Drug Laws andRegulations forSheep and Goats

Virginia R. Fajt, DVM, PhD

KEYWORDS

� Antimicrobial resistance � Extralabel drug use� Food animal residue avoidance databank (FARAD)� Goat � Minor species � Sheep � Tissue residue� Withdrawal period

Although the process of pharmacotherapeutic decision making seems intuitive to theexperienced veterinary clinician, it is important to periodically assess the process, toensure that appropriate decisions are being made. Decision making for drug use andselection involves the following steps:

1. Identification of the physiologic or pathophysiologic process requiring alteration inthe patient (eg, increased gastrointestinal parasite load, hypovolemia, bacterialinfection of the lungs)

2. Decision whether use of a drug would affect the pathophysiologic changes3. Identification of potential drugs that may produce the desired effect (this implies

knowledge of mechanisms of action and therapeutic effects of drugs)4. For each drug identified, establishing whether there are any of the following obsta-

cles to its use; (a) undesirable adverse effects, (b) contra-indications in the patient,(c) concurrent disease states, (d) inability to monitor efficacy or (e) legal implicationsfor its use

5. Selection of drug and drug regimen for administration.

This article focuses on step 4(e) by reviewing the legal obligations and potentialregulatory obstacles to use of drugs, in the United States in particular, with other coun-tries mentioned as appropriate. To set the stage for defining legal drug use, a review ofthe drug approval process is provided, as well as a discussion of drugs currentlyapproved for use in sheep and goats in the United States.

The author has nothing to disclose.Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine andBiomedical Sciences, Texas A&M University, MS 4466, College Station, TX 77843-4466, USAE-mail address: vfajt@cvm.tamu.edu

Vet Clin Food Anim 27 (2011) 1–21doi:10.1016/j.cvfa.2010.10.006 vetfood.theclinics.com0749-0720/11/$ – see front matter � 2011 Elsevier Inc. All rights reserved.

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The author is not nor has ever been an employee of a regulatory or legal agency;therefore, all interpretations are the author’s alone. The respective agency shouldbe contacted with questions regarding any information contained herein.

LABELED/LICENSED DRUGSApproval of New Veterinary Drugs

Drugs are defined by US federal laws as articles intended for use in the diagnosis,cure, mitigation, treatment, or prevention of diseases and articles (other than food)intended to affect the structure or any function of the body.1 Therefore, a drug isdefined not by whether it is termed a drug or not, but rather its intended use. If waterwere used for treatment of disease, that water would be a drug and would be subjectto laws and regulations; if that water is not approved for that specific use, such use isa violation of the Federal Food Drug and Cosmetic Act. Similar definitions are alsolegally used by Health Canada.The process for approval or so-called labeling or licensing of drugs for sheep and

goats involves collection of data on safety and efficacy.2 This approval process differsfrom country to country. Safety of drugs includes safety of the target animal, safety ofhumans exposed to the drug during administration and use, safety of humansconsuming animal products after the animal has been treated with the drug, and safetyfor the environment of animals treated with the drug. The evidence required to docu-ment efficacy of a drug in the United States is outlined in Guidance #612 (Table 1) andincludes recommendations for parasiticides, antimicrobials, and production drugs,with suggested options when appropriate for use of data from other species (in partic-ular cattle) to document efficacy.Tables 2–5 list veterinary drugs currently approved for sheep and goats in the

United States and Canada. Experienced veterinarians are aware that there is a paucityof drugs licensed for these animal species, resulting in either inability to treat particularconditions or requiring the use of drugs in an extralabel manner, in particular the use ofdrugs approved in other species of animals. The European Medicines Agencyapproves veterinary drugs for the European Union, although individual Europeancountries also have national agencies that license drugs at country level (see Table 1).

Office of Minor Use and Minor Species at the US Food and Drug AdministrationCenter for Veterinary Medicine

Within the US Food and Drug Administration (FDA) Center for Veterinary Medicine(CVM), the Office of Minor Use and Minor Species (MUMS) supports the developmentof these drugs. MUMS can designate a new animal drug as one for a minor use orminor species, in which case grants may be available to support drug approval anda period of exclusivity applies to that approval (designation does not imply that thedrug may be marketed; drug approval must first be granted). MUMS also maintainsa list of so-called indexed drugs; these are drugs that may be marketed before collec-tion of safety and efficacy data. Indexing is not available for drugs for food animals.The list of designated drugs at the time of writing (2010) includes, for sheep, mox-

idectin and the progesterone EAZI-BREED CIDR, with both now approved for use. Forgoats, albendazole and the progesterone EAZI-BREED CIDR have been designated,but neither has yet been approved for use. Their designation allows a drug sponsorto apply for grants for data development that would lead to approval. Drug sponsorsfor drugs for minor species are not always pharmaceutical companies, but may beuniversity or extension personnel with an interest in minor species. Approvals of drugsfor minor species may use data published in Public Master Files, which may include

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safety or efficacy data generated by companies or other sponsors, or these approvalsmay use data acquired via requesting permission from a pharmaceutical company toshare proprietary data from previous drug approvals in other species.Historically, the NRSP-7 (National Research Support Project No. 7) of the US

Department of Agriculture has provided support for the development of data for minorspecies, including sheep and goats. This project continues to operate in the UnitedStates, in cooperation with the FDA MUMS office, to provide support and fundingthat will lead to the approval of new animal drugs for small ruminants.

EXTRALABEL USE OF VETERINARY DRUGSLegal Basis for Extralabel Use of Veterinary Drugs in the United States

The Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 authorized veter-inarians in the United States to use drugs in an extralabel manner under particularcircumstances.3 Extralabel use is the use in any manner not included on the label(ie, not licensed), and may include nonlicensed route of administration, indications,animal species, dose, or frequency. This authorization for extralabel use appliesonly to drugs approved by the FDA and does not include authorization for extralabeluse of other products used in animals that are approved by other agencies, such aspesticides (approved by the US Environmental Protection Agency) or vaccines andother biologic or immunologic products (approved by the US Department of Agricul-ture). There is no legal provision for using these products in any manner not includedon the label, and the veterinarian may incur liability should these products be used ina nonlabeled manner.Extralabel use may be permissible under AMDUCA, when the health of the animal is

threatened and death or suffering may result if the animal is not treated. Extralabel useis not permitted for production drugs, including drugs that manipulate the estrus cycle,drugs that enhance growth, or drugs that induce lactation. Extralabel use of drugsmust be performed by or on the order of a licensed veterinarian, within the contextof a veterinarian-client-patient relationship (VCPR). A VCPR is present under thefollowing circumstances: (1) the veterinarian has assumed responsibility for makingclinical judgments regarding the health of the animal(s) and the need for medical treat-ment, and the client has agreed to follow the veterinarian’s instructions; (2) the veter-inarian has sufficient knowledge of the animal(s) to initiate at least a general orpreliminary diagnosis of the medical condition of the animal(s); this means that theveterinarian has recently seen and is personally acquainted with the keeping andcare of the animal(s) by virtue of an examination of the animal(s), or by medicallyappropriate and timely visits to the premises where the animal(s) are kept; (3) the veter-inarian is readily available or has arranged for emergency coverage, for follow-upevaluation in the event of adverse reactions or the failure of the treatment regime.The law does not define exactly what timely visits are, under the assumption that

this may differ for different types of animals and types of operations. Species groupsare encouraged to develop their own definitions of timely to give guidance to veterinar-ians working with those species.

Permissible Extralabel Use of Veterinary Drugs in the United States

To determine if a particular extralabel use being contemplated is legal, the AmericanVeterinary Medical Association (AVMA) has developed an algorithm (see Table 1). Asstated earlier, the first requirements are the presence of a VCPR and at least a prelim-inary diagnosis, as well as the therapeutic (ie, nonproduction use) need for the use. Ifthe animal is a food animal, which includes all sheep and goats, if a drug exists that is

Table 1Recommended Web sites for information about drug regulation

Topic Description Electronic Address

US-based Web Sites

American Veterinary Medical Association(AVMA) Animal Medicinal Drug UseClarification Act Flowchart

Hierarchy and algorithm for determiningacceptability of extralabel drug use

http://www.avma.org/reference/amduca/amduca1.asp

AVMA Guidance on Internet pharmacies — http://www.avma.org/issues/prescribing/default.asp

AVMA Guidance on prescribing anddispensing drugs

— http://www.avma.org/issues/prescribing/prescribing_faq.asp

AVMA Guidelines for judiciousantimicrobial use

General guidelines; some species groupshave expanded these into morecomprehensive and specific guidelines

http://www.avma.org/issues/policy/jtua.asp

Food and Drug Administration Centerfor Veterinary Medicine (FDA CVM)

Home page for the CVM http://www.fda.gov/AnimalVeterinary/default.htm

FDA CVM Compliance Policy Guide oncompounding

Outlines FDA policy on acceptable andunacceptable compounding

http://www.fda.gov/downloads/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/UCM200461.pdf

FDA CVM Form FDA 1932a for AdverseDrug Event Reporting

Veterinary Adverse Experience, Lack ofEffectiveness or Product Defect Report

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/AnimalDrugForms/ucm048817.pdf

FDA CVM Guidance #61 Guidance for Industry: FDA Approval ofNew Animal Drugs for Minor Usesand for Minor Species

http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052375.pdf

Food Animal Residue AvoidanceDatabank (FARAD)

Provides recommended withdrawaltimes for drugs and chemicals

http://www.farad.org

Food Safety and Inspection Service,US Department of Agriculture

The Blue Book outlines the NationalResidue Program (ie, the plan forsampling for drug and chemicalresidues in meat in the United States)

http://www.fsis.usda.gov/PDF/2009_Blue_Book.pdf

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Food Safety and Inspection Service,US Department of Agriculture

The Red Book present results fromscheduled and inspector-generatedsampling for drug and chemicalresidues in meat in the United States

http://www.fsis.usda.gov/PDF/2008_Red_Book.pdf

Minor Species/Minor Use Program US program for increasing approval forminor species and minor uses of drugs

http://www.nrsp-7.org/introduction.htm

National Association of Boardsof Pharmacy

To find contact information for stateboard of pharmacy

http://www.nabp.net/boards-of-pharmacy/

National Association of Boards ofPharmacy Vet-VIPPS (VerifiedInternet Pharmacy Practice Sites)

Accreditation program for Internetpharmacies; refers to nonfood andcompanion animals only

http://www.nabp.net/programs/accreditation/vet-vipps/

National Organic Program Regulations related to organic productionin the United States

http://www.ams.usda.gov/nop/indexIE.htm

Pasteurized Milk Ordinance All regulations related to producing milk http://www.fda.gov/Food/FoodSafety/Product-SpecificInformation/MilkSafety/NationalConferenceonInterstateMilkShipmentsNCIMSModelDocuments/PasteurizedMilkOrdinance2007/default.htm

Canada-based Web sites

Canadian Food Inspection Agency Regulations regarding livestock feedsincluding medicated feeds in Canada

http://www.inspection.gc.ca/english/anima/feebet/feebete.shtml

Canadian global FARAD (gFARAD) One branch of gFARAD that providesCanadian-specific recommendationsfor withdrawal times

http://www.cgfarad.usask.ca/

Canadian Veterinary MedicalAssociation policy on extralabeldrug use

— http://canadianveterinarians.net/ShowText.aspx?ResourceID563

Health Canada Veterinary DrugDirectorate

Home page for veterinary drugs inCanada

http://www.hc-sc.gc.ca/dhp-mps/vet/index-eng.php

European Union-based Web site

European Medicines Agency Committeefor Medicinal Products forVeterinary Use

European agency responsible for drugregulations and drug approval in theEuropean Union

http://www.ema.europa.eu/index/indexv1.htm

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Table 2Drugs approved in the United States, for administration to sheep and currently marketed

Active Ingredient Example Trade Name Pharmaceutical FormType(s) of Sheep forWhich Approved Indications

Dose Rate and Routeof Administration

Albendazole Valbazen Oral suspension Nonpregnant Control of internalparasites

7.5 mg/kg bw by mouth

Ceftiofur sodium Naxcel Injectable solution Not specified Respiratory disease 1.0–2.2 mg/kg bw imfor 3 d

Chlortetracycline Pfichlor, Chlorachel,Chlormax

Medicated premix Breeding animals Reduction ofCampylobacterabortion incidence

80 mg/head/d in the feed

Chlortetracycline Aureomycin, Pfichlor Medicated premix Growing animals Increase weight gainand feed efficiency

20–50 g/t feed

Decoquinate Deccox Medicated premix Young, nonlactating Prevention of coccidiosis 0.5 mg/kg bw bymouth (13.6 g/t feed)

Ivermectin Ivomec Oral drench Not specified Control of internalparasites

0.2 mg/kg bw by mouth

Lasalocid Bovatec Medicated premix Sheep inconfinement

Prevention of coccidiosis 20–30 g/t of feed

Levamisole Tramisole, Levasole Oral suspension,tablet

Not specified Control of nematodeinfections

8 mg/kg bw by mouth

Moxidectin Cydectin Oral drench Not specified Control of internalparasites

0.2 mg/kg bw by mouth

Neomycin Neomix, Neosol,NeoMed

Soluble powder (foraddition todrinking water ormilk replacer)

Not specified Treatment and controlof gastrointestinalcolibacillosis

22 mg/kg bw by mouth,divided doses daily fora maximum of 14 d

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Neomycin typeA medicatedarticle for milkreplacer or feed

Neomix 325 MedicatedPremix

Medicated premix Not specified Treatment and controlof gastrointestinalcolibacillosis

22 mg/kg bw by mouth,for a maximum of 14 d

Neostigmine Stiglyn Injectable solution Nonpregnant,nonlactating

Rumen atony, bowelevacuation, bladderevacuation

1–1.5 mg/45.36 kg(100 lb) bw sc

Oxytetracycline Terramycin SP Soluble powder (foraddition todrinking water ormilk replacer)

Not specified Bacterial enteritis,bacterial respiratoryinfection

22 mg/kg bw daily in thedrinking water or milkreplacer

Oxytetracycline 1

polymyxinTerramycin Ophthalmic ointment Not specified Ocular infections External application in

the eye 2–4 times daily

Oxytetracycline Terramycin-100 typeA medicated article,TM-50 typeA medicated article

Medicated premix Not specified Bacterial enteritis,bacterial respiratoryinfection

22 mg/kg bw daily(10–20 g/t of feed)

Penicillin G Agricillin, Aqua-cillin Injectable suspension Not specified Respiratory infectioncaused by Pasteurellamultocida

6600 IU/kg bw im daily

Tilmicosin Micotil Injectable solution Not specified Respiratory infectionassociated withMannheimia haemolytica

10 mg/kg bw sc

Vitamin E 1 sodiumselenite

BO-SE Injectable solution Newborn,nonpregnant

Control of white muscledisease

2.5 mL/45.36 kg (100 lb)bw im or sc

Zeranol Ralgro Subcutaneousimplant

Feedlot lambs Increase weight gainand feed efficiency

One implant sc behindthe ear

Abbreviations: bw, bodyweight; im, intramuscularly; sc, subcutaneously.Data from Animal Drugs, FDA.

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Table 3Drugs approved in Canada for administration to sheep

Active Ingredient Example Trade Name Pharmaceutical Form IndicationsDose Rate and Routeof Administration

Acepromazine Acepro-25, Atravet Injectable solution Sedation 0.05 mg–0.1 mg/kg bw im

Calcium borogluconate 1

electrolytesCalMagPhos, Mag-Cal,

NorcalciphosInjectable solution Electrolyte replacement 50–125 mL iv, sc

Ceftiofur sodium Excenel sterile powder Injectable solution Respiratory infection associatedwith Mannheimia haemolytica

2 mg/kg bw once daily for 3 d im

Chlortetracycline Aureomycin Medicated premix As an aid in reduction of lossescaused by enterotoxaemia infeedlot lambs

22 mg/kg (0.0022 %) of completefeed by mouth

Dioctyl sodiumsulfosuccinate

Anti-bloat, Bloat-Eze Oral solution Treatment of bloat Range of 0.5–1 mL/kg bwby mouth

Equine chorionicgonadotrophin

Folligon,Novormon 5000

Injectable solution Follicle stimulating 300–1000 IU im, iv, sc

Estradiol cypionate — Injectable solution Anestrus 0.5–1 mg im

Ivermectin Ivomec Injectable solution,oral drench

— 200 mg/kg bw sc,by mouth

Lactated Ringer solution Lact-R Injectable solution Dehydration and electrolytedisturbances

To effect iv

Lasalocid Bovatec Medicated premix Prevention of coccidiosis Mix 240 g (0.24 kg) of premix in 1 t(1000 kg) 100% dry matter basisof diet (including roughage) toprovide 0.0036 % (36 ppm) oflasalocid sodium activity

Lidocaine or lidocaine 1

epinephrine— Injectable solution Nerve block and anesthesia Epidural, infiltration

Luteinizing hormone Lutropin-V Injectable solution Breeding disorders 2 mL (2.5 mg) iv, sc

Mineral oil — Oral solution Intestinal constipation By mouth

Neomycin Neomycin 325, Biosol Oral solution Bacterial enteritis 1 g powder/50 kg bw by mouth

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Neomycin 1 (methyl violetor gentian violet)

Keraplex, Co-opPinkeye Spray

Spray for localapplication

Wound dressing, treatment ofinfectious keratoconjunctivitis

External application

Neomycin 1 sulfathiazole 1

sulfamethazineNeorease, Scour Treat Oral solution Bacterial enteritis and pneumonia 10 mL/5 kg bw twice a day

by mouth

Neomycin 1

methscopolamineScour solution Oral solution Bacterial enteritis 1 mL/5 kg bw in water or milk

for 1–3 days

Neomycin 1

succinylsulfathiazole 1

atropine 1 hyoscyamine

Scour suspension Oral solution Bacterial enteritis 2 mL/kg bw divided twice a dayby mouth

Oxytetracycline Noromycin LP,Oxymycine LP

Injectable solution Respiratory infection associatedwith Mannheimia haemolytica,mastitis, metritis, joint ill

3 mL/45 kg bw im, iv once a dayfor 3 d

Oxytetracycline Terramycin-100 Premix Medicated premix (1) Bacterial enteritis andrespiratory infection associatedwith Mannheimia haemolytica

(2) As an aid in the reduction oflosses caused by enterotoxemiain feedlot lambs

(1) 110 mg/kg complete feed(2) 22 mg/kg complete feed

Oxytocin Oxy-20 Injectable solution Treatment of obstetric disorders 30–50 IU

Penicillin Gpenicillin G 1 benzethine

penicillin

Depocillin,Hi-pencin 300,Longisil

Injectable solution Respiratory infection caused byPasteurella multocida, metritis,wound infections

21,000 IU/kg bw (0.7 mL/10 kg)once a day im

0.5 mL/10 kg

Progesterone 5% — Injectable solution Reproductive disorders 10–15 mg per animal daily, asneeded im

Propylene glycol Glycol-P Oral solution Prevention and treatment ofpregnancy toxemia

Prevention: 50–100 mL daily;treatment: 75–125 mL dailyfor 10 d by mouth

Pyrilamine — — Antihistamine 1 mL/45 kg bw

Sodium iodide Sodide Injectable solution Expectorant 5–10 mL iv

Sulfamethazine Sulfa 25 Soluble powder (foraddition to drinkingwater or milk replacer)

Metritis, bacterial enteritis,mastitis, respiratory infections

225 mg/kg in water or milkreplacer on day 1, 112.5 mg/kgon day 2–5

(continued on next page)

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Table 3(continued)

Active Ingredient Example Trade Name Pharmaceutical Form IndicationsDose Rate and Routeof Administration

Sulfamethazine Sulfa 25 Bolus Metritis, bacterial enteritis,mastitis, respiratory infections

1 bolus/80 kg bw by mouth on day1, 1/2 bolus/80 kg bw on day 2–3

Sulfamerazine 1

sulfathiazoleSulectim Soluble powder (for

addition to drinkingwater or milk replacer)

Bacterial enteritis, respiratoryinfections

454 g to 727 L (180 gallons) ofdrinking water for 5–10 days

Testosterone Uni-test suspension Injectable solution Impotence, testicular deficiency 10–25 mg once a day im

Tetracycline Onycin 250,Onycin 1000

Soluble powder (foraddition to drinkingwater or milk replacer)

Bacterial enteritis, respiratoryinfection associated withMannheimia haemolytica

Add in water 0.25 g of powderper 25 kg bw, every 12 h givenas a drench for 4 or 5 d

Thiopental Thiotal Injectable solution Anesthetic iv

Tilmicosin Micotil Injectable solution Respiratory infection associatedwith Mannheimia haemolytica

1 mL per 30 kg bw/1.5 mLper 45.36 kg (100 lb) bw sc

Vitamin A 1 vitamin D Co-op A1D Injectable solution Control of respective deficiencies im

Vitamin E 1 selenium Dystosel, Selon-E Injectable solution Control of white muscle disease Prevention: newborns 0.25 mLper animal; animals aged 2–8 wk0.5 mL per animal; treatment:0.5 mL per animal

Abbreviations: bw, bodyweight; im, intramuscularly; iv, intravenously; sc, subcutaneously.Data from Health Canada Drug Product Database (drugs listed are not necessarily marketed; the list does not include all products approved for use in sheep in

Canada).

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Table 4Drugs approved in the United States for administration to goats and currently marketed

Active Ingredient Example Trade Name Pharmaceutical FormType(s) of Animalsfor Which Approved Indications

Dose Rate and Routeof Administration

Albendazole Valbazen Oral suspension Nonpregnant,nonlactating

Control of adult liverflukes

10 mg/kg bw by mouth

Ceftiofur sodium Naxcel Injectable solution Not specified Respiratory disease 1.0–2.2 mg/kg bw im for 3 d

Decoquinate Deccox Medicated premix Young, nonlactating Prevention ofcoccidiosis

0.5 mg/kg bw by mouth(13.6 g/t feed)

Fenbendazole Safeguard, Panacur Oral suspension Nonlactating Control of stomachworms

5 mg/kg bw by mouth

Morantel Rumatel Feed additive Not specified — 0.44 g/45.36 kg (100 lb) bw(0.44–4.4 g/0.45 kg [1 lb]of feed)

Neomycin Neomix, Neosol,NeoMed

Soluble powder (foraddition todrinking wateror milk replacer)

Not specified Treatment and controlof gastrointestinalcolibacillosis

22 mg/kg bw by mouth,divided doses daily fora maximum of 14 d

Neomycin typeA medicated articlefor milk replaceror feed

Neomix 325Medicated Premix

Medicated premix Not specified Treatment and controlof gastrointestinalcolibacillosis

22 mg/kg bw by mouth,for a maximum of 14 d

Abbreviations: bw, bodyweight; im, intramuscularly.Data from Animal Drugs, FDA.

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Table 5Drugs approved in Canada for administration to goats

Active IngredientExampleTrade Name

PharmaceuticalForm Indications

Route ofAdministration

Acepromazine Acepro-25,Atravet

Injectable solution Sedation im

Dioctyl sodiumsulfosuccinate

Anti-bloat,Bloat-Eze

Oral solution Treatmentof bloat

By mouth

Mineral oil — Oral solution Intestinalconstipation

By mouth

Neomycin 1

sulfathiazole 1

sulfamethazine

Neorease,Scour Treat

Oral solution Bacterial enteritisand pneumonia

By mouth

Progesterone 5% — Injectable solution Reproductivedisorders

im

Abbreviation: im, intramuscularly.Data from Health Canada Drug Product Database (drugs listed are not necessarily marketed, the

list does not include all products approved for use in sheep in Canada).

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labeled for the condition being treated, which contains the needed ingredient, which isin the proper dosage form, and which is clinically effective, that labeled (ie, licensed)drug must be used. If those conditions are not all met, then extralabel use of a drugapproved for a food animal may be considered. If there is no drug that is approvedfor a food animal that can be used in an extralabel manner to treat the condition,then a drug approved for humans or companion animals may be considered. If nodrug approved for humans or companion animals can be used in an extralabelmanner, then a compounded drug may be considered; however, this extralabel usemust be compounded from approved drugs and must not be compounded frombulk or raw drug (also known as the active pharmaceutical ingredient [API]).Other provisions of AMDUCA include the requirements for labeling of the drug

(it must include the name and address of the veterinarian, the name and address ofthe dispensing pharmacy if applicable, the established name of the drug and, if thereis more than one active ingredient, the established name of each ingredient, directionsfor use including identity of treated animals, dose, route, frequency, route and dura-tion, cautionary statements, and the veterinarian’s specified withdrawal time for anyfood that might be derived from treated animals) and the requirements for the veteri-narian’s keeping records for 2 years after prescribing (established name of drug and/oractive ingredients, condition treated, species of animal treated, dosage prescribed,duration prescribed, number of animals treated, and specified withdrawal times).Although technically illegal in the United States, the use of drugs in feed in an extra-

label manner in minor species, such as sheep and goats, is the subject of some guid-ance from the FDA CVM.4 Minor species are all species except horses, cattle, pigs,dogs, cats, chickens, and turkeys. The Compliance Policy Guide Section 615.115states that the FDA does not ordinarily consider regulatory action against the veteri-narian, producer, or feed mill provided the following are true.

1. The medicated feed is for use only in a minor species.2. The medicated feed is approved (a) for use in a major species and the feed is

formulated and labeled according to its approved labeling (ie, dosage, formulation,

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nutrient content) or (b) for use in a food-producing minor species and the feed isapproved in a major food-producing species.

3. The feed is limited to farmed or confined minor species.4. The use of the medicated feed is only with the express prior written recommenda-

tion and oversight of a licensed veterinarian with a valid VCPR.5. The extralabel use is limited to therapeutic use, when the health of the animal is

threatened and suffering or death may result from the failure to treat.6. There must be no labeled drug that could be used, or that drug must be clinically

ineffective, and there must be no therapeutic dosage form drug that can be prac-tically used under AMDUCA.

In addition, the veterinarian must establish an extended withdrawal time, mustassure that the identity of treated animals is maintained, andmust have written recom-mendations within 3 months before the use (with copies with the veterinarian and theproducer). The producer must keep accurate feed records for at least 1 year fromdelivery of the feed, must maintain identity of treated animals, must assure withdrawaltimes are met, must use and dispose of any medicated feed in accordance with local,state, and federal regulations, and must follow safety provision of the approvedproduct label.In Canada, the regulations differ in that extralabel use of medicated feed may be

prescribed by a veterinarian, as long as the drug is an approved drug product.5 Themedicated feed must be for a therapeutic purpose, rather than for a productionpurpose, such as growth promotion or feed efficiency. A valid VCPR must exist andall parties (client, prescribing veterinarian, and feed mill) must maintain a proper andvalid veterinary prescription on file.

Illegal Extralabel Use of Drugs in the United States

Extralabel use of veterinary drugs is considered illegal under AMDUCA in thefollowing cases.1. Extralabel use of drugs in or on feed2. Extralabel use from unapproved (nonlicensed) drugs or bulk drug (API)3. Extralabel use outside a VCPR4. Extralabel use of any of the drugs mentioned in Box 15. Any use that leads to a violative residue or higher than safe levels or tolerance.

Canadian regulations state that the following drugs may not be sold for administra-tion to animals that produce food or are intended for consumption as food:chloramphenicol (or its salts or derivatives), 5-nitrofurans, clenbuterol (or its salts orderivatives), 5-nitroimidazoles, diethylstilbestrol, or other stilbene compounds.6 Cana-dian policy regarding extralabel drug use in food animals states that veterinariansshould preferentially not use the category 1 antimicrobials mentioned in Table 6extralabel, because of their importance in human health and the potential for selectionfor antimicrobial resistance in pathogens of human significance.

Withdrawal Time Estimation

If drugs are used in accordance with the label, the withdrawal times legally providedshould be sufficient to prevent excess residues in meat or milk. In the United States,this withdrawal time is determined in the following way. During the approval process,the drug sponsor must present data to determine an NOEL (no observed effectlevel), which is the amount of drug expected to cause no harm if ingested byhumans. Dividing this by a safety factor results in an acceptable daily intake (ADI)

Box 1

Drugs prohibited for extralabel use in food-producing animals

Chloramphenicol

Clenbuterol

Diethylstilbestrol

Dimetridazole

Ipronidazole and other nitroimidazoles (such as metronidazole)

Furazolidone, nitrofurazone, and other nitrofurans

Sulfonamides in lactating dairy cattle (except approved uses of sulfadimethoxine,sulfabromomethazine, and sulfaethoxypyridazine)

Fluoroquinolones

Glycopeptides

Phenylbutazone in female dairy cattle 20 months of age or older

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of the drug. A safe concentration is then calculated by multiplying ADI by theaverage adult human weight and dividing by an estimate of amount of edible productconsumed per day by the average adult (assumptions are that an adult consumes300 g muscle, 100 g liver, 50 g kidney, 50 g fat, 1.5 L milk, and 100 g eggs). Thissafe concentration is the threshold that is then compared with the tissue concentra-tions of the drug in the animal products over time. Typically, the licensed dose ofdrug is administered in 20 target-species animals; then, 5 animals are killed at

Table 6Category 1 antimicrobial drugs discouraged by Health Canada’s policy for use infood-producing animals under extralabel provisions

Antimicrobial Drug Group Example Drug

Carbapenems Imipenem

Third- and fourth-generationcephalosporins

Cefotaxime

Fluoroquinolones Enrofloxacin

Glycopeptides Vancomycin

Glycylcyclines Tigecycline

Ketolides Telithromycin

Lipopeptides Daptomycin

Monobactams Aztreonam

Nitroimidazoles Metronidazole

Oxazolidinones Linezolid

Penicillin/b-lactamase inhibitorcombinations

Ticarcillin-clavulanic acid

Polymyxins Colistin

Streptogramins Dalfopristin/quinupristin

Therapeutic agents for tuberculosis Ethambutol, isoniazid, pyrazinamide, rifampin

Data from Anon. Health Canada categorization of antimicrobial drugs based on importance inhuman medicine. In: Health Canada, 2009.

Drug Laws and Regulations for Sheep and Goats 15

each of 4 different time points after administration and the concentration of drug invarious tissues is determined; control animals are also included in the study. Theresulting time-concentration curve is used to statistically evaluate (using confidenceintervals) the time point after drug administration at which the tissue concentration ispredicted to be less than the safe concentration in 99% of the animals with 95%confidence.7

If drugs are used in an extralabel manner, withdrawal times on the label may beinsufficient to prevent illegal residues for several reasons, including differences informulations (eg, conventional vs long-acting, differing salts such as benzathine vsprocaine), route of administration, metabolism, long half-lives resulting in accumula-tion of drug, increased dose, or differing administration frequency of the drug.8 There-fore, it is particularly important to consider ways to accurately estimate the effects ofextralabel use on withdrawal time estimates. One important resource in the UnitedStates for this information is the Food Animal Residue Avoidance Databank (FARAD),a national cooperative project sponsored by the US Department of Agriculture, witha primary mission to prevent or mitigate illegal residues of drugs, pesticides, and otherchemicals in foods of animal origin. FARAD has personnel at the University of Califor-nia-Davis, the University of Florida, and North Carolina State University, who canreview their extensive database of residue information to provide estimates of with-drawal intervals to prevent illegal residues. Veterinarians can directly contact FARAD(see Table 1) with a withdrawal time question. FARAD also periodically publishesFARAD Digests in the Journal of the American Veterinary Medical Association.A compilation of published recommendations to date for withdrawal intervals formeat and milk for drugs and antidotes used in an extralabel manner (ie, drugs notcurrently approved for sheep or goats in the United States) are presented in Table 7.In recent years, FARAD has branched out internationally with global or gFARAD.

Cooperating gFARAD countries gain access to the FARAD database, as well ascompiling drug information and tolerance (or maximum residue levels [MRLs]) datafrom their countries. For example, Canada has developed Canadian gFARAD, witha Web site and voicemail for customized withdrawal time estimates for extralabeluses of drugs and other chemicals (see Table 1).If FARAD is not available or the veterinarian’s location does not permit access to

a gFARAD office, recommendations have been made on how practitioners can esti-mate a withdrawal time.9 The apparent elimination half-life of the drug (the time fordrug concentration to drop by 50%) and the tolerance (safe level, safe concentration,or MRL) are used to develop such an estimate. Given that after 10 elimination half-lives, more than 99.9% of the drug has been eliminated, multiplying the half-life by10 and then rounding up to the nearest day provides an initial estimate of withdrawalinterval. However, the serum elimination half-life may not be completely representativeof the tissue elimination half-life in which residues are measured. Residues at harvestare determined from a target tissue, such asmuscle or liver, not from plasma or serum;hence knowledge of the tissue elimination half-life is more useful. However, tissueelimination kinetics is often not publicly available, so veterinarians may have to useserum concentration data and assume homogeneous distribution of drug betweentissues and serum. Although more than 99.9% of the drug may have been eliminatedafter 10 elimination half-lives, the less than 0.01% of the drug remaining may still bemore than a safe concentration, tolerance, or MRL, and therefore may be illegal. Ifan estimate of the elimination half-life is available only in cattle, some comparativepharmacokinetic data suggest that sheep and goats eliminate drugs at a similar orfaster rate than cattle, although this type of extrapolation should be performed withextreme caution, because individual drugs may have different pharmacokinetic

Table 7Published recommendations from FARADa for withdrawal times for drugs and antidotes used in sheep and goats

DrugYear ofPublication

Animal SpeciesReferred To Therapeutic Regime

Withdrawal Period

Meat Milk

Acepromazine 199721 Ruminants <0.13 mg/kg bw iv OR <0.44 mg/kg bw im 7 d 48 h

Activated charcoal 200522 Food animals Not specified Zero Zero

Aspirin 199723 Ruminants All recommended doses 1 d 24 h

Atropine 200522 Food animals 0.2 mg/kg bw iv or im; multipleadministrations, as treatment oforganophosphate toxicity

28 d 6 d

Butorphanol 199624 Food animals Not specified 48 h b

Detomidine 199721,24 Ruminants <0.08 mg/kg bw iv or im 4 d 72 h

Dimercaprol 200522 Food animals — 5 d 5 d

EDTA 200522 Food animals Not specified 2 d 2 d

Epinephrine 200522 Food animals Not specified Zero Zero

Gentamicin 200525 Sheep and goats 5 mg/kg bw im or sc >18 mo 10 d; testing of milkis recommended

Guafenesin 199721 Ruminants <100 mg/kg bw iv 3 d 48 h

Ivermectin 200026 Goats 0.4 mg/kg bw by mouth 14 d 9 d

Ivermectin 200026 Goats 0.2 mg/kg bw sc 35 d 40 d

Ivermectin 200026 Goats 0.5 mg/kg bw external use b 7 d

Ketamine 199721 Ruminants <2 mg/kg bw iv or <10 mg/kg bw im 3 d 48 h

Ketoprofen 199723 Sheep and goats 3.3 mg/kg bw iv or im, every 24 h for up to 3 d 7 d 24 h

Lidocaine 1

epinephrine199721 Ruminants Infiltration; epidural 1 d 24 h

Methylene blue 200522 Food animals Not specified 14 d 4 d

Molybdate salts (ammoniummolybdate, ammoniumtetrathiomolybdate)

200522 Food animals Not specified 10 d 5 d

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16

Moxidectin 200026 Goats 0.2 mg/kg bw by mouth 14 d b

Moxidectin 200026 Goats 0.5 mg/kg bw by mouth 23 d b

Moxidectin 200026 Goats sc b b

Moxidectin 200026 Goats 0.5 mg/kg bw external application 1 d 1 d

Oxytetracycline 199727 Sheep and goats 6.6–11.0 mg/kg bw iv or im, once Cattle withdrawaltime is adequate

96 h and testingof milk

Oxytetracycline 199727 Sheep and goats >11.0 mg/kg bw iv or im, once6.6–11.0 mg/kg bw iv or im, multiple doses

Cattle withdrawaltime is adequate

144 h and testingof milk

Oxytetracycline(long-acting)

200328 — 20 mg/kg bw im 28 d 96 h

Penicillamine 200522 Food animals Not specified 21 d 3 d

Pentobarbital 199624 Food animals Not specified 4 d 4 d

Phenylbutazone 200328 — Use discouraged b b

Pralidoxime (2-PAM) 200522 Sheep 30 mg/kg bw every 8 h 28 d 6 d

Penicillin G (procaine) 2006 Sheep and goats >6600 U/kg bw Testing of urine isrecommended

Testing of milk isrecommended

Sodium nitrite 200522 Food animals Not specified, iv 24 h 48 h

Sodium thiosulfate 200522 Food animals Not specified, iv 24 h b

Thiamylal 199721 Ruminants <5.5 mg/kg bw 1 d 24 h

Thiobarbital 199721 Ruminants <9.4 mg/kg bw 1 d 24 h

Vitamin K1 200522 Sheep and goats 0.5–2.5 mg/kg bw im, iv, or sc Zero Zero

Xylazine 199721 Ruminants 0.016–0.1 mg/kg bw iv or0.05–0.3 mg/kg bw im

5 d 72 h

Xylazine 199721 Ruminants 0.3–2.0 mg/kg bw im 10 d 120 h

Yohimbine 199721 Ruminants <0.3 mg/kg bw iv 7 d 72 h

Abbreviations: bw, bodyweight; im, intramuscularly; iv, intravenously; sc, subcutaneously.Veterinarians are advised to review current sources and contact FARAD to verify these recommendations, because new scientific evidence related to pharma-

cokinetics frequently affects the recommendations, and tolerances and residue levels may change over time.a Veterinarians in Canada should consult the Canadian gFARAD because regulations and thus withdrawal times may be different.b Relevant withdrawal periods not established.

DrugLa

wsandRegulatio

nsforSh

eepandGoats

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properties in sheep or goats compared with those in cattle. Given the potential forerror in making any of these estimates, veterinarians are cautioned to providegenerous withdrawal time estimates or to make every effort to contact FARAD or otherequally weighty sources to protect the food supply and to protect animal owners fromthe ramifications of illegal residues.In the European Union, regulations stipulate that in cases of extralabel use of a drug,

a withdrawal period of 28 days for meat or 7 days for milk should be prescribed andobserved. This strategy raises the issue of withdrawal periods during extralabel use ofdrugs, which already have longer than the withdrawal periods mentioned earlier inother animal species. For example, moxidectin injectable solution has a licensed with-drawal period of 65 days for cattle meat and 82 days for sheep milk. Hence, it seemswrong to maintain a 28-day withdrawal period for meat of goats, if the drug would beadministered under extralabel circumstances in that animal species. To avoid suchcircumstances, blanket statements, such as “Not to be used in animals producingmilk for human consumption or for industrial purposes” or “Not to be used in animalsyounger than �� months,” have been devised and are enforced.

MONITORING OF DRUG USEResidues in Foods

In the United States, the Food Safety and Inspection Service (FSIS) of the US Depart-ment of Agriculture is responsible for ensuring the safety of food products fromanimals. It publishes a yearly plan for which samples will be collected at harvest facil-ities in the next year, the so-called Blue Book10 (see Table 1). It also publishes yearlyreports on the previous year’s sampling and findings, the Red Book11 (see Table 1).The most recent report published is for the calendar year 2008, and data are reportedon scheduled samples, as well as inspector-generated samples. Inspector-generatedsamples are those that were not regularly scheduled, but rather were collected byin-plant public health veterinarians because of the appearance of the animals anteor post mortem, suggesting medication use, previous history of the producer ofanimals with violative residues, or other suspicions raised during the on-site inspec-tions. These samples may be tested via in-plant fast antimicrobial screen test(FAST) or kidney inhibition swab (KIS) test or they may be forwarded to the FSIS labo-ratory for testing. In-plant FAST-positive samples are also sent to the FSIS laboratoryfor testing for nonsteroidal antiinflammatory drugs.In 2008, of 980 scheduled samples in goats, there was one sample with antibiotic

violation (oxytetracycline); of 814 scheduled samples in lambs, there were 9 nonviola-tive positive samples (3 antimicrobials, one avermectin); of 472 scheduled samples insheep, there were no violations.11 Inspector-generated samples revealed thefollowing: of 180 samples from goats there were no FAST-positive samples; of 370samples from lambs there was one FAST-positive sample (sulfadimethoxine); and of137 samples from sheep there were no FAST-positive samples.11 Overall, these find-ings show a low level of violative residues in meat from sheep and goats in the UnitedStates.Scheduled sampling for 2009 included the following: testing for antibiotic residues in

90 samples after random collection from goats, in 300 samples from lambs, and in 300samples from sheep. The samples are tested for presence of antibiotics (includingfluoroquinolones, which are currently illegal for use in sheep and goats in the UnitedStates) and avermectins. The confirmatory 7-plate bioassay tests for antibioticsinclude tetracyclines, aminoglycosides, macrolides, b-lactams, and fluoroquinolones.Samples from goats are also tested for b-agonists, such as clenbuterol.

Drug Laws and Regulations for Sheep and Goats 19

Pharmacovigilance

Another important aspect of monitoring drug use, pharmacovigilance, involves thecataloging of adverse reactions to the drug product after approval, sometimes calledphase IV or postmarketing surveillance. This area of data collection is undergoingconsiderable change, with the FDA CVM and the AVMA considering ways to appropri-ately and accurately gather data on adverse drug reactions. Amajor issue with adversereactions is correct attribution of a reaction to the drug itself; another is who bears theburden of data collection and analysis. Drug sponsors are required to submit reports tothe FDA CVM of any adverse reactions that are reported to the company. In addition,the FDA CVM has a form, Form FDA 1932a, “Veterinary Adverse Experience, Lack ofEffectiveness or Product Defect Report”, available online for submission directly to theFDA CVM (see Table 1), or the report can be submitted by telephone to 1-888-FDA-VETS. There are periodically published reports in the literature from various regulatoryor epidemiologic experts, which examine adverse event data to attempt to attributedrugs to risks.12–14 In Europe, pharmacovigilance procedures involve centralized(pan-European) and member-state (individual-country) responsibilities for reportingand follow-up of adverse reactions from veterinary drugs.15

OTHER REGULATIONS RELATED TO USE OF VETERINARY DRUGS IN SHEEP AND GOATSCompounding

Compounding is not distinguished from manufacturing in the Federal Food Drug andCosmetic Act; therefore, any manipulation of an approved drug not included in thelicense or use of an unapproved drug would be considered compounding and, tech-nically, would be illegal for animal drugs. The FDA CVM has issued a CompliancePolicy Guide for Compounding, which outlines the FDA’s policy and regulatory prior-ities for compounded drugs.16 The important parts of the Guide include the state-ment that compounding from bulk drugs (API) for food animals is considereda regulatory priority, as is compounding when not used for therapeutic purposes(AMDUCA authorizes compounding from approved drugs, but only when animalhealth is threatened).Evidence of the regulatory priority of the use of bulk drugs for compounding for

animals comes from the recent legal filing by the FDA CVM against Franck’s Pharmacyin Florida, which was implicated in the death of polo ponies after they were adminis-tered a compounded vitamin product.17 The issues with food animals of compoundingfrom bulk drug include the potential for inclusion of toxic compounds resulting inunsafe food products, as well as the unpredictable bioavailability of compoundedproducts, resulting in the potential for violative residues.18

Drug Use in Natural or Organic Farms

The regulations promulgated for the National Organic Program specifically state allsynthetic substances that are permissible in animals being produced for certificationas organic. At the time of writing (2010), these included aspirin, atropine, butorphanol,flunixin, furosemide, electrolytes, glucose, ivermectin, lidocaine, magnesiumhydroxide, magnesium sulfate, mineral oil, oxytocin, poloxalene, and tolazoline, albeit,in most cases, with longer withdrawal times than those applied in conventionalfarms.19,20 Veterinarians working with organic farmers must become familiar withthe substances that are permissible in these operations, to assist producers in main-taining their organic status, as well as to assist them in understanding when it is appro-priate to remove animals from the organic stream if they require nonlisted drugs(eg, antimicrobials). Animal welfare considerations and veterinary medical ethics do

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not provide for withholding of therapeutics just to maintain an animal in the organicarm of a farm.

Drug Use in Sheep or Goat Dairy Farms

Veterinarians working with sheep or goat dairy farms in the United States, which farmmarket products commercially, must be familiar with the Pasteurized Milk Ordinance.This ordinance relates to permissible drug uses, as well as drug storage and labelingon dairy farms (see Table 1).

SUMMARY

This article reviews laws and regulations related to drug use in sheep and goats, withspecial reference to legislation in the United States. The discussion includes the drug-licensing procedures (including issues related to minor species), legalities of extralabeldrug use, withdrawal time estimation, and residues in sheep and goat tissues andproducts; it points out a few other important regulations related to organic production,dairy production, and compounding. Canadian and European regulations are alsomentioned. Veterinarians working with sheep and goats must be familiar with regula-tions governing use of drugs in these species, to prevent legal action, fulfill their fidu-ciary responsibility to the producers, and help protect and provide for a wholesomeand safe food supply.

REFERENCES

1. 21 U.S.C. 321. Definitions. In: Federal Food Drug and Cosmetic Act. 2009.2. Anon. Guidance #61: Guidance for industry FDA approval of new animal drugs

for minor uses and for minor species. Rockville (MD): Food and Drug Administra-tion Center for Veterinary Medicine; 2008. p. 1–82.

3. Extralabel drug use in animals. Final rule, 21 CFR Part 530. Fed Regist 1996;61:57731–46.

4. Anon. Compliance policy guide 615.115 Extra-label use of medicated feeds forminor species. Rockville (MD): Food and Drug Administration Center for Veteri-nary Medicine; 2001.

5. Anon. Policy on extra-label drug use (ELDU) in food producing animals. Ottawa,Ontario (Canada): Health Canada Veterinary Drug Directorate; 2010.

6. Anon. Food and Drug Regulations Part C Drugs C.01.610.1. Ottawa, Ontario(Canada): Canada Department of Justice; 2010. p. 771.

7. Anon. Guidance #3: Guidance for industry general principles for evaluating thesafety of compounds used in food-producing animals. Rockville (MD): Foodand Drug Administration Center for Veterinary Medicine; 2006. p. 1–42.

8. KuKanich B, Gehring R, Webb AI, et al. Effect of formulation and route of admin-istration on tissue residues and withdrawal times. J Am Vet Med Assoc 2005;227:1574–7.

9. Riviere JE, Webb AI, Craigmill AL. FARAD digest – primer on estimating with-drawal times after extralabel drug use. J Am Vet Med Assoc 1998;213:966–8.

10. Anon. Food Safety and Inspection Service 2009–National residue programscheduled sampling plans. Washington, DC: US Department of Agriculture;2009. p. 1–178.

11. Anon. Food Safety and Inspection Service 2008–National residue program data.Washington, DC: US Department of Agriculture; 2009. p. 1–147.

12. Linnett PJ. APVMA veterinary pharmacovigilance program: suspected adverseexperience reports for 2005. Aust Vet J 2006;84:418–20.

Drug Laws and Regulations for Sheep and Goats 21

13. Muntener C, Bruckner L, Sturer A, et al. Vigilance for veterinary medicinal prod-ucts: declarations of adverse reactions in the year 2008. Schweiz Arch Tierheilkd2009;151:583–90.

14. Naidoo V, Sykes R. Overview of suspected adverse reactions to veterinary medic-inal products reported in South Africa (March 2004–February 2006). J S Afr VetAssoc 2006;77:164–7.

15. Woodward KN. Veterinary pharmacovigilance. Part 1. The legal basis in the Euro-pean Union. J Vet Pharmacol Ther 2005;28:131–47.

16. Anon. Compliance policy guide 608.400–Compounding of drugs for use inanimals. Rockville (MD): Food and Drug Administration Center for VeterinaryMedicine; 2003.

17. Anon. FDA seeks injunction against Florida animal drug compounder. Rockville(MD): Food and Drug Administration; 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm208983.htm. Accessed November28, 2010.

18. Riviere JE. Influence of compounding on bioavailability. J Am Vet Med Assoc1994;205:226–31.

19. Anon. 7 CFR Sec. 205.603 Synthetic substances allowed for use in organic live-stock production. Agricultural Marketing Service, US Department of Agriculture.College Park (MD): National Archives and Records Administration; 2009.

20. Anon. 7 CFR Sec. 205.60 Nonsynthetic substances prohibited for use in organiclivestock production. Agricultural Marketing Service, US Department of Agricul-ture. College Park (MD): National Archives and Records Administration; 2009.

21. Craigmill AL, Rangel-Lugo M, Damian P, et al. Extralabel use of tranquilizers andgeneral anesthetics. J Am Vet Med Assoc 1997;211:302–4.

22. Haskell SR, Payne M, Webb A, et al. Antidotes in food animal practice. J Am VetMed Assoc 2005;226:884–7.

23. Damian P, Craigmill AL, Riviere JE. Extralabel use of nonsteroidal anti-inflamma-tory drugs. J Am Vet Med Assoc 1997;211:860–1.

24. Papich MG. Drug residue considerations for anesthetics and adjunctive drugs infood-producing animals. Vet Clin North Am Food Anim Pract 1996;12:693–706.

25. Gehring R, Haskell SR, Payne MA, et al. Aminoglycoside residues in food ofanimal origin. J Am Vet Med Assoc 2005;227:63–6.

26. Baynes RE, Payne M, Martin-Jimenez T, et al. Extralabel use of ivermectin andmoxidectin in food animals. J Am Vet Med Assoc 2000;217:668–71.

27. Martin-Jimenez T, Craigmill AL, Riviere JE. Extralabel use of oxytetracycline. J AmVet Med Assoc 1997;211:42–4.

28. Haskell SR, Gehring R, Payne MA, et al. Update on FARAD food animal drugwithholding recommendations. J Am Vet Med Assoc 2003;223:1277–8.