Drug Laws and Regulations for Sheep and Goats

Virginia R. Fajt,
KEYWORDS     Antimicrobial resistance  Extralabel drug use Food animal residue avoidance databank (FARAD) Goat  Minor species  Sheep  Tissue residue Withdrawal period
DVM, PhD

Although the process of pharmacotherapeutic decision making seems intuitive to the experienced veterinary clinician, it is important to periodically assess the process, to ensure that appropriate decisions are being made. Decision making for drug use and selection involves the following steps: 1. Identification of the physiologic or pathophysiologic process requiring alteration in the patient (eg, increased gastrointestinal parasite load, hypovolemia, bacterial infection of the lungs) 2. Decision whether use of a drug would affect the pathophysiologic changes 3. 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 obstacles 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 implications for its use 5. Selection of drug and drug regimen for administration. This article focuses on step 4(e) by reviewing the legal obligations and potential regulatory obstacles to use of drugs, in the United States in particular, with other countries mentioned as appropriate. To set the stage for defining legal drug use, a review of the drug approval process is provided, as well as a discussion of drugs currently approved 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 and Biomedical Sciences, Texas A&M University, MS 4466, College Station, TX 77843-4466, USA E-mail address: vfajt@cvm.tamu.edu Vet Clin Food Anim 27 (2011) 121 doi:10.1016/j.cvfa.2010.10.006 vetfood.theclinics.com 0749-0720/11/$ 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 authors alone. The respective agency should be contacted with questions regarding any information contained herein.
LABELED/LICENSED DRUGS Approval 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 is defined not by whether it is termed a drug or not, but rather its intended use. If water were used for treatment of disease, that water would be a drug and would be subject to laws and regulations; if that water is not approved for that specific use, such use is a violation of the Federal Food Drug and Cosmetic Act. Similar definitions are also legally 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 differs from country to country. Safety of drugs includes safety of the target animal, safety of humans exposed to the drug during administration and use, safety of humans consuming animal products after the animal has been treated with the drug, and safety for the environment of animals treated with the drug. The evidence required to document efficacy of a drug in the United States is outlined in Guidance #612 (Table 1) and includes recommendations for parasiticides, antimicrobials, and production drugs, with suggested options when appropriate for use of data from other species (in particular cattle) to document efficacy. Tables 25 list veterinary drugs currently approved for sheep and goats in the United States and Canada. Experienced veterinarians are aware that there is a paucity of drugs licensed for these animal species, resulting in either inability to treat particular conditions or requiring the use of drugs in an extralabel manner, in particular the use of drugs approved in other species of animals. The European Medicines Agency approves veterinary drugs for the European Union, although individual European countries 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 Administration Center 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 development of these drugs. MUMS can designate a new animal drug as one for a minor use or minor species, in which case grants may be available to support drug approval and a period of exclusivity applies to that approval (designation does not imply that the drug may be marketed; drug approval must first be granted). MUMS also maintains a list of so-called indexed drugs; these are drugs that may be marketed before collection 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, moxidectin and the progesterone EAZI-BREED CIDR, with both now approved for use. For goats, albendazole and the progesterone EAZI-BREED CIDR have been designated, but neither has yet been approved for use. Their designation allows a drug sponsor to apply for grants for data development that would lead to approval. Drug sponsors for drugs for minor species are not always pharmaceutical companies, but may be university or extension personnel with an interest in minor species. Approvals of drugs for minor species may use data published in Public Master Files, which may include

Drug Laws and Regulations for Sheep and Goats

safety or efficacy data generated by companies or other sponsors, or these approvals may use data acquired via requesting permission from a pharmaceutical company to share 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 minor species, including sheep and goats. This project continues to operate in the United States, in cooperation with the FDA MUMS office, to provide support and funding that will lead to the approval of new animal drugs for small ruminants.
EXTRALABEL USE OF VETERINARY DRUGS Legal Basis for Extralabel Use of Veterinary Drugs in the United States

The Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 authorized veterinarians in the United States to use drugs in an extralabel manner under particular circumstances.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 applies only to drugs approved by the FDA and does not include authorization for extralabel use of other products used in animals that are approved by other agencies, such as pesticides (approved by the US Environmental Protection Agency) or vaccines and other biologic or immunologic products (approved by the US Department of Agriculture). There is no legal provision for using these products in any manner not included on the label, and the veterinarian may incur liability should these products be used in a 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 use is not permitted for production drugs, including drugs that manipulate the estrus cycle, drugs that enhance growth, or drugs that induce lactation. Extralabel use of drugs must be performed by or on the order of a licensed veterinarian, within the context of a veterinarian-client-patient relationship (VCPR). A VCPR is present under the following circumstances: (1) the veterinarian has assumed responsibility for making clinical judgments regarding the health of the animal(s) and the need for medical treatment, and the client has agreed to follow the veterinarians instructions; (2) the veterinarian has sufficient knowledge of the animal(s) to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s); this means that the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s), or by medically appropriate and timely visits to the premises where the animal(s) are kept; (3) the veterinarian is readily available or has arranged for emergency coverage, for follow-up evaluation 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 groups are encouraged to develop their own definitions of timely to give guidance to veterinarians 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 American Veterinary Medical Association (AVMA) has developed an algorithm (see Table 1). As stated earlier, the first requirements are the presence of a VCPR and at least a preliminary diagnosis, as well as the therapeutic (ie, nonproduction use) need for the use. If the animal is a food animal, which includes all sheep and goats, if a drug exists that is

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Table 1 Recommended Web sites for information about drug regulation Topic US-based Web Sites American Veterinary Medical Association (AVMA) Animal Medicinal Drug Use Clarification Act Flowchart AVMA Guidance on Internet pharmacies AVMA Guidance on prescribing and dispensing drugs AVMA Guidelines for judicious antimicrobial use Food and Drug Administration Center for Veterinary Medicine (FDA CVM) FDA CVM Compliance Policy Guide on compounding FDA CVM Form FDA 1932a for Adverse Drug Event Reporting FDA CVM Guidance #61 Hierarchy and algorithm for determining acceptability of extralabel drug use General guidelines; some species groups have expanded these into more comprehensive and specific guidelines Home page for the CVM Outlines FDA policy on acceptable and unacceptable compounding Veterinary Adverse Experience, Lack of Effectiveness or Product Defect Report Guidance for Industry: FDA Approval of New Animal Drugs for Minor Uses and for Minor Species Provides recommended withdrawal times for drugs and chemicals The Blue Book outlines the National Residue Program (ie, the plan for sampling for drug and chemical residues in meat in the United States) http://www.avma.org/reference/amduca/amduca1.asp Description Electronic Address

http://www.avma.org/issues/prescribing/default.asp http://www.avma.org/issues/prescribing/prescribing_faq.asp http://www.avma.org/issues/policy/jtua.asp

http://www.fda.gov/AnimalVeterinary/default.htm http://www.fda.gov/downloads/ICECI/ComplianceManuals/ CompliancePolicyGuidanceManual/UCM200461.pdf http://www.fda.gov/downloads/AboutFDA/ ReportsManualsForms/Forms/AnimalDrugForms/ ucm048817.pdf http://www.fda.gov/downloads/AnimalVeterinary/ GuidanceComplianceEnforcement/GuidanceforIndustry/ UCM052375.pdf http://www.farad.org http://www.fsis.usda.gov/PDF/2009_Blue_Book.pdf

Food Animal Residue Avoidance Databank (FARAD) Food Safety and Inspection Service, US Department of Agriculture

Food Safety and Inspection Service, US Department of Agriculture

The Red Book present results from scheduled and inspector-generated sampling for drug and chemical residues in meat in the United States US program for increasing approval for minor species and minor uses of drugs To find contact information for state board of pharmacy Accreditation program for Internet pharmacies; refers to nonfood and companion animals only Regulations related to organic production in the United States All regulations related to producing milk

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

Minor Species/Minor Use Program National Association of Boards of Pharmacy National Association of Boards of Pharmacy Vet-VIPPS (Verified Internet Pharmacy Practice Sites) National Organic Program Pasteurized Milk Ordinance

http://www.nrsp-7.org/introduction.htm http://www.nabp.net/boards-of-pharmacy/ http://www.nabp.net/programs/accreditation/vet-vipps/

http://www.ams.usda.gov/nop/indexIE.htm http://www.fda.gov/Food/FoodSafety/Product-SpecificInformation/ MilkSafety/NationalConferenceonInterstateMilkShipments NCIMSModelDocuments/PasteurizedMilkOrdinance2007/ default.htm http://www.inspection.gc.ca/english/anima/feebet/feebete.shtml http://www.cgfarad.usask.ca/

Drug Laws and Regulations for Sheep and Goats

Canada-based Web sites Canadian Food Inspection Agency Canadian global FARAD (gFARAD) Regulations regarding livestock feeds including medicated feeds in Canada One branch of gFARAD that provides Canadian-specific recommendations for withdrawal times

Canadian Veterinary Medical Association policy on extralabel drug use Health Canada Veterinary Drug Directorate European Union-based Web site European Medicines Agency Committee for Medicinal Products for Veterinary Use

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

Home page for veterinary drugs in Canada European agency responsible for drug regulations and drug approval in the European Union

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

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

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Table 2 Drugs approved in the United States, for administration to sheep and currently marketed Active Ingredient Albendazole Ceftiofur sodium Chlortetracycline Example Trade Name Valbazen Naxcel Pfichlor, Chlorachel, Chlormax Aureomycin, Pfichlor Deccox Ivomec Bovatec Tramisole, Levasole Cydectin Neomix, Neosol, NeoMed Pharmaceutical Form Oral suspension Injectable solution Medicated premix Type(s) of Sheep for Which Approved Nonpregnant Not specified Breeding animals Indications Control of internal parasites Respiratory disease Reduction of Campylobacter abortion incidence Increase weight gain and feed efficiency Prevention of coccidiosis Control of internal parasites Prevention of coccidiosis Control of nematode infections Control of internal parasites Treatment and control of gastrointestinal colibacillosis Dose Rate and Route of Administration 7.5 mg/kg bw by mouth 1.02.2 mg/kg bw im for 3 d 80 mg/head/d in the feed

Chlortetracycline Decoquinate Ivermectin Lasalocid Levamisole Moxidectin Neomycin

Medicated premix Medicated premix Oral drench Medicated premix Oral suspension, tablet Oral drench Soluble powder (for addition to drinking water or milk replacer)

Growing animals Young, nonlactating Not specified Sheep in confinement Not specified Not specified Not specified

2050 g/t feed 0.5 mg/kg bw by mouth (13.6 g/t feed) 0.2 mg/kg bw by mouth 2030 g/t of feed 8 mg/kg bw by mouth 0.2 mg/kg bw by mouth 22 mg/kg bw by mouth, divided doses daily for a maximum of 14 d

Neomycin type A medicated article for milk replacer or feed Neostigmine

Neomix 325 Medicated Premix

Medicated premix

Not specified

Treatment and control of gastrointestinal colibacillosis Rumen atony, bowel evacuation, bladder evacuation Bacterial enteritis, bacterial respiratory infection Ocular infections Bacterial enteritis, bacterial respiratory infection Respiratory infection caused by Pasteurella multocida Respiratory infection associated with Mannheimia haemolytica Control of white muscle disease Increase weight gain and feed efficiency

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

Stiglyn

Injectable solution

Nonpregnant, nonlactating Not specified

11.5 mg/45.36 kg (100 lb) bw sc 22 mg/kg bw daily in the drinking water or milk replacer External application in the eye 24 times daily 22 mg/kg bw daily (1020 g/t of feed)

Oxytetracycline

Terramycin SP

Soluble powder (for addition to drinking water or milk replacer) Ophthalmic ointment Medicated premix

Oxytetracycline 1 polymyxin Oxytetracycline

Terramycin Terramycin-100 type A medicated article, TM-50 type A medicated article Agricillin, Aqua-cillin

Not specified Not specified

Drug Laws and Regulations for Sheep and Goats

Penicillin G

Injectable suspension

Not specified

6600 IU/kg bw im daily

Tilmicosin

Micotil

Injectable solution

Not specified

10 mg/kg bw sc

Vitamin E 1 sodium selenite Zeranol

BO-SE Ralgro

Injectable solution Subcutaneous implant

Newborn, nonpregnant Feedlot lambs

2.5 mL/45.36 kg (100 lb) bw im or sc One implant sc behind the ear

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

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Table 3 Drugs approved in Canada for administration to sheep Active Ingredient Acepromazine Calcium borogluconate 1 electrolytes Ceftiofur sodium Chlortetracycline Example Trade Name Acepro-25, Atravet CalMagPhos, Mag-Cal, Norcalciphos Excenel sterile powder Aureomycin Pharmaceutical Form Injectable solution Injectable solution Injectable solution Medicated premix Indications Sedation Electrolyte replacement Respiratory infection associated with Mannheimia haemolytica As an aid in reduction of losses caused by enterotoxaemia in feedlot lambs Treatment of bloat Follicle stimulating Anestrus Dehydration and electrolyte disturbances Prevention of coccidiosis Dose Rate and Route of Administration 0.05 mg0.1 mg/kg bw im 50125 mL iv, sc 2 mg/kg bw once daily for 3 d im 22 mg/kg (0.0022 %) of complete feed by mouth Range of 0.51 mL/kg bw by mouth 3001000 IU im, iv, sc 0.51 mg im 200 mg/kg bw sc, by mouth To effect iv Mix 240 g (0.24 kg) of premix in 1 t (1000 kg) 100% dry matter basis of diet (including roughage) to provide 0.0036 % (36 ppm) of lasalocid sodium activity Epidural, infiltration 2 mL (2.5 mg) iv, sc By mouth 1 g powder/50 kg bw by mouth

Dioctyl sodium sulfosuccinate Equine chorionic gonadotrophin Estradiol cypionate Ivermectin Lactated Ringer solution Lasalocid

Anti-bloat, Bloat-Eze Folligon, Novormon 5000 Ivomec Lact-R Bovatec

Oral solution Injectable solution Injectable solution Injectable solution, oral drench Injectable solution Medicated premix

Lidocaine or lidocaine 1 epinephrine Luteinizing hormone Mineral oil Neomycin

Lutropin-V Neomycin 325, Biosol

Injectable solution Injectable solution Oral solution Oral solution

Nerve block and anesthesia Breeding disorders Intestinal constipation Bacterial enteritis

Neomycin 1 (methyl violet or gentian violet) Neomycin 1 sulfathiazole 1 sulfamethazine Neomycin 1 methscopolamine Neomycin 1 succinylsulfathiazole 1 atropine 1 hyoscyamine Oxytetracycline

Keraplex, Co-op Pinkeye Spray Neorease, Scour Treat Scour solution Scour suspension

Spray for local application Oral solution Oral solution Oral solution

Wound dressing, treatment of infectious keratoconjunctivitis Bacterial enteritis and pneumonia Bacterial enteritis Bacterial enteritis

External application 10 mL/5 kg bw twice a day by mouth 1 mL/5 kg bw in water or milk for 13 days 2 mL/kg bw divided twice a day by mouth 3 mL/45 kg bw im, iv once a day for 3 d (1) 110 mg/kg complete feed (2) 22 mg/kg complete feed

Noromycin LP, Oxymycine LP Terramycin-100 Premix

Injectable solution

Respiratory infection associated with Mannheimia haemolytica, mastitis, metritis, joint ill (1) Bacterial enteritis and respiratory infection associated with Mannheimia haemolytica (2) As an aid in the reduction of losses caused by enterotoxemia in feedlot lambs Treatment of obstetric disorders Respiratory infection caused by Pasteurella multocida, metritis, wound infections Reproductive disorders Prevention and treatment of pregnancy toxemia Antihistamine Expectorant Metritis, bacterial enteritis, mastitis, respiratory infections

Oxytetracycline

Medicated premix

Drug Laws and Regulations for Sheep and Goats

Oxytocin Penicillin G penicillin G 1 benzethine penicillin Progesterone 5% Propylene glycol

Oxy-20 Depocillin, Hi-pencin 300, Longisil Glycol-P

Injectable solution Injectable solution

3050 IU 21,000 IU/kg bw (0.7 mL/10 kg) once a day im 0.5 mL/10 kg 1015 mg per animal daily, as needed im Prevention: 50100 mL daily; treatment: 75125 mL daily for 10 d by mouth 1 mL/45 kg bw 510 mL iv 225 mg/kg in water or milk replacer on day 1, 112.5 mg/kg on day 25 (continued on next page)

Injectable solution Oral solution

Pyrilamine Sodium iodide Sulfamethazine

Sodide Sulfa 25

Injectable solution Soluble powder (for addition to drinking water or milk replacer)

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Table 3 (continued) Active Ingredient Sulfamethazine Sulfamerazine 1 sulfathiazole Testosterone Tetracycline Example Trade Name Sulfa 25 Sulectim Pharmaceutical Form Bolus Soluble powder (for addition to drinking water or milk replacer) Injectable solution Soluble powder (for addition to drinking water or milk replacer) Injectable solution Injectable solution Injectable solution Injectable solution Indications Metritis, bacterial enteritis, mastitis, respiratory infections Bacterial enteritis, respiratory infections Impotence, testicular deficiency Bacterial enteritis, respiratory infection associated with Mannheimia haemolytica Anesthetic Respiratory infection associated with Mannheimia haemolytica Control of respective deficiencies Control of white muscle disease Dose Rate and Route of Administration 1 bolus/80 kg bw by mouth on day 1, 1/2 bolus/80 kg bw on day 23 454 g to 727 L (180 gallons) of drinking water for 510 days 1025 mg once a day im Add in water 0.25 g of powder per 25 kg bw, every 12 h given as a drench for 4 or 5 d iv 1 mL per 30 kg bw/1.5 mL per 45.36 kg (100 lb) bw sc im Prevention: newborns 0.25 mL per animal; animals aged 28 wk 0.5 mL per animal; treatment: 0.5 mL per animal

Uni-test suspension Onycin 250, Onycin 1000 Thiotal Micotil Co-op A1D Dystosel, Selon-E

Thiopental Tilmicosin Vitamin A 1 vitamin D Vitamin E 1 selenium

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).

Table 4 Drugs approved in the United States for administration to goats and currently marketed Active Ingredient Albendazole Ceftiofur sodium Decoquinate Fenbendazole Morantel Example Trade Name Valbazen Naxcel Deccox Safeguard, Panacur Rumatel Pharmaceutical Form Oral suspension Injectable solution Medicated premix Oral suspension Feed additive Type(s) of Animals for Which Approved Nonpregnant, nonlactating Not specified Young, nonlactating Nonlactating Not specified Indications Control of adult liver flukes Respiratory disease Prevention of coccidiosis Control of stomach worms Dose Rate and Route of Administration 10 mg/kg bw by mouth 1.02.2 mg/kg bw im for 3 d 0.5 mg/kg bw by mouth (13.6 g/t feed) 5 mg/kg bw by mouth 0.44 g/45.36 kg (100 lb) bw (0.444.4 g/0.45 kg [1 lb] of feed) 22 mg/kg bw by mouth, divided doses daily for a maximum of 14 d 22 mg/kg bw by mouth, for a maximum of 14 d

Drug Laws and Regulations for Sheep and Goats

Neomycin

Neomix, Neosol, NeoMed

Soluble powder (for addition to drinking water or milk replacer) Medicated premix

Not specified

Treatment and control of gastrointestinal colibacillosis Treatment and control of gastrointestinal colibacillosis

Neomycin type A medicated article for milk replacer or feed

Neomix 325 Medicated Premix

Not specified

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

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Table 5 Drugs approved in Canada for administration to goats Active Ingredient Acepromazine Dioctyl sodium sulfosuccinate Mineral oil Neomycin 1 sulfathiazole 1 sulfamethazine Progesterone 5% Example Trade Name Acepro-25, Atravet Anti-bloat, Bloat-Eze Neorease, Scour Treat Pharmaceutical Form Injectable solution Oral solution Oral solution Oral solution Indications Sedation Treatment of bloat Intestinal constipation Bacterial enteritis and pneumonia Reproductive disorders Route of Administration im By mouth By mouth By mouth

Injectable solution

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).

labeled for the condition being treated, which contains the needed ingredient, which is in 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 drug approved for a food animal may be considered. If there is no drug that is approved for 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 no drug approved for humans or companion animals can be used in an extralabel manner, then a compounded drug may be considered; however, this extralabel use must be compounded from approved drugs and must not be compounded from bulk 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 of the dispensing pharmacy if applicable, the established name of the drug and, if there is more than one active ingredient, the established name of each ingredient, directions for use including identity of treated animals, dose, route, frequency, route and duration, cautionary statements, and the veterinarians specified withdrawal time for any food that might be derived from treated animals) and the requirements for the veterinarians keeping records for 2 years after prescribing (established name of drug and/or active 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 extralabel manner in minor species, such as sheep and goats, is the subject of some guidance from the FDA CVM.4 Minor species are all species except horses, cattle, pigs, dogs, cats, chickens, and turkeys. The Compliance Policy Guide Section 615.115 states that the FDA does not ordinarily consider regulatory action against the veterinarian, 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,

Drug Laws and Regulations for Sheep and Goats

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3. 4. 5. 6.

nutrient content) or (b) for use in a food-producing minor species and the feed is approved in a major food-producing species. The feed is limited to farmed or confined minor species. The use of the medicated feed is only with the express prior written recommendation and oversight of a licensed veterinarian with a valid VCPR. 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. 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 practically used under AMDUCA.

In addition, the veterinarian must establish an extended withdrawal time, must assure that the identity of treated animals is maintained, and must have written recommendations within 3 months before the use (with copies with the veterinarian and the producer). The producer must keep accurate feed records for at least 1 year from delivery of the feed, must maintain identity of treated animals, must assure withdrawal times 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 approved product 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 The medicated feed must be for a therapeutic purpose, rather than for a production purpose, such as growth promotion or feed efficiency. A valid VCPR must exist and all parties (client, prescribing veterinarian, and feed mill) must maintain a proper and valid veterinary prescription on file.
Illegal Extralabel Use of Drugs in the United States

Extralabel use of veterinary drugs is considered illegal under AMDUCA in the following cases. 1. Extralabel use of drugs in or on feed 2. Extralabel use from unapproved (nonlicensed) drugs or bulk drug (API) 3. Extralabel use outside a VCPR 4. Extralabel use of any of the drugs mentioned in Box 1 5. 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 administration to animals that produce food or are intended for consumption as food: chloramphenicol (or its salts or derivatives), 5-nitrofurans, clenbuterol (or its salts or derivatives), 5-nitroimidazoles, diethylstilbestrol, or other stilbene compounds.6 Canadian policy regarding extralabel drug use in food animals states that veterinarians should preferentially not use the category 1 antimicrobials mentioned in Table 6 extralabel, because of their importance in human health and the potential for selection for antimicrobial resistance in pathogens of human significance.
Withdrawal Time Estimation

If drugs are used in accordance with the label, the withdrawal times legally provided should 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 effect level), which is the amount of drug expected to cause no harm if ingested by humans. Dividing this by a safety factor results in an acceptable daily intake (ADI)

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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

of the drug. A safe concentration is then calculated by multiplying ADI by the average adult human weight and dividing by an estimate of amount of edible product consumed per day by the average adult (assumptions are that an adult consumes 300 g muscle, 100 g liver, 50 g kidney, 50 g fat, 1.5 L milk, and 100 g eggs). This safe concentration is the threshold that is then compared with the tissue concentrations of the drug in the animal products over time. Typically, the licensed dose of drug is administered in 20 target-species animals; then, 5 animals are killed at

Table 6 Category 1 antimicrobial drugs discouraged by Health Canadas policy for use in food-producing animals under extralabel provisions Antimicrobial Drug Group Carbapenems Third- and fourth-generation cephalosporins Fluoroquinolones Glycopeptides Glycylcyclines Ketolides Lipopeptides Monobactams Nitroimidazoles Oxazolidinones Penicillin/b-lactamase inhibitor combinations Polymyxins Streptogramins Therapeutic agents for tuberculosis Example Drug Imipenem Cefotaxime Enrofloxacin Vancomycin Tigecycline Telithromycin Daptomycin Aztreonam Metronidazole Linezolid Ticarcillin-clavulanic acid Colistin Dalfopristin/quinupristin Ethambutol, isoniazid, pyrazinamide, rifampin

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

Drug Laws and Regulations for Sheep and Goats

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each of 4 different time points after administration and the concentration of drug in various tissues is determined; control animals are also included in the study. The resulting time-concentration curve is used to statistically evaluate (using confidence intervals) the time point after drug administration at which the tissue concentration is predicted 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 be insufficient to prevent illegal residues for several reasons, including differences in formulations (eg, conventional vs long-acting, differing salts such as benzathine vs procaine), route of administration, metabolism, long half-lives resulting in accumulation of drug, increased dose, or differing administration frequency of the drug.8 Therefore, it is particularly important to consider ways to accurately estimate the effects of extralabel use on withdrawal time estimates. One important resource in the United States for this information is the Food Animal Residue Avoidance Databank (FARAD), a national cooperative project sponsored by the US Department of Agriculture, with a primary mission to prevent or mitigate illegal residues of drugs, pesticides, and other chemicals in foods of animal origin. FARAD has personnel at the University of California-Davis, the University of Florida, and North Carolina State University, who can review their extensive database of residue information to provide estimates of withdrawal intervals to prevent illegal residues. Veterinarians can directly contact FARAD (see Table 1) with a withdrawal time question. FARAD also periodically publishes FARAD Digests in the Journal of the American Veterinary Medical Association. A compilation of published recommendations to date for withdrawal intervals for meat and milk for drugs and antidotes used in an extralabel manner (ie, drugs not currently 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 as compiling drug information and tolerance (or maximum residue levels [MRLs]) data from their countries. For example, Canada has developed Canadian gFARAD, with a Web site and voicemail for customized withdrawal time estimates for extralabel uses of drugs and other chemicals (see Table 1). If FARAD is not available or the veterinarians location does not permit access to a gFARAD office, recommendations have been made on how practitioners can estimate a withdrawal time.9 The apparent elimination half-life of the drug (the time for drug 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 halflives, more than 99.9% of the drug has been eliminated, multiplying the half-life by 10 and then rounding up to the nearest day provides an initial estimate of withdrawal interval. However, the serum elimination half-life may not be completely representative of the tissue elimination half-life in which residues are measured. Residues at harvest are determined from a target tissue, such as muscle or liver, not from plasma or serum; hence knowledge of the tissue elimination half-life is more useful. However, tissue elimination kinetics is often not publicly available, so veterinarians may have to use serum concentration data and assume homogeneous distribution of drug between tissues and serum. Although more than 99.9% of the drug may have been eliminated after 10 elimination half-lives, the less than 0.01% of the drug remaining may still be more than a safe concentration, tolerance, or MRL, and therefore may be illegal. If an estimate of the elimination half-life is available only in cattle, some comparative pharmacokinetic data suggest that sheep and goats eliminate drugs at a similar or faster rate than cattle, although this type of extrapolation should be performed with extreme caution, because individual drugs may have different pharmacokinetic

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Table 7 Published recommendations from FARADa for withdrawal times for drugs and antidotes used in sheep and goats Year of Publication 199721 200522 199723 200522 Animal Species Referred To Ruminants Food animals Ruminants Food animals Withdrawal Period Therapeutic Regime <0.13 mg/kg bw iv OR <0.44 mg/kg bw im Not specified All recommended doses 0.2 mg/kg bw iv or im; multiple administrations, as treatment of organophosphate toxicity Not specified <0.08 mg/kg bw iv or im Not specified Not specified 5 mg/kg bw im or sc <100 mg/kg bw iv 0.4 mg/kg bw by mouth 0.2 mg/kg bw sc 0.5 mg/kg bw external use <2 mg/kg bw iv or <10 mg/kg bw im 3.3 mg/kg bw iv or im, every 24 h for up to 3 d Infiltration; epidural Not specified Not specified Meat 7d Zero 1d 28 d Milk 48 h Zero 24 h 6d

Drug Acepromazine Activated charcoal Aspirin Atropine

Butorphanol Detomidine Dimercaprol EDTA Epinephrine Gentamicin Guafenesin Ivermectin Ivermectin Ivermectin Ketamine Ketoprofen Lidocaine 1 epinephrine Methylene blue Molybdate salts (ammonium molybdate, ammonium tetrathiomolybdate)

199624 1997
21,24

Food animals Ruminants Food animals Food animals Food animals Sheep and goats Ruminants Goats Goats Goats Ruminants Sheep and goats Ruminants Food animals Food animals

48 h 4d 5d 2d Zero >18 mo 3d 14 d 35 d
b

72 h 5d 2d Zero 10 d; testing of milk is recommended 48 h 9d 40 d 7d 48 h 24 h 24 h 4d 5d

200522 200522 200522 200525 199721 200026 200026 200026 199721 199723 199721 200522 200522

3d 7d 1d 14 d 10 d

Moxidectin Moxidectin Moxidectin Moxidectin Oxytetracycline Oxytetracycline Oxytetracycline (long-acting) Penicillamine Pentobarbital Phenylbutazone Pralidoxime (2-PAM) Penicillin G (procaine) Sodium nitrite Sodium thiosulfate Thiamylal Thiobarbital Vitamin K1 Xylazine Xylazine Yohimbine

200026 200026 200026 200026 199727 199727 200328 200522 199624 200328 200522 2006 200522 200522 199721 199721 200522 199721 199721 199721

Goats Goats Goats Goats Sheep and goats Sheep and goats Food animals Food animals Sheep Sheep and goats Food animals Food animals Ruminants Ruminants Sheep and goats Ruminants Ruminants Ruminants

0.2 mg/kg bw by mouth 0.5 mg/kg bw by mouth sc 0.5 mg/kg bw external application 6.611.0 mg/kg bw iv or im, once >11.0 mg/kg bw iv or im, once 6.611.0 mg/kg bw iv or im, multiple doses 20 mg/kg bw im Not specified Not specified Use discouraged 30 mg/kg bw every 8 h >6600 U/kg bw Not specified, iv Not specified, iv <5.5 mg/kg bw <9.4 mg/kg bw 0.52.5 mg/kg bw im, iv, or sc 0.0160.1 mg/kg bw iv or 0.050.3 mg/kg bw im 0.32.0 mg/kg bw im <0.3 mg/kg bw iv

14 d 23 d
b

b b b

1d Cattle withdrawal time is adequate Cattle withdrawal time is adequate 28 d 21 d 4d

b

1d 96 h and testing of milk 144 h and testing of milk 96 h 3d 4d

b

Drug Laws and Regulations for Sheep and Goats

28 d Testing of urine is recommended 24 h 24 h 1d 1d Zero 5d 10 d 7d

6d Testing of milk is recommended 48 h

b

24 h 24 h Zero 72 h 120 h 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 pharmacokinetics 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.

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properties in sheep or goats compared with those in cattle. Given the potential for error in making any of these estimates, veterinarians are cautioned to provide generous withdrawal time estimates or to make every effort to contact FARAD or other equally weighty sources to protect the food supply and to protect animal owners from the 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 and observed. This strategy raises the issue of withdrawal periods during extralabel use of drugs, which already have longer than the withdrawal periods mentioned earlier in other animal species. For example, moxidectin injectable solution has a licensed withdrawal period of 65 days for cattle meat and 82 days for sheep milk. Hence, it seems wrong to maintain a 28-day withdrawal period for meat of goats, if the drug would be administered under extralabel circumstances in that animal species. To avoid such circumstances, blanket statements, such as Not to be used in animals producing milk for human consumption or for industrial purposes or Not to be used in animals younger than months, have been devised and are enforced.
MONITORING OF DRUG USE Residues in Foods

In the United States, the Food Safety and Inspection Service (FSIS) of the US Department of Agriculture is responsible for ensuring the safety of food products from animals. It publishes a yearly plan for which samples will be collected at harvest facilities in the next year, the so-called Blue Book10 (see Table 1). It also publishes yearly reports on the previous years sampling and findings, the Red Book11 (see Table 1). The most recent report published is for the calendar year 2008, and data are reported on scheduled samples, as well as inspector-generated samples. Inspector-generated samples are those that were not regularly scheduled, but rather were collected by in-plant public health veterinarians because of the appearance of the animals ante or post mortem, suggesting medication use, previous history of the producer of animals with violative residues, or other suspicions raised during the on-site inspections. 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 laboratory for testing. In-plant FAST-positive samples are also sent to the FSIS laboratory for 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 nonviolative positive samples (3 antimicrobials, one avermectin); of 472 scheduled samples in sheep, there were no violations.11 Inspector-generated samples revealed the following: of 180 samples from goats there were no FAST-positive samples; of 370 samples from lambs there was one FAST-positive sample (sulfadimethoxine); and of 137 samples from sheep there were no FAST-positive samples.11 Overall, these findings show a low level of violative residues in meat from sheep and goats in the United States. 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 300 samples from sheep. The samples are tested for presence of antibiotics (including fluoroquinolones, which are currently illegal for use in sheep and goats in the United States) and avermectins. The confirmatory 7-plate bioassay tests for antibiotics include tetracyclines, aminoglycosides, macrolides, b-lactams, and fluoroquinolones. Samples from goats are also tested for b-agonists, such as clenbuterol.

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Pharmacovigilance

Another important aspect of monitoring drug use, pharmacovigilance, involves the cataloging of adverse reactions to the drug product after approval, sometimes called phase IV or postmarketing surveillance. This area of data collection is undergoing considerable change, with the FDA CVM and the AVMA considering ways to appropriately and accurately gather data on adverse drug reactions. A major issue with adverse reactions is correct attribution of a reaction to the drug itself; another is who bears the burden of data collection and analysis. Drug sponsors are required to submit reports to the 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 of Effectiveness or Product Defect Report, available online for submission directly to the FDA CVM (see Table 1), or the report can be submitted by telephone to 1-888-FDAVETS. There are periodically published reports in the literature from various regulatory or epidemiologic experts, which examine adverse event data to attempt to attribute drugs to risks.1214 In Europe, pharmacovigilance procedures involve centralized (pan-European) and member-state (individual-country) responsibilities for reporting and follow-up of adverse reactions from veterinary drugs.15
OTHER REGULATIONS RELATED TO USE OF VETERINARY DRUGS IN SHEEP AND GOATS Compounding

Compounding is not distinguished from manufacturing in the Federal Food Drug and Cosmetic Act; therefore, any manipulation of an approved drug not included in the license or use of an unapproved drug would be considered compounding and, technically, would be illegal for animal drugs. The FDA CVM has issued a Compliance Policy Guide for Compounding, which outlines the FDAs policy and regulatory priorities for compounded drugs.16 The important parts of the Guide include the statement that compounding from bulk drugs (API) for food animals is considered a regulatory priority, as is compounding when not used for therapeutic purposes (AMDUCA authorizes compounding from approved drugs, but only when animal health 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 Francks Pharmacy in Florida, which was implicated in the death of polo ponies after they were administered a compounded vitamin product.17 The issues with food animals of compounding from bulk drug include the potential for inclusion of toxic compounds resulting in unsafe food products, as well as the unpredictable bioavailability of compounded products, 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 all synthetic substances that are permissible in animals being produced for certification as organic. At the time of writing (2010), these included aspirin, atropine, butorphanol, flunixin, furosemide, electrolytes, glucose, ivermectin, lidocaine, magnesium hydroxide, magnesium sulfate, mineral oil, oxytocin, poloxalene, and tolazoline, albeit, in most cases, with longer withdrawal times than those applied in conventional farms.19,20 Veterinarians working with organic farmers must become familiar with the substances that are permissible in these operations, to assist producers in maintaining their organic status, as well as to assist them in understanding when it is appropriate 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 organic arm of a farm.
Drug Use in Sheep or Goat Dairy Farms

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

This article reviews laws and regulations related to drug use in sheep and goats, with special reference to legislation in the United States. The discussion includes the druglicensing procedures (including issues related to minor species), legalities of extralabel drug use, withdrawal time estimation, and residues in sheep and goat tissues and products; it points out a few other important regulations related to organic production, dairy production, and compounding. Canadian and European regulations are also mentioned. Veterinarians working with sheep and goats must be familiar with regulations governing use of drugs in these species, to prevent legal action, fulfill their fiduciary responsibility to the producers, and help protect and provide for a wholesome and 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 Administration Center for Veterinary Medicine; 2008. p. 182. 3. Extralabel drug use in animals. Final rule, 21 CFR Part 530. Fed Regist 1996;61: 5773146. 4. Anon. Compliance policy guide 615.115 Extra-label use of medicated feeds for minor species. Rockville (MD): Food and Drug Administration Center for Veterinary 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 the safety of compounds used in food-producing animals. Rockville (MD): Food and Drug Administration Center for Veterinary Medicine; 2006. p. 142. 8. KuKanich B, Gehring R, Webb AI, et al. Effect of formulation and route of administration on tissue residues and withdrawal times. J Am Vet Med Assoc 2005;227: 15747. 9. Riviere JE, Webb AI, Craigmill AL. FARAD digest primer on estimating withdrawal times after extralabel drug use. J Am Vet Med Assoc 1998;213:9668. 10. Anon. Food Safety and Inspection Service 2009National residue program scheduled sampling plans. Washington, DC: US Department of Agriculture; 2009. p. 1178. 11. Anon. Food Safety and Inspection Service 2008National residue program data. Washington, DC: US Department of Agriculture; 2009. p. 1147. 12. Linnett PJ. APVMA veterinary pharmacovigilance program: suspected adverse experience reports for 2005. Aust Vet J 2006;84:41820.

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13. Muntener C, Bruckner L, Sturer A, et al. Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2008. Schweiz Arch Tierheilkd 2009;151:58390. 14. Naidoo V, Sykes R. Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2004February 2006). J S Afr Vet Assoc 2006;77:1647. 15. Woodward KN. Veterinary pharmacovigilance. Part 1. The legal basis in the European Union. J Vet Pharmacol Ther 2005;28:13147. 16. Anon. Compliance policy guide 608.400Compounding of drugs for use in animals. Rockville (MD): Food and Drug Administration Center for Veterinary Medicine; 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 November 28, 2010. 18. Riviere JE. Influence of compounding on bioavailability. J Am Vet Med Assoc 1994;205:22631. 19. Anon. 7 CFR Sec. 205.603 Synthetic substances allowed for use in organic livestock 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 organic livestock production. Agricultural Marketing Service, US Department of Agriculture. College Park (MD): National Archives and Records Administration; 2009. 21. Craigmill AL, Rangel-Lugo M, Damian P, et al. Extralabel use of tranquilizers and general anesthetics. J Am Vet Med Assoc 1997;211:3024. 22. Haskell SR, Payne M, Webb A, et al. Antidotes in food animal practice. J Am Vet Med Assoc 2005;226:8847. 23. Damian P, Craigmill AL, Riviere JE. Extralabel use of nonsteroidal anti-inflammatory drugs. J Am Vet Med Assoc 1997;211:8601. 24. Papich MG. Drug residue considerations for anesthetics and adjunctive drugs in food-producing animals. Vet Clin North Am Food Anim Pract 1996;12:693706. 25. Gehring R, Haskell SR, Payne MA, et al. Aminoglycoside residues in food of animal origin. J Am Vet Med Assoc 2005;227:636. 26. Baynes RE, Payne M, Martin-Jimenez T, et al. Extralabel use of ivermectin and moxidectin in food animals. J Am Vet Med Assoc 2000;217:66871. 27. Martin-Jimenez T, Craigmill AL, Riviere JE. Extralabel use of oxytetracycline. J Am Vet Med Assoc 1997;211:424. 28. Haskell SR, Gehring R, Payne MA, et al. Update on FARAD food animal drug withholding recommendations. J Am Vet Med Assoc 2003;223:12778.