Navigating through drug regulations

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Veterinarians are finding themselves in the choppy waters of changing drug regulations that in one instance seems like a slippery fish to grasp, and in another a shark ready to take a bite out your ability to make scientifically-based decisions in practice.

Navigating through the intricacies of some of the drug regulations and understanding their importance can be a challenge for veterinarians.

What are some of the issues? The Food and Drug Administration (FDA) has tightened regulations on some drugs used in food-producing animals, the Food Safety Inspection Service of the USDA has instituted new broader-based residue testing schemes; the American Veterinary Medical Association (AVMA) has approved modifications to the Model Veterinary Practice Act involving the veterinarian-client-patient-relationship (VCPR); and many veterinarians still struggle to come to terms with provisions under the Animal Medicinal Drug Use Clarification Act (AMDUCA).

The ultimate goal of regulations for drugs used in food animals is to produce a safe, wholesome food supply, but getting through the intricacies of some of the regulations and understanding why they are important (even debatable), can be mind-numbing. One logical place to start is with the VCPR, which should be the underpinning of a relationship between a food-animal veterinarian and his/her client.

The VCPR

The FDA defines a valid veterinarian-client-patient relationship (21 CFR 530.3(i)), as one in which:

a. A veterinarian has assumed the responsibility for making medical judgments regarding the health of (an) animal(s) and the need for medical treatment, and the client (the owner of the animal or animals or other caretaker) has agreed to follow the instruct tions of the veterinarian;

b. There is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s); and

c. The practicing veterinarian is readily available for follow-up in case of adverse reactions or failure of the regimen of therapy.

Such a relationship can exist only when the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of examination of the animal(s), and/or by medically appropriate and timely visits to the premises where the animal(s) are kept.

Recent changes in wording of the definition of a VCPR by the AVMA has created some issues with food-animal veterinarians. As of its August 2012 annual meeting, the AVMA House of Delegates approved recommendations by a task force examining the VCPR definition for the AVMA Model Veterinary Practice Act. This definition is now slightly different from that embodied in federal regulation relating to extralabel drug use.

The recommendation says, “With the new definition of ‘patient’ as ‘an animal or group of animals,’ the requirement of VCPR in the model act now clearly applies to individual animals as well as a group or groups of animals within an operation or production system.”

Also, a new subsection states that patient records must be maintained to establish a VCPR. States can then specify that “sufficient knowledge” of patients in VCPR for large operations can be supplemented by: 1) examination of health, laboratory, or production records; 2) consultation with owners, caretakers or supervisory staff regarding a health management program for the patient; or 3) information regarding the local epidemiology of diseases for the appropriate species. (Read more at www.avma.org/KB/VMA/Pages/AVMA-makes-changes-to-the-VCPRmodel-language.aspx)

The American Association of Bovine Practitioners (AABP) has expressed concern that applying the VCPR in a uniform manner across an ever-diverse profession would be a challenging task (see editorial column, Bovine Veterinarian, September 2012). An AABP online member survey demonstrated that veterinarians overwhelmingly supported a VCPR that includes on-site visits.

Virginia Fajt, DVM, PhD Veterinarians are not usually the ones getting in trouble with violations – it’s producers who are not working with them. “If you take a look at the FDA warning letters, one of the highlights is usually that there is not a VCPR in place,” says Virginia Fajt, DVM, PhD, Texas A&M University. For fiscal year 2011, the FDA Center for Veterinary Medicine’s Tissue Residue Information Management System (TRIMS) indicated that 59% of residue violations that were investigated (not all violations for 2011) occurred on operations for which there was no VCPR.

Working within a VCPR

If you have a VCPR with a client and his/her operation and have made the decision to use a drug in an extralabel manner, what steps do you as the veterinarian need to take to make sure you are complying with AMDUCA and working within the VCPR’s parameters? You should check into your own state’s practice act and VCPR definition (AVMA has a listing of state VCPR definitions at www.avma.org/Advocacy/StateAndLocal/Documents/vcpr_and_prescriptions.pdf).

 A medical diagnosis is the first step, and then selection of a product. Applying an appropriate withdrawal time becomes trickier. The Food Animal Residue Avoidance Databank (FARAD) at www.farad.org has the most comprehensive data for establishing extralabel withdrawal times.

“Because of the complicated algorithms they have developed and the proprietary data they have at their disposal, FARAD is the place to go,” advises Fajt. “Simply adding days to a labeled withdrawal time will likely result in violations, since extending the withdrawal time with an extralabel dose should involve assessment of elimination halflife, effect of change in dose or route on elimination half-life, etc.”

Identification of animals treated on or off-label is an issue fraught with minefields, but the law says animals must be identified, Fajt says. “Somehow the animal treated must be identified, whether that’s an ear tag, a physical description, a name, whatever. The goal is to be able to prevent an animal from entering the food chain before it is deemed safe to enter. If you identify a pen only, then I would think the whole pen would be subject to being withheld from harvest for the withdrawal period.”

Prescribing or recommending the use of an over-the-counter drug in an extralabel manner such as dosing penicillin at a higher dose than on the label, also triggers all the requirements of AMDUCA. “You cannot just tell a client to use the over-the-counter penicillin at an extralabel dose,” Fajt says. “You must put a label on it and add an extended withdrawal time.” Fajt recommends reading the label requirements under the AMDUCA regulations (21 CFR 530.12).

Recordkeeping is not clearly defined except that records need to be kept by the producer or veterinarian for two years in the event FDA needs to look at extralabel use if there is an issue. Fajt says in some states there may be requirements about where medical records are kept, so that should be determined by the veterinarian consulting his/her state practice act.

But if a producer is not working under a VCPR with a veterinarian, what can the veterinarian do? In some cases, not much. “In my view, the best way to stay out of trouble is to help your clients stay out of trouble, and to not sit back and let the ones who won’t let you help them taint the entire industry,” Fajt says. “We are working on our consumer perception problem with animal welfare; let’s not compound it with a consumer perception problem about drugs in meat and milk.”

AMDUCA

The Animal Medicinal Drug Use Clarification Act (AMDUCA) gives veterinarians the legal right to use drugs in a manner for which they were not approved, in order to reduce animal suffering and improve animal health and welfare. “There are a lot of important things about AMDUCA that veterinarians need to keep in mind, but I think one important point is that AMDUCA requires that a labeled drug be used first, and if a drug is not labeled for the indication (or is clinically ineffective), a drug approved in a food animal may be used extralabel,” Fajt explains.

But AMDUCA does not give veterinarians carte blanche to use any drug whenever and however they want, Fajt notes. AMDUCA also limits extralabel use to therapeutic purposes, which means that production purposes like estrus synchronization or feed efficiency cannot be addressed with extralabel drug use.

Fajt emphasizes that AMDUCA limits compounding, at least at the federal level, to compounding already approved drugs, not drugs from bulk. “All you have to think about is the melamine crisis, and you will be able to paint a picture of the havoc on animal health and on consumer confidence of cattle drugs compounded from bulk drug purchased off-shore, which is not subject to the same manufacturing controls as approved products are.” This is an educational issue for producers as well, since many may not be aware of the importance of purchasing drugs with known provenance.

Another good reason for VCPRs within AMDUCA is that the veterinarian will generally know what the disposition will be of an animal that is treated with labeled or off-labeled drugs under AMDUCA. “The importance of this cannot be overstated, and veterinarians should not be using slaughter as the final option for animals that did not respond to treatment,” Fajt says. “That is one way to end up with a residue, the most common tissue violations being in dairy cows.”

In fact, dairy herds being downsized or liquidated due to the drought-exacerbated high feed costs may present a challenge in observing proper withdrawal times for dairy animals treated with drugs. In late August, Dairy Herd Management reported that a substantially higher number of dairy cows went to slaughter in July than the same month a year earlier, an indication that high feed costs are causing some herds to liquidate. According to the August 24 USDA Livestock Slaughter report, 239,000 dairy cows went to slaughter in July, compared to 207,000 in July 2011, which is a 32,000-cow increase.

“Veterinarians working with these producers should be particularly vigilant as these cows are being liquidated, so they can help producers prevent animals with potential residues from entering the food supply,” Fajt says.”

What are the violative drugs?

Scrolling through the 111-page FSIS United States National Residue Program for Meat, Poultry, and Egg Products 2010 Residue Sample Results report (see page 4), you can see the most commonly listed drugs that cause both violative and non-violative residues in cattle. Neomycin topped the list followed by flunixin and penicillin for violative residues. For non-violative residues, neomycin again topped the list, followed by dihydrostreptomycin and tetracycline.

FDA has established a tolerance of 7.2 ppm for residues of neomycin in the kidney tissue of cattle, but this tolerance does not apply to use of neomycin in bob veal calves (pre-ruminatingcalves), where the majority of the violations occur.

And gentamicin, which is not FDA-approved for use in cattle or has a scientifically established a withdrawal time for cattle, continues to be used and is still being found in samples. Fajt says gentamicin residues have been found in dairy cattle that might have been treated for non-response to other drugs, then they are culled. Aminoglycoside violations occur because the drug concentrates in kidney tubular cells and the kidney is the organ that gets swabbed for residue testing. “Aminoglycosides hang around in the kidney at detectable levels for months to years,” Fajt says.

Sulfas and penicillin which often make the list are mostly over-the-counter products, easy to obtain and inexpensive. “Any sulfamethazine is completely illegal in dairy cows, since only on-label use of sulfadimethoxine is permitted in lactating dairy cows,” Fajt says. “I would guess that one of the big reasons for penicillin violations is that extralabel doses are being used, but the withdrawal time used is the one on the label.”

Flunixin has also been a common problem with dairy cows, but mostly because of a change in route of administration. Extralabel administration in the muscle or subcutaneously rather than IV can create a residue. “The labeled withdrawal time only works for IV, and the other routes result in prolonged drug concentrations in the animal,” Fajt explains.

A word about compounding

Veterinarians have a responsibility to maintain a healthy food supply, to prevent animal suffering, and to improve animal welfare. None of those are accomplished with drugs compounded from bulk. “What would Katie Couric ask you about those drugs?” Fajt asks. “Imagine the news story:‘Drugs bought on the internet and mixed and bottled in a warehouse in the rural Midwest are being injected into cattle that end up on your plate’.”

The FDA has explicit rules about compounding drugs for veterinary use and the Code of Federal Regulations 530.41 (a) details the compounding of drugs that are prohibited for extralabel use in food-producing animals because the drugs present a risk to the public health. Despite the warnings and the illegality of compounding products for food animals, it still happens all too frequently.

Dairy herds being downsized or liquidated due to drought and high feed costs may present a challenge in observing proper withdrawal times if they have been treated.

“The important thing about compounding is that there are very limited needs for it in bovine medicine,” Fajt says. She notes that one important use, which is still technically illegal but mentioned by the FDA in the Compliance Policy Guide, is antidotes for toxicities, like methylene blue or sodium thiosulfate. Apart from that, however, compounding can lead to ineffective treatments as well as food safety risks. “Veterinarians should know that if you mix xylazine and butorphanol in a syringe, you are technically compounding, and the biggest issue is probably drug stability,” Fajt says. “The general advice is to only do that at animal side, not in large volumes in bottles sitting on the shelf. Otherwise, the best advice is to not compound or use any compounded drugs in food animals.”

 

 (Sidebar):

Quiz – Are these uses illegal?

Do you know if or why these uses that you might see in your daily practice

are illegal, or not? Virginia Fajt, DVM, PhD, offers these examples of drug

use in food-animals, and explains why they are or are not legal under FDA

regulations. Take this quiz and see how up to speed you are on FDA drug

use regulations. See the answers here.

1. Metronidazole (Flagyl) for Giardia in a lamb

2. Gentamicin for respiratory disease in a steer

3. Clotrimazole topically for ringworm

4. Tilmicosin for seminal vesiculitis in yearling bull

5. Ketoprofen for bovine respiratory disease

6. Oxytetracycline feed additive at 10 mg/lb for Mycoplasma arthritis

7. Distilled water with baking soda and 50% dextrose for fluid therapy in a neonate

8. Intramammary aloe vera for treatment of mastitis

9. Intramammary colloidal silver for treatment of mastitis

10. Ceftiofur for treatment of metritis in a goat

11. Ceftiofur for treatment of calf septicemia

12. Enrofloxacin for treatment of respiratory disease in a dairy cow

13. Tilmicosin for treatment of respiratory disease in a dairy cow

14. Six growth promotant implants in a steer for heat detection

15. Sulfachlorpyridazine for treatment of metritis in dairy cows

16. Pediatric human-labeled trimethoprim-sulfa for E. coli in a neonatal calf

 

Prohibited ELDU drugs

The FDA prohibits extralabel drug use in food animals for the following drugs:

• Chloramphenicol

• Clenbuterol

• Diethylstilbestrol

• Dimetridazole

• Ipronidazole

• Other nitroimidazoles

• Furazolidone (except for approved topical use)

• Nitrofurazone (except for approved topical use)

• Sulfonamide drugs in lactating dairy cows (except approved use of sulfadimethoxine, sulfabromomethazine and sulfaethoxypyridazine)

• Fluoroquinolones

• Glycopeptides (example is vancomycin)

• Cephalosporins (not including cephapirin) in cattle, swine, chickens or turkeys: (i) for disease prevention purposes; (ii) at unapproved doses, frequencies, durations, or routes of administration; or (iii) if the drug is not approved for that species and production class


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