Veterinarians often focus on an area of veterinary medicine and become competent in the pharmacology of drugs associated with that area. As either a veterinarian or a clinical pharmacologist working with food animals, there are additional considerations beyond the animal–drug interaction.

When using drugs in food animals, there must be a consideration of the effect of the drug on the entire population of animals within the production environment, and also within the ultimate supply chain for human consumption. Addressing the safety of meat, milk, and eggs produced by modern agriculture not only involves the evaluation of safety of drug residues, but also other effects such as environmental safety, and selection for resistant bacterial pathogens. The safety of drugs in food animals is no longer only closely observed by regulatory and legislative bodies, but now also by food distribution/retail chains as well as their customers, the consumer. At the time of this writing, due to evolving food retailer policies, we are coming into a period where the effects of social media trends and marketing studies may supersede regulatory and legislative pressures as a major driver in determining what drugs are used in food animals.

The use of drugs in animals intended for use as food primarily involves a subset of veterinary drugs focused on prevention, control, and treatment of infection (both bacterial and parasitic), inflammation, analgesia, anesthesia, reproduction, and performance enhancement. Specific characteristics of these drugs are described elsewhere in this book. This chapter summarizes drugs that should be familiar to a veterinarian involved with food animals, and also describes special considerations related to these drugs when used in food animals.

The lists of drugs and drug groups presented in this chapter are US centric. There are other drugs used around the world in food animals, and perhaps other drug groups. These lists are presented as a means of general appreciation of the breadth of drugs widely employed in food animal production along with considerations for use unique to food animal production; representations of approval or lack of approval, availability, or legality in specific countries are neither intended nor implied.

The legality of the use of a drug in food animals in an extralabel manner is dependent on the country in which the drug is used. An example of a cross-border difference is the extralabel use (ELDU) of drugs in the feed of food animals in the USA and Canada. Drugs may be used in feed in an extralabel manner in Canada, but this use is prohibited for food animals in the USA (Health Canada, 2015) An exception in the USA is the allowance for ELDU under regulatory discretion of drugs in the feed for minor food animal species, such as sheep and goats (FDA, 2016). This Compliance Policy Guide (CPG) states that enforcement discretion will be exercised provided that certain requirements are met for ELDU in the feed of minor species.

The regulations for ELDU in food animals in the USA were promulgated and finalized in 1996 to codify the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 (FDA, 1996). Under the regulations, ELDU is “limited to treatment modalities when the health of an animal is threatened or suffering or death may result from failure to treat.” This precludes ELDU for production purposes; examples are unapproved estrous synchronization protocols, lactation induction protocols, and extralabel use of growth-promoting hormonal implants. Specific ELDU considerations related to some drug classes are discussed below. It is also important that the veterinarian know the list of drugs for which ELDU in food animals is specifically prohibited. As of this writing, the most current list contains the following drugs (FDA, 2015a).

Under the AMDUCA provisions, FDA has the right to prohibit extralabel uses of certain drugs in animals. The following drugs (both human and animal), families of drugs, and substances are prohibited from extralabel uses in all food-producing animals, including horses intended for human food:

• Chloramphenicol
  
• Clenbuterol
  
• Diethylstilbestrol (DES)
  
• Dimetridazole
  
• Ipronidazole and other nitroimidazoles
  
• Furazolidone and nitrofurazone
  
• Sulfonamide drugs in lactating dairy cattle, except for the approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine
  
• Fluoroquinolones
  
• Glycopeptides
  
• Phenylbutazone in female dairy cattle 20 months of age or older
  
• Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys:
  
  
  
  • For disease prevention purposes;
    
  • At unapproved doses, frequencies, durations, or routes of administration; or
    
  • If the drug is not approved for that species and production class.

The following drugs, or classes of drugs, that are approved for treating or preventing influenza A are prohibited from extralabel uses in chickens, turkeys, and ducks:

• Adamantane
  
• Neuraminidase inhibitors

The above list can be found at Title 21 of the CFR, Part 530.41. Currently, no approved drugs are prohibited from extralabel uses in companion animals.

The list of prohibited drugs in the country in which a veterinarian is practicing, or to which food products are being exported, should be well understood. In the United States, it is important to understand that a lactating dairy cow and a dairy cow 20 months of age or older are the same animal for regulatory purposes; the fact that a dairy cow greater than 20 months of age is in the dry period does not change her status as a lactating dairy cow.

An area of ELDU that receives special attention in regulations is the preparation of compounded drug products. In the USA, the use of compounded drugs in food animals had been the subject of compliance policy guide (CPG) Section 608.400 in addition to inclusion in the AMDUCA regulations (FDA, 1996). While the AMDUCA regulations remain unchanged, CPG 608.400 was withdrawn May 19, 2015, and a new draft Guidance for Industry (GFI #230) was released related to compounding from bulk substances. Guidance for Industry #230 addresses compounding from bulk substances in food animals only in that this is not allowed (FDA, 2015b). At the time of this writing the FDA/CVM has asked for input on a list of drugs for which compounding from bulk substances may be allowed in companion animals, with the subject of compounding drugs such as antidotes for food animals from bulk substances remaining unaddressed.

Bulk substances are drug forms which are not the subject of a final New Animal Drug Application (NADA) or New Drug Application (NDA) approval. Compounding in the USA is a very contentious issue as some compounding pharmacies and veterinarians are able to make substantial margins on selling unapproved drug compounds. There are potential downfalls of compounded products, whether from bulk substances or approved drugs, of which the prescribing (or selling) veterinarian should be aware. These include sterility and presence of endotoxin for injectable products, purity, potency, toxicity, violative residues, instability of the final compounded product, and potential lack of efficacy due to insufficient bioavailability. Another issue with compounded products specific to food animals is uncertainty as to the withdrawal time to assure that no violative residues enter the food chain. A compounded product should in no way be confused with a generic product; the latter has an approved FDA label and is subject to good manufacturing processes, which are inspected by the FDA.

The issue of compounding of drugs for use in food animals is a good example of regulatory flux, and that veterinarians must be ever vigilant for regulatory changes.

The foremost additional responsibility of using drugs in food animals is to protect the safety of the food products from the treated animal(s) by assuring that violative residues do not enter the food chain. An overview of the regulatory process related to residues in animal food products may be found in Food and Drug Administration Center for Veterinary Medicine (FDA/CVM) Guidance for Industry (GFI) #3 (FDA, 2006) and in Chapters 55 and 61 of the present text. The classic approach for determining a slaughter withdrawal time in the USA has been to first determine the toxicity of the compound in laboratory animals by establishing a No Observable Effect Level (NOEL). The NOEL is combined with the regulatory average human weight and a safety factor to establish a total Acceptable Daily Intake (ADI) for the drug residues over a human lifetime. A safe concentration in edible tissues is then calculated by estimating daily intake of muscle tissue, liver, kidney, and fat and using the ADI to establish the residue concentration that may be present in each tissue based on intake. In addition, the presence of residues in milk and eggs are considered for appropriate production classes; if the drug is to be used in an animal producing milk or eggs, the ADI must be partitioned between a serving of muscle tissue, liver, kidney, or fat and consumption of milk or eggs, which may also contain the same residue. In the USA, a tolerance addressing a single marker residue is then developed for the target residue organ (and possibly for other tissues, including milk and eggs if appropriate). In other countries a Maximum Residue Level (MRL) is established, which may be for one residue or a group of residues from the drug. Finally, a withdrawal time for label use of the product is established based on evaluating the MRL/tolerance in light of a study determining depletion of the drug from edible tissues in the target species, and applying statistical methods to these data.

Along with the process of establishing a slaughter withdrawal time, the sponsor must develop and validate an assay for detection of marker drug residue(s) in the target residue organ Other countries may have differing requirements for the process of establishing a withdrawal time for food animal drugs.

In the USA, as in some other countries, the extralabel use of drugs in food animals is allowed when used in accordance with the Animal Medicinal Drug Use Clarification Act (AMDUCA) regulations (FDA, 1996). In these cases, the veterinarian is responsible for assuring that no violative residues enter the food chain and is required to assign an exaggerated slaughter withdrawal time. In cases where the drug is approved for use in that species, during the approval process it was required to establish a tolerance, regulatory method to detect residues, and withdrawal time for that approval. Therefore, the veterinarian is often able to minimally extend the withdrawal time if the label regimen is used. If there is no approval in that species, or an altered regimen from that on the label is used, then the veterinarian must find information to support the assignment of an exaggerated slaughter withdrawal time, or else the animal must not enter the food chain. For the USA, and some other countries, the veterinarian has access to the Food Animal Residue Avoidance Databank (FARAD, or gFARAD for the global version) to aid in this process (FARAD, 2015). If information is not able to be found to assure that no violative residues will occur, the treated animal must not enter the food chain.

The lack of a tolerance for a drug used in food animals requires full attention to potential residues. The presence or absence of a tolerance may be evaluated in the USA by accessing 21 CFR part 556 (FDA, 2015c). Other countries or unions may have their own lists, or adopt standards such as Codex Alimentarius (CODEX, 2013). If there is no tolerance for the species in which the drug is being used, then the concentration that can be detected by the most sensitive assay essentially becomes the tolerance, which historically has continued to decline as analytical technology advances. Estimating slaughter withdrawal times by extrapolating beyond available data down to “zero” may be hampered by the fact that drug elimination from edible tissue may be very different at concentrations lower than concentrations observed in available data. This topic is further discussed in Chapter 61.

Another common challenge in avoiding violative residues is the difference in tolerances and/or MRLs between exporting and importing countries. If a food animal product originates in the USA, use of drugs in production settings must take into account whether the food product(s) might be exported to Russia, the European Union, Japan, China, or South Korea, as examples. In some cases the difference may be as extreme as the US tolerance for total residues of tetracyclines (e.g., chlortetracycline, oxytetracycline, and tetracycline) of 2000 ppb compared to no tolerance or an MRL of 10 ppb in an importing country.

There are some specific cases in the USA where a lapse of residue awareness can cause significant regulatory issues for a veterinarian and their client(s). The first example is that gentamicin has an approval in cattle for topical use in the eye for infectious bovine keratoconjunctivitis. However, during the approval process, no systemic concentrations were detected after the label regimen and therefore no tolerance was required in edible tissues. It has been demonstrated that gentamicin has prolonged depletion characteristics in the bovine kidney after extralabel systemic administration, which when combined with the absence of an acceptable concentration at slaughter, sets up a drastically prolonged required ELDU withdrawal time of approximately 18 months in cattle.

Another example is the use of penicillin G in swine. Penicillin G is approved for swine; however, the tolerance for swine currently listed in 21CFR Part 556 is zero. The sensitivity of the Kidney Inhibition Swab (KIS) test (35 ppb) and the follow-up Food Safety and Inspection Service (FSIS) mass spectrometery test (25 ppb) have resulted in an issue with violative residues in sows if a sufficient exaggerated withdrawal time has not been used. A tolerance of 50 ppb (negligible residue) in the uncooked edible tissues of cattle has been established.

Alteration of the injection site while observing the rest of the label regimen may be sufficient to drastically alter the slaughter withdrawal requirements. Ceftiofur crystalline free acid is labeled for administration to cattle in either the middle third of the ear or at the base of the ear. Some veterinarians have advised producers to inject this product subcutaneously in the neck for convenience. However, the altered regimen results in a significantly prolonged residue profile, contributing to increased risk for violative residues in addition to unproven efficacy by this route. This is an example of the attending veterinarian not thinking through all the ramifications of ELDU.

The issue of extralabel use of florfenicol in lactating dairy cattle illustrates that the use class of the treated food animal on the product label may be as important as the species. Examination of the tolerances in 21 CFR part 556 reveals a tolerance of 3700 ppb for florfenicol in the liver of cattle. However, lactating dairy cattle are not included on the label as a use class, resulting in an interpretation of no tolerance for florfenicol in edible tissues of a lactating dairy cow. This results in an extremely prolonged slaughter withdrawal time requirement for extralabel use in a lactating dairy cow as opposed to a beef animal. A lactating dairy cow for regulatory purposes is a dairy cow 20 months of age or older, regardless of lactation status. In addition, there is no tolerance for florfenicol in milk, resulting in a prolonged milk discard time. Florfenicol use in lactating dairy cows was highlighted in the 2012 FDA milk residue study; although only 15 violative residues were found out of 1912 samples (0.78%), 10 of these violative residues were florfenicol (FDA, 2015d). Other antibiotics for which this is an issue in lactating dairy cows include tilmicosin, gamithromycin, and tildipirosin.

Here the term “antibiotics” is used according to the societal use, to include antimicrobials. The relationship of the terms antibiotic and antimicrobial is sufficiently complicated to have merited entire book chapters (Bennett, 2015). While this may at first seem a case of trivial semantics, the subject is actually quite important for products marketed with claims such as “antibiotic free”. For example, would sulfonamides and fluoroquinolones be allowed in an animal-derived product which is promoted as antibiotic free? Yes, according to the most pedantic interpretation of the terms because they are by definition antimicrobials and not antibiotics, but in practical usage, no.