craigmill A, et al. Estimating provi- sional acceptable residues for extralabel drug use in livestock. Regul 20. FOI. Freedom of information summary, NADA 141-099 Toxicol Pharmacol 1999;29:287–299.
(original); cydectin (moxidectin); Jan 28th, 1998.

Source: http://faculty.vet.cornell.edu/smith/Sheep%20and%20Goat%20Course/Lab%201%20Parasites/FARAD%20ivermectin%20ELUD.pdf


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