- Email: [email protected]
Regulatory considerations in the United States
Vet Clin Food Anim 19 (2003) 695–705
Regulatory considerations in the United States Virginia R. Fajt, DVM, PhD* Veterinary Antimicrobial Decision Support System, Iowa State University, College of Veterinary Medicine, PO Box 3020, Ames, IA 50011-3020, USA
As the focus on the safety of our food supply continues to tighten, food safety professionals such as cattle veterinarians will be on the front lines of providing assurance of safe and wholesome animal products. Maintaining the safety of animal food products is one of the purposes of the laws and regulations associated with drug use in food animals. This article enumerates some of the important regulations that govern selection and use of pharmaceutical products in cattle. The reader is advised, however, that the author’s interpretation of the regulations is not final, and if there are any questions, the appropriate regulatory body should be contacted (see Appendix 1 for contact information).
Regulations related to drug selection The selection of drugs for use in the treatment of cattle diseases and conditions requires more vigilance than for other nonfood animal species, because the end products are human consumables. It is not simply a matter of selecting a product approved for the given condition, because many conditions are treated for which no labeled product exists (requiring ‘‘extralabel’’ use). Constraints on the final product, such as targeting specific markets (eg, organic), may restrict further the use of certain drugs. This section discusses extralabel use, compounding, and organic livestock production. Animal Medicinal Drug Use Clarification Act Using drugs in an extralabel manner—for example, at a different dose or for a different species—was legalized in veterinary medicine in 1994 with the * 6 Sedum Court, Pueblo, CO 81001. E-mail address: [email protected] 0749-0720/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0749-0720(03)00050-1
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passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA) [1]. Previously, extralabel use had been permitted under the Food and Drug Administration Center for Veterinary Medicine (FDA-CVM) discretionary policy but was technically illegal. The legaliza tion of extralabel drug use, however, should not be interpreted as allowing any usage of any legally available drug. The onus is still on the veterinarian to justify the extralabel use, and restrictions do exist. AMDUCA applies only to FDA-approved animal and human drugs, permits extralabel use only by or under the order of a licensed veterinarian within the context of a valid veterinarian–client– patient relationship, and must not result in violative drug residues. Although allowing extralabel use only in the event that the health of the animal is threatened or death or suffering may result if treatment does not occur, AMDUCA does not permit extralabel use of drugs in feed or extralabel use of production drugs, such as growth promotant or reproductive drugs. A useful algorithm for determining whether an extralabel use is legal has been provided by the American Veterinary Medical Association (see web site information in Appendix 1) [2]. There is a hierarchy of drug selection that allows the use of extralabel drugs if labeled products are either not approved or are clinically ineffective. In essence, the hierarchy for food animals is (1) a product approved for the condition being treated that is effective as labeled, (2) a product approved for a food animal that may be used in an extralabel manner, and (3) a product approved in nonfood animals or humans that may be used in an extralabel manner. If no products exist that satisfy these requirements, a compounded product may be permitted, and the compliance policy guide on compounding should be consulted (see following discussion). AMDUCA specifically prohibits the extralabel use of certain compounds. These compounds are fluoroquinolones, glycopeptides, furazolidone, nitrofurazone, chloramphenicol, dimetridazole, ipronidazole, other nitroimidazoles (such as metronidazole), sulfonamide drugs in lactating dairy animals (except for approved uses of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine), clenbuterol, and diethylstilbestrol. Until recently, the topical use of furazolidone and nitrofurazone was permitted, but this use has been made illegal [3]. If extralabel use is determined to be necessary and legal, there are labeling and record-keeping requirements that must be fulfilled. The regulations should be consulted for full details on what must be included in the label, but the major components are the prescribing veterinarian’s contact information, a complete description of animals being treated, complete directions for use, and meat- or milk-withholding times. It is also the responsibility of the veterinarian to ensure that treated animals can be identified, to allow adherence to proper withholding times. Suggestions for withholding times for extralabel drugs can be obtained from the Food Animal Residue Avoidance Databank using the contact information in
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Appendix 1. If withholding times cannot be established—for example, if there is insufficient information on which to base them—the drug in question should not be used or the animal must not be permitted to enter the food supply. Compounding Compounding is defined as ‘‘any manipulation to produce a dosage for drug other than that manipulation that is provided for in the directions for use on the labeling of the approved drug product, for example, the reconstitution of a sterile powder with sterile water for injection’’ in the Compliance Policy Guide 608.400 [4] published by the FDA. Compliance policy guides (CPGs) are used by the FDA to communicate regulatory guidance to their field personnel to assist them in enforcing laws and regulations. Examples of compounded products include oxytetracycline powder in a footbath, xylazine and ketamine mixed in a single syringe, or gentamicin injected into a bottle of iron dextran. By definition, compounding results in an unapproved or adulterated drug according to the Food, Drug, and Cosmetic Act, and is therefore illegal. According to CPG 608.400, however, regulatory action may not be taken under certain circumstances, including the following: 1. A legitimate medical need is identified (the health of animals is threatened and suffering or death would result from failure to treat the affected animals). 2. There is a need for an appropriate dosage regimen for the species, age, size, or medical condition of the patient. 3. There is no marketed, approved animal drug, when used as labeled or in an ‘‘extralabel’’ manner, or human-label drug, which may treat the condition diagnosed in the available dosage form, or there is some other rare extenuating circumstance. CPG 608.400 goes into explicit detail about the labeling requirements and the assurances required regarding target animal safety and efficacy, human safety, withdrawal times, and expiration dates. The practitioner who wants to compound should review the CPG carefully for further information. CPG 608.400 states that the following actions may be considered of high regulatory priority [5]: 1. Compounding of bulk drugs for food animals except under special circumstances, such as antidotes or large-volume electrolytes (FDACVM should be contacted for advice on what drugs fall in this category, as they are subject to change) 2. The use of fanciful names, colorings, or other additives 3. Dispensing large quantities of compounded products 4. Occurrence of residues associated with compounded products 5. Compounded products not bearing required labeling
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AMDUCA also addresses compounding: compounding of approved drugs is permissible if there is no approved animal or human drug which, in the available dosage form and concentration, will treat appropriately the condition diagnosed. AMDUCA does not permit the compounding of unapproved products. Guidelines in CPG 608.400 as to labeling, withdrawal times, and so on should be followed if compounding is going to be performed according to AMDUCA regulations. Organic livestock production As the market for organically produced livestock product continues to grow, many veterinarians are being asked to provide services to organic producers. There is a national organic certification program administered through the US Department of Agriculture. Limited space prohibits a complete discussion of organic livestock production and the impact on drug selection for the practitioner. More information may be obtained from the National Organic Program of the US Department of Agriculture; see Appendix 1 for contact information. A list of currently allowed synthetic substances is presented in Box 1, however [5]. For specific restrictions on the listed substances, the veterinarian should refer to the regulations. Other substances may be added periodically as their addition is petitioned.
Regulations related to drug usage and storage Although there is considerable overlap among these laws and regulations, the following discussion covers some of the rules regarding the prescribing, usage, and storage of drugs, rather than which drugs may be used. Prescribing practices Many of the regulations related to prescribing practices are the purview of the boards of pharmacy of individual states. (See Appendix 1 for the Web site address of the National Association of Boards of Pharmacy for information on pharmacy practice acts and regulations [6].) For example, whether a veterinarian may fill the prescription from another clinic depends on state law. In some states, only licensed pharmacists may fill prescriptions. The American Veterinary Medical Association has compiled detailed information on prescribing and dispensing practices [7]; see Appendix 1 for contact information and Web sites. Pasteurized Milk Ordinance The Grade ‘‘A’’ Pasteurized Milk Ordinance (PMO) is a collaborative effort among federal, state, and municipal public health officials and is the standard used in the voluntary milk sanitation program for the certification
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of interstate milk shipments, as approved by the National Conference on Interstate Milk Shipments [8]. The importance of the PMO to the dairy veterinarian is in the regulation of drug use and drug storage. The main objectives of this section of the PMO seem to be to prevent contamination of milk by (1) keeping drugs segregated so that drugs to be used in nonlactating animals cannot be used inadvertently in lactating animals, (2) keeping accurate records of treated animals, and (3) labeling drugs so that treatment occurs appropriately. Some excerpts relevant to this discussion are as follows: Animal drugs and drug administration equipment shall be stored in such a way that milk, milking equipment, wash vats, and hand sinks are not subject to contamination. Animal drugs shall be properly labeled and segregated, lactating from nonlactating. Unapproved drugs shall not be used. Equipment used to administer drugs is not cleaned in the wash vats and is stored so as not to contaminate the milk or milk contact surfaces of equipment. Drugs intended for treatment of nonlactating dairy animals are segregated from those drugs used for lactating animals. Separate shelves in cabinets, refrigerators, or other storage facilities satisfy this Item. Drugs shall be properly labeled to include the name and address of the manufacturer or distributor for OTC [over-the-counter] drugs or veterinary practitioner dispensing the product for [prescription] and extralabel-use drugs. Drug labels shall also include: Directions for use and prescribed withholding times; Cautionary statements, if needed; and Active ingredient(s) in the drug product. Unapproved or improperly labeled drugs are not used to treat dairy animals and are not stored in the milkhouse, milking barn, stable, or parlor. Drugs are stored in such a manner that they cannot contaminate the milk or milk product–contact surfaces of the containers, utensils, or equipment. NOTE: Topical antiseptics and wound dressings, unless intended for direct injection into the teat, vaccines and other biologics, and dosage form vitamins or mineral products are exempt from labeling and storage requirements except when it is determined that they are stored in such a manner that they may contaminate the milk or milk product surfaces of containers, utensils, or equipment.
The PMO also contains an appendix section on Drug Residue Avoidance Control Measures: Animal identification and record keeping are critical for avoiding milk drug residues. Producers should establish systems to ensure that animal drugs are used properly and [should] be able to provide evidence that adequate control over the administration of drugs to prevent residues in
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Box 1. Substances permitted in organic livestock production As disinfectants, sanitizer, and medical treatments as applicable Alcohols Aspirin Chlorine materials Chlorohexidine Electrolytes Glucose Glycerin Iodine Hydrogen peroxide Magnesium sulfate Oxytocin Parasiticides Ivermectin—prohibited in slaughter stock, allowed in emergency treatment for dairy and breeder stock when organic system plan– approved preventive management does not prevent infestation. Milk or milk products from a treated animal cannot be labeled as provided for in subpart D of this part for 90 days after treatment. In breeder stock, treatment cannot occur during the last third of gestation if the progeny will be sold as organic and must not be used during the lactation period of breeding stock. Phosphoric acid As topical treatment, external parasiticide, or local anesthetic as applicable Iodine Lidocaine—as a local anesthetic; use requires a withdrawal period of 90 days after administering to livestock intended for slaughter and 7 days after administering to dairy animals. Lime, hydrated Mineral oil Procaine—as a local anesthetic; use requires a withdrawal period of 90 days after administering to livestock intended for slaughter and 7 days after administering to dairy animals. Copper sulfate As feed supplements Milk replacers—without antibiotics, as emergency use only, no nonmilk products or products from bovine somatotropin (BST)treated animals.
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Box 1. (continued ) As feed additives Trace minerals, used for enrichment or fortification when FDAapproved, including copper sulfate and magnesium sulfate Vitamins, used for enrichment or fortification when FDA-approved
From 7 CFR 205.603—Synthetic substances allowed for use in organic livestock production. Code of Federal Regulations 2002;416.
milk or meat has been implemented. These control systems should accomplish the following objectives: 1. Identification and tracking the location of treated animals. 2. Maintenance of a system of medication/treatment records that, at a minimum, records the identity of the animals(s) being treated, the date(s) of treatment, the drugs(s) or other chemicals administered, who administered the treatment, the dosage, and the prescribed withdrawal time for milk and slaughter. 3. Quarantine/segregation of treated animals or other means to preclude the sale of milk or offering of treated animals for sale for slaughter before the end of the prescribed withdrawal time. 4. Education of all farm personnel involved in treating animals on proper drug use and methods to avoid marketing adulterated milk or meat for human food.
Whether specific drugs are prohibited by the PMO is not clear; practitioners are advised to contact their state departments of agriculture or the FDA-CVM for information about compounds such as dimethyl sulfoxide or formaldehyde that may be of particular concern and that are not banned specifically in all food animals, according to AMDUCA.
Regulations related to nonhealth uses of drugs Many states have their own regulations about drug use in animals—in particular, drug use during livestock exhibitions. For example, Colorado state law prohibits ‘‘tampering’’ with livestock, including the use of drugs for the purposes of making the animal appear as something it is not (eg, breed, conformation, color, temperament, and so forth). As a general rule, most uses of drugs for these purposes also would be a violation of either the Federal Food, Drug, and Cosmetic Act or the AMDUCA, because the extralabel use of drugs is prohibited except in cases in which an animal’s health is threatened.
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Future regulations Minor Use Minor Species Act The Minor Use Minor Species Act was introduced in the US Congress in 2001, but it was not voted on in the 107th Congress. This legislation would provide a framework for approving drugs for minor species (anything other than cattle, swine, turkeys, chickens, dogs, cats, and horses) and for minor uses in the major species. A minor-use drug is one used for a condition that occurs infrequently or in a limited geographic area. This act would make it more efficient and possibly less expensive to receive approval for minor-use drugs, giving veterinarians more options in the treatment of these conditions (see Appendix 1 for more information). Antimicrobial drug availability A topic of great interest in the public health arena is the growing prevalence of antimicrobial resistance in human and animal pathogens. What role the use of antimicrobials in food animals has in the evolution of resistance in human pathogens is currently under considerable study and debate, and this issue is trickling down to the regulatory level. Bills have been introduced in Congress to eliminate or to limit the use of antimicrobials in feed. The FDA-CVM has drafted guidelines for the pharmaceutical industry that have the potential to drastically change the availability of antimicrobials for the prevention, control, and treatment of bacterial diseases in cattle and other food animals. What the ultimate outcome will be is uncertain, but this topic remains an issue for food animal veterinarians to follow closely and to weigh in on when given the opportunity.
Regulatory priorities Although the author does not work for any regulatory agency, certain issues seem to be of high regulatory priority at the present time, as evidenced by news reports and discussions within organized veterinary medicine. Some specific drugs have been under investigation recently: A new test for the nonsteroidal anti-inflammatory drug phenylbutazone was given to the US Department of Agriculture in 2002, although it is not clear whether routine testing for it will be performed [10]. On February 28, 2003, FDA issued an order to prohibit the use of phenylbutazone animal and human drugs in dairy cattle 20 months of age and older, based on evidence that such use will cause an adverse event in humans [9]. Because phenylbutazone does not have an approval for use in cattle, there is no tolerance set, meaning that the detection of any amount would be considered violative, which is of concern because of the potentially serious human health effects of the drug.
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The antimicrobial gentamicin continues to be discussed [11]; many veterinary and producer groups have policy statements recommending against the extralabel use of the aminoglycosides. Gentamicin binds to kidney cells and therefore can be found at slaughter many months after administration. Gentamicin does not have an established legal tolerance in cattle tissue, so any amount detected is violative. The use of the Internet for pharmacy services continues to increase. The American Veterinary Medical Association has issued a position statement related to Internet pharmacies that provides guidance for practitioners [12]. The entire position statement may be requested from the American Veterinary Medical Association; highlights include the following: (1) ethical duties (and in some cases, legal obligations) require that if a client prefers, a prescription should be offered rather than dispensing the drug product directly; (2) a written record should be maintained; and (3) ‘‘veterinarians asked by pharmacies to approve prescriptions they have not initiated should do so only if they have a valid veterinarian–client–patient relationship and if the prescription is appropriate.’’ The FDA has stated that Internet pharmacies and compounding pharmacies are high-priority areas for investigation [13]. As animal production units become larger and the role of the veterinarian changes to consultant, an issue of concern is the prescribing and distributing of drugs. If the veterinarian does not examine and treat every case on the farm, his or her role as the dispenser of drugs becomes less important. Some practitioners state that drug-distribution companies are supplying drugs in the absence of prescriptions or in the presence of a prescription written by a veterinarian with a questionable veterinarian–client–patient relationship. The practitioner with questions about this scenario should address them to his or her state board of pharmacy, because the laws regarding who can write and fill prescriptions are governed by these boards rather than the FDA.
Summary The author’s interpretation of some of the regulations involved in drug selection and usage by bovine veterinarians has been presented here. If necessary, the practitioner should address further questions to the appropriate regulatory agencies. The role of the veterinarian in protecting the US food supply has never been more critical, and familiarity with the applicable regulations regarding drugs used in food animals is an important component of the food animal veterinarian’s knowledge base.
References [1] Extrala bel drug use in animals. Final rule. Federal Register 1996;61(217):57731–46. [2] American Veterinary Medical Association AMDUCA flowchart. Available at: http:// www.avma.org/scienact/amduca/amduca2.asp. Accessed January 15, 2003.
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[3] Topical nitrofurans. Extralabel animal drug use: order of prohibition. Federal Register 2002;67(25):5470–1. [4] Office of Regulatory Affairs, US Food and Drug Administration. Compliance policy guide 608.400. Compounding of drugs for use in animals. Available at: http://www.fda.gov/ora/ compliance_ref/cpg/cpgvet/cpg608-400.html. Accessed January 15, 2003. [5] 7 CFR 205.603 Synthetic substances allowed for use in organic livestock production. Code of Federal Regulations. 2002;416. [6] Boards of pharmacy. National Association of Boards of Pharmacy. Available at: http:// www.nabp.net. Accessed January 15, 2003. [7] Addressing prescribing and dispensing in your practice. American Veterinary Medical Association Professional Resources. Available at: http://www.avma.org/resources/ default.asp. Accessed January 15, 2003. [8] Public Health Service, US Food and Drug Administration. Grade ‘‘A’’ pasteurized milk ordinance. Rockville (MD): Public Health Service, US Food and Drug Administration; 1999. [9] Phenylbutazone use surveyed, caution advised. J Am Vet Med Assoc 2001;219(9):1196. [10] New animal drugs; phenylbutazone; extralabel animal drug use; order of prohibition. Final rule. Federal Register 2003;68(40):9258–530. [11] FDA warns against aminoglycoside residue in cattle. J Am Vet Med Assoc 2001; 219(4):423. [12] Untangling the web of internet pharmacies. J Am Vet Med Assoc 2001;218(11):1689–90. [13] Internet pharmacies and compounding are high-priority areas, FDA says. J Am Vet Med Assoc 2002;220(6):727–8.
Appendix 1 Contacts FDA-CVM Communications Staff 7519 Standish Place, HFV-12 Rockville, Maryland 20855 Telephone: (301) 827-3800 FDA-CVM Office of Surveillance and Compliance Director, Dr. Clifford I. Johnson Telephone: (301) 827-4354 Food Animal Residue Avoidance Databank Telephone: (888) US-FARAD National Organic Program Program Manager, Richard Mathews US Department of Agriculture-AMS-TMP-NOP Room 4008–South Building 1400 Independence Avenue, SW Washington, DC 20250-0020 Telephone: (202) 720-3252 Fax: (202) 205-7808 E-mail address: [email protected] Web sites FDA-CVM Web site http://www.fda.gov/cvm/default.html
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FDA-CVM Compliance Policy Guide on Compounding http://www.fda.gov/ora/compliance_ref/cpg/cpgvet/cpg608-400.html American Veterinary Medical Association Professional Resources http://www.avma.org/resources/default.asp (Select ‘‘Addressing prescribing and dispensing in your practice.’’) American Veterinary Medical Association AMDUCA flowchart http://www.avma.org/scienact/amduca/amduca2.asp (This document is in the member center and may be accessed only by American Veterinary Medical Association members.) National Organic Program http://www.ams.usda.gov/nop/ Minor Species/Minor Use Program http://www.nrsp-7.org/introduction.htm Pasteurized Milk Ordinance http://vm.cfsan.fda.gov/ear/p-nci.html National Association of Boards of Pharmacy http://www.nabp.net (Select ‘‘Who We Are,’’ then ‘‘Boards of Pharmacy’’ for contact information for an individual state’s pharmacy board.)
Regulatory considerations in the United States Virginia R. Fajt, DVM, PhD* Veterinary Antimicrobial Decision Support System, Iowa State University, College of Veterinary Medicine, PO Box 3020, Ames, IA 50011-3020, USA
As the focus on the safety of our food supply continues to tighten, food safety professionals such as cattle veterinarians will be on the front lines of providing assurance of safe and wholesome animal products. Maintaining the safety of animal food products is one of the purposes of the laws and regulations associated with drug use in food animals. This article enumerates some of the important regulations that govern selection and use of pharmaceutical products in cattle. The reader is advised, however, that the author’s interpretation of the regulations is not final, and if there are any questions, the appropriate regulatory body should be contacted (see Appendix 1 for contact information).
Regulations related to drug selection The selection of drugs for use in the treatment of cattle diseases and conditions requires more vigilance than for other nonfood animal species, because the end products are human consumables. It is not simply a matter of selecting a product approved for the given condition, because many conditions are treated for which no labeled product exists (requiring ‘‘extralabel’’ use). Constraints on the final product, such as targeting specific markets (eg, organic), may restrict further the use of certain drugs. This section discusses extralabel use, compounding, and organic livestock production. Animal Medicinal Drug Use Clarification Act Using drugs in an extralabel manner—for example, at a different dose or for a different species—was legalized in veterinary medicine in 1994 with the * 6 Sedum Court, Pueblo, CO 81001. E-mail address: [email protected] 0749-0720/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0749-0720(03)00050-1
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passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA) [1]. Previously, extralabel use had been permitted under the Food and Drug Administration Center for Veterinary Medicine (FDA-CVM) discretionary policy but was technically illegal. The legaliza tion of extralabel drug use, however, should not be interpreted as allowing any usage of any legally available drug. The onus is still on the veterinarian to justify the extralabel use, and restrictions do exist. AMDUCA applies only to FDA-approved animal and human drugs, permits extralabel use only by or under the order of a licensed veterinarian within the context of a valid veterinarian–client– patient relationship, and must not result in violative drug residues. Although allowing extralabel use only in the event that the health of the animal is threatened or death or suffering may result if treatment does not occur, AMDUCA does not permit extralabel use of drugs in feed or extralabel use of production drugs, such as growth promotant or reproductive drugs. A useful algorithm for determining whether an extralabel use is legal has been provided by the American Veterinary Medical Association (see web site information in Appendix 1) [2]. There is a hierarchy of drug selection that allows the use of extralabel drugs if labeled products are either not approved or are clinically ineffective. In essence, the hierarchy for food animals is (1) a product approved for the condition being treated that is effective as labeled, (2) a product approved for a food animal that may be used in an extralabel manner, and (3) a product approved in nonfood animals or humans that may be used in an extralabel manner. If no products exist that satisfy these requirements, a compounded product may be permitted, and the compliance policy guide on compounding should be consulted (see following discussion). AMDUCA specifically prohibits the extralabel use of certain compounds. These compounds are fluoroquinolones, glycopeptides, furazolidone, nitrofurazone, chloramphenicol, dimetridazole, ipronidazole, other nitroimidazoles (such as metronidazole), sulfonamide drugs in lactating dairy animals (except for approved uses of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine), clenbuterol, and diethylstilbestrol. Until recently, the topical use of furazolidone and nitrofurazone was permitted, but this use has been made illegal [3]. If extralabel use is determined to be necessary and legal, there are labeling and record-keeping requirements that must be fulfilled. The regulations should be consulted for full details on what must be included in the label, but the major components are the prescribing veterinarian’s contact information, a complete description of animals being treated, complete directions for use, and meat- or milk-withholding times. It is also the responsibility of the veterinarian to ensure that treated animals can be identified, to allow adherence to proper withholding times. Suggestions for withholding times for extralabel drugs can be obtained from the Food Animal Residue Avoidance Databank using the contact information in
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Appendix 1. If withholding times cannot be established—for example, if there is insufficient information on which to base them—the drug in question should not be used or the animal must not be permitted to enter the food supply. Compounding Compounding is defined as ‘‘any manipulation to produce a dosage for drug other than that manipulation that is provided for in the directions for use on the labeling of the approved drug product, for example, the reconstitution of a sterile powder with sterile water for injection’’ in the Compliance Policy Guide 608.400 [4] published by the FDA. Compliance policy guides (CPGs) are used by the FDA to communicate regulatory guidance to their field personnel to assist them in enforcing laws and regulations. Examples of compounded products include oxytetracycline powder in a footbath, xylazine and ketamine mixed in a single syringe, or gentamicin injected into a bottle of iron dextran. By definition, compounding results in an unapproved or adulterated drug according to the Food, Drug, and Cosmetic Act, and is therefore illegal. According to CPG 608.400, however, regulatory action may not be taken under certain circumstances, including the following: 1. A legitimate medical need is identified (the health of animals is threatened and suffering or death would result from failure to treat the affected animals). 2. There is a need for an appropriate dosage regimen for the species, age, size, or medical condition of the patient. 3. There is no marketed, approved animal drug, when used as labeled or in an ‘‘extralabel’’ manner, or human-label drug, which may treat the condition diagnosed in the available dosage form, or there is some other rare extenuating circumstance. CPG 608.400 goes into explicit detail about the labeling requirements and the assurances required regarding target animal safety and efficacy, human safety, withdrawal times, and expiration dates. The practitioner who wants to compound should review the CPG carefully for further information. CPG 608.400 states that the following actions may be considered of high regulatory priority [5]: 1. Compounding of bulk drugs for food animals except under special circumstances, such as antidotes or large-volume electrolytes (FDACVM should be contacted for advice on what drugs fall in this category, as they are subject to change) 2. The use of fanciful names, colorings, or other additives 3. Dispensing large quantities of compounded products 4. Occurrence of residues associated with compounded products 5. Compounded products not bearing required labeling
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AMDUCA also addresses compounding: compounding of approved drugs is permissible if there is no approved animal or human drug which, in the available dosage form and concentration, will treat appropriately the condition diagnosed. AMDUCA does not permit the compounding of unapproved products. Guidelines in CPG 608.400 as to labeling, withdrawal times, and so on should be followed if compounding is going to be performed according to AMDUCA regulations. Organic livestock production As the market for organically produced livestock product continues to grow, many veterinarians are being asked to provide services to organic producers. There is a national organic certification program administered through the US Department of Agriculture. Limited space prohibits a complete discussion of organic livestock production and the impact on drug selection for the practitioner. More information may be obtained from the National Organic Program of the US Department of Agriculture; see Appendix 1 for contact information. A list of currently allowed synthetic substances is presented in Box 1, however [5]. For specific restrictions on the listed substances, the veterinarian should refer to the regulations. Other substances may be added periodically as their addition is petitioned.
Regulations related to drug usage and storage Although there is considerable overlap among these laws and regulations, the following discussion covers some of the rules regarding the prescribing, usage, and storage of drugs, rather than which drugs may be used. Prescribing practices Many of the regulations related to prescribing practices are the purview of the boards of pharmacy of individual states. (See Appendix 1 for the Web site address of the National Association of Boards of Pharmacy for information on pharmacy practice acts and regulations [6].) For example, whether a veterinarian may fill the prescription from another clinic depends on state law. In some states, only licensed pharmacists may fill prescriptions. The American Veterinary Medical Association has compiled detailed information on prescribing and dispensing practices [7]; see Appendix 1 for contact information and Web sites. Pasteurized Milk Ordinance The Grade ‘‘A’’ Pasteurized Milk Ordinance (PMO) is a collaborative effort among federal, state, and municipal public health officials and is the standard used in the voluntary milk sanitation program for the certification
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of interstate milk shipments, as approved by the National Conference on Interstate Milk Shipments [8]. The importance of the PMO to the dairy veterinarian is in the regulation of drug use and drug storage. The main objectives of this section of the PMO seem to be to prevent contamination of milk by (1) keeping drugs segregated so that drugs to be used in nonlactating animals cannot be used inadvertently in lactating animals, (2) keeping accurate records of treated animals, and (3) labeling drugs so that treatment occurs appropriately. Some excerpts relevant to this discussion are as follows: Animal drugs and drug administration equipment shall be stored in such a way that milk, milking equipment, wash vats, and hand sinks are not subject to contamination. Animal drugs shall be properly labeled and segregated, lactating from nonlactating. Unapproved drugs shall not be used. Equipment used to administer drugs is not cleaned in the wash vats and is stored so as not to contaminate the milk or milk contact surfaces of equipment. Drugs intended for treatment of nonlactating dairy animals are segregated from those drugs used for lactating animals. Separate shelves in cabinets, refrigerators, or other storage facilities satisfy this Item. Drugs shall be properly labeled to include the name and address of the manufacturer or distributor for OTC [over-the-counter] drugs or veterinary practitioner dispensing the product for [prescription] and extralabel-use drugs. Drug labels shall also include: Directions for use and prescribed withholding times; Cautionary statements, if needed; and Active ingredient(s) in the drug product. Unapproved or improperly labeled drugs are not used to treat dairy animals and are not stored in the milkhouse, milking barn, stable, or parlor. Drugs are stored in such a manner that they cannot contaminate the milk or milk product–contact surfaces of the containers, utensils, or equipment. NOTE: Topical antiseptics and wound dressings, unless intended for direct injection into the teat, vaccines and other biologics, and dosage form vitamins or mineral products are exempt from labeling and storage requirements except when it is determined that they are stored in such a manner that they may contaminate the milk or milk product surfaces of containers, utensils, or equipment.
The PMO also contains an appendix section on Drug Residue Avoidance Control Measures: Animal identification and record keeping are critical for avoiding milk drug residues. Producers should establish systems to ensure that animal drugs are used properly and [should] be able to provide evidence that adequate control over the administration of drugs to prevent residues in
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Box 1. Substances permitted in organic livestock production As disinfectants, sanitizer, and medical treatments as applicable Alcohols Aspirin Chlorine materials Chlorohexidine Electrolytes Glucose Glycerin Iodine Hydrogen peroxide Magnesium sulfate Oxytocin Parasiticides Ivermectin—prohibited in slaughter stock, allowed in emergency treatment for dairy and breeder stock when organic system plan– approved preventive management does not prevent infestation. Milk or milk products from a treated animal cannot be labeled as provided for in subpart D of this part for 90 days after treatment. In breeder stock, treatment cannot occur during the last third of gestation if the progeny will be sold as organic and must not be used during the lactation period of breeding stock. Phosphoric acid As topical treatment, external parasiticide, or local anesthetic as applicable Iodine Lidocaine—as a local anesthetic; use requires a withdrawal period of 90 days after administering to livestock intended for slaughter and 7 days after administering to dairy animals. Lime, hydrated Mineral oil Procaine—as a local anesthetic; use requires a withdrawal period of 90 days after administering to livestock intended for slaughter and 7 days after administering to dairy animals. Copper sulfate As feed supplements Milk replacers—without antibiotics, as emergency use only, no nonmilk products or products from bovine somatotropin (BST)treated animals.
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Box 1. (continued ) As feed additives Trace minerals, used for enrichment or fortification when FDAapproved, including copper sulfate and magnesium sulfate Vitamins, used for enrichment or fortification when FDA-approved
From 7 CFR 205.603—Synthetic substances allowed for use in organic livestock production. Code of Federal Regulations 2002;416.
milk or meat has been implemented. These control systems should accomplish the following objectives: 1. Identification and tracking the location of treated animals. 2. Maintenance of a system of medication/treatment records that, at a minimum, records the identity of the animals(s) being treated, the date(s) of treatment, the drugs(s) or other chemicals administered, who administered the treatment, the dosage, and the prescribed withdrawal time for milk and slaughter. 3. Quarantine/segregation of treated animals or other means to preclude the sale of milk or offering of treated animals for sale for slaughter before the end of the prescribed withdrawal time. 4. Education of all farm personnel involved in treating animals on proper drug use and methods to avoid marketing adulterated milk or meat for human food.
Whether specific drugs are prohibited by the PMO is not clear; practitioners are advised to contact their state departments of agriculture or the FDA-CVM for information about compounds such as dimethyl sulfoxide or formaldehyde that may be of particular concern and that are not banned specifically in all food animals, according to AMDUCA.
Regulations related to nonhealth uses of drugs Many states have their own regulations about drug use in animals—in particular, drug use during livestock exhibitions. For example, Colorado state law prohibits ‘‘tampering’’ with livestock, including the use of drugs for the purposes of making the animal appear as something it is not (eg, breed, conformation, color, temperament, and so forth). As a general rule, most uses of drugs for these purposes also would be a violation of either the Federal Food, Drug, and Cosmetic Act or the AMDUCA, because the extralabel use of drugs is prohibited except in cases in which an animal’s health is threatened.
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Future regulations Minor Use Minor Species Act The Minor Use Minor Species Act was introduced in the US Congress in 2001, but it was not voted on in the 107th Congress. This legislation would provide a framework for approving drugs for minor species (anything other than cattle, swine, turkeys, chickens, dogs, cats, and horses) and for minor uses in the major species. A minor-use drug is one used for a condition that occurs infrequently or in a limited geographic area. This act would make it more efficient and possibly less expensive to receive approval for minor-use drugs, giving veterinarians more options in the treatment of these conditions (see Appendix 1 for more information). Antimicrobial drug availability A topic of great interest in the public health arena is the growing prevalence of antimicrobial resistance in human and animal pathogens. What role the use of antimicrobials in food animals has in the evolution of resistance in human pathogens is currently under considerable study and debate, and this issue is trickling down to the regulatory level. Bills have been introduced in Congress to eliminate or to limit the use of antimicrobials in feed. The FDA-CVM has drafted guidelines for the pharmaceutical industry that have the potential to drastically change the availability of antimicrobials for the prevention, control, and treatment of bacterial diseases in cattle and other food animals. What the ultimate outcome will be is uncertain, but this topic remains an issue for food animal veterinarians to follow closely and to weigh in on when given the opportunity.
Regulatory priorities Although the author does not work for any regulatory agency, certain issues seem to be of high regulatory priority at the present time, as evidenced by news reports and discussions within organized veterinary medicine. Some specific drugs have been under investigation recently: A new test for the nonsteroidal anti-inflammatory drug phenylbutazone was given to the US Department of Agriculture in 2002, although it is not clear whether routine testing for it will be performed [10]. On February 28, 2003, FDA issued an order to prohibit the use of phenylbutazone animal and human drugs in dairy cattle 20 months of age and older, based on evidence that such use will cause an adverse event in humans [9]. Because phenylbutazone does not have an approval for use in cattle, there is no tolerance set, meaning that the detection of any amount would be considered violative, which is of concern because of the potentially serious human health effects of the drug.
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The antimicrobial gentamicin continues to be discussed [11]; many veterinary and producer groups have policy statements recommending against the extralabel use of the aminoglycosides. Gentamicin binds to kidney cells and therefore can be found at slaughter many months after administration. Gentamicin does not have an established legal tolerance in cattle tissue, so any amount detected is violative. The use of the Internet for pharmacy services continues to increase. The American Veterinary Medical Association has issued a position statement related to Internet pharmacies that provides guidance for practitioners [12]. The entire position statement may be requested from the American Veterinary Medical Association; highlights include the following: (1) ethical duties (and in some cases, legal obligations) require that if a client prefers, a prescription should be offered rather than dispensing the drug product directly; (2) a written record should be maintained; and (3) ‘‘veterinarians asked by pharmacies to approve prescriptions they have not initiated should do so only if they have a valid veterinarian–client–patient relationship and if the prescription is appropriate.’’ The FDA has stated that Internet pharmacies and compounding pharmacies are high-priority areas for investigation [13]. As animal production units become larger and the role of the veterinarian changes to consultant, an issue of concern is the prescribing and distributing of drugs. If the veterinarian does not examine and treat every case on the farm, his or her role as the dispenser of drugs becomes less important. Some practitioners state that drug-distribution companies are supplying drugs in the absence of prescriptions or in the presence of a prescription written by a veterinarian with a questionable veterinarian–client–patient relationship. The practitioner with questions about this scenario should address them to his or her state board of pharmacy, because the laws regarding who can write and fill prescriptions are governed by these boards rather than the FDA.
Summary The author’s interpretation of some of the regulations involved in drug selection and usage by bovine veterinarians has been presented here. If necessary, the practitioner should address further questions to the appropriate regulatory agencies. The role of the veterinarian in protecting the US food supply has never been more critical, and familiarity with the applicable regulations regarding drugs used in food animals is an important component of the food animal veterinarian’s knowledge base.
References [1] Extrala bel drug use in animals. Final rule. Federal Register 1996;61(217):57731–46. [2] American Veterinary Medical Association AMDUCA flowchart. Available at: http:// www.avma.org/scienact/amduca/amduca2.asp. Accessed January 15, 2003.
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[3] Topical nitrofurans. Extralabel animal drug use: order of prohibition. Federal Register 2002;67(25):5470–1. [4] Office of Regulatory Affairs, US Food and Drug Administration. Compliance policy guide 608.400. Compounding of drugs for use in animals. Available at: http://www.fda.gov/ora/ compliance_ref/cpg/cpgvet/cpg608-400.html. Accessed January 15, 2003. [5] 7 CFR 205.603 Synthetic substances allowed for use in organic livestock production. Code of Federal Regulations. 2002;416. [6] Boards of pharmacy. National Association of Boards of Pharmacy. Available at: http:// www.nabp.net. Accessed January 15, 2003. [7] Addressing prescribing and dispensing in your practice. American Veterinary Medical Association Professional Resources. Available at: http://www.avma.org/resources/ default.asp. Accessed January 15, 2003. [8] Public Health Service, US Food and Drug Administration. Grade ‘‘A’’ pasteurized milk ordinance. Rockville (MD): Public Health Service, US Food and Drug Administration; 1999. [9] Phenylbutazone use surveyed, caution advised. J Am Vet Med Assoc 2001;219(9):1196. [10] New animal drugs; phenylbutazone; extralabel animal drug use; order of prohibition. Final rule. Federal Register 2003;68(40):9258–530. [11] FDA warns against aminoglycoside residue in cattle. J Am Vet Med Assoc 2001; 219(4):423. [12] Untangling the web of internet pharmacies. J Am Vet Med Assoc 2001;218(11):1689–90. [13] Internet pharmacies and compounding are high-priority areas, FDA says. J Am Vet Med Assoc 2002;220(6):727–8.
Appendix 1 Contacts FDA-CVM Communications Staff 7519 Standish Place, HFV-12 Rockville, Maryland 20855 Telephone: (301) 827-3800 FDA-CVM Office of Surveillance and Compliance Director, Dr. Clifford I. Johnson Telephone: (301) 827-4354 Food Animal Residue Avoidance Databank Telephone: (888) US-FARAD National Organic Program Program Manager, Richard Mathews US Department of Agriculture-AMS-TMP-NOP Room 4008–South Building 1400 Independence Avenue, SW Washington, DC 20250-0020 Telephone: (202) 720-3252 Fax: (202) 205-7808 E-mail address: [email protected] Web sites FDA-CVM Web site http://www.fda.gov/cvm/default.html
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FDA-CVM Compliance Policy Guide on Compounding http://www.fda.gov/ora/compliance_ref/cpg/cpgvet/cpg608-400.html American Veterinary Medical Association Professional Resources http://www.avma.org/resources/default.asp (Select ‘‘Addressing prescribing and dispensing in your practice.’’) American Veterinary Medical Association AMDUCA flowchart http://www.avma.org/scienact/amduca/amduca2.asp (This document is in the member center and may be accessed only by American Veterinary Medical Association members.) National Organic Program http://www.ams.usda.gov/nop/ Minor Species/Minor Use Program http://www.nrsp-7.org/introduction.htm Pasteurized Milk Ordinance http://vm.cfsan.fda.gov/ear/p-nci.html National Association of Boards of Pharmacy http://www.nabp.net (Select ‘‘Who We Are,’’ then ‘‘Boards of Pharmacy’’ for contact information for an individual state’s pharmacy board.)