Extralabel drug use in cattle practice

Dehorning young calves is a standard industry practice that improves the safety of the growing animal and of livestock producers and veterinarians working with these animals. Though dehorning (disbudding) calves before they are three weeks of age (before the horn buds attach to the skull) is the least painful time for this process, there is still some pain involved. Increasing scrutiny on pain-inducing practices of livestock such as dehorning and castrating has brought this issue to the forefront.

In a 2008 position statement, the American Veterinary Medical Association "recommends the use of procedures and practices that reduce or eliminate these effects, including the use of approved or AMDUCA-permissible clinically effective medications whenever possible."

However, this is easier said than done. "It is remarkable that although administration of local anesthesia prior to castration and dehorning is legislated in several European countries, there are currently no analgesic drugs specifically approved for pain relief in livestock by the U.S Food and Drug Administration," explains Hans Coetzee, BVSc, Cert CHP, PhD, Dipl. ACVCP, Kansas State University. "FDA Guidance Document 123 for the development of effectiveness data for non-steroidal antiinflammatory drugs (NSAIDs) states that ‘validated methods of pain assessment must be used in order for a drug to be indicated for pain relief in the target species". The identification and validation of robust, repeatable pain measurements is therefore fundamental for the development and approval of effective analgesic drug regimens for use in livestock."

In the absence of validated and approved analgesic drugs for livestock, existing analgesics from other species must then be use in an extralabel manner. This article will discuss the current extralabel use regulations under the Animal Medicinal Drug Clarification Act for analgesics used in livestock, and what the ramifications may be for veterinarians and their clients. A follow-up article will then revisit the discussion on dehorning of young calves, what analgesics can be used by veterinarians (under the provisions of AMDUCA), and how to strategically use them with the current knowledge we have to mitigate dehorning pain.

Extralabel use under AMDUCA

There are several challenges associated with providing effective analgesia in food animals in the United States, especially when there are currently no analgesic drugs specifically approved for the alleviation of pain in livestock. The use of any drug for pain relief constitutes extralabel drug use (ELDU). Under the 1994 AMDUCA, ELDU is permitted for relief of suffering in cattle provided specific conditions are met, Coetzee explains.

These conditions include:

1 ELDU is allowed only by or under the supervision of a veterinarian.

2 ELDU is allowed only for FDA approved animal and human drugs.

3 ELDU is only permitted when the health of the animal is threatened and not for production purposes.

4 ELDU in feed is prohibited.

5 ELDU is not permitted if it results in a violative drug residue in food intended for human consumption.

"Therefore, use of an analgesic to alleviate pain associated with castration in calves in the United States, for example, would be required by law to comply with these regulations," he says.

The consequences for violating the condition related to ELDU under the supervision of a veterinarian could include inappropriate withdrawal times resulting in violative residues, since a layperson might not have the knowledge or resources to appropriately extrapolate an extended withdrawal time as required by AMDUCA, Virginia Fajt, DVM, PhD, Dipl. ACVCP explains. "In addition, drugs used outside of a veterinarian's supervision may not be used for the right condition, at the right time, or with the right regimen to optimize efficacy."

Routes of administration

A third challenge is that the route or method of analgesic drug administration may require specialized training and expertise or may be hazardous to the operator. "It has been demonstrated many times that administering drugs by different routes of administration can impact drug pharmacokinetics and therefore withdrawal times," Fajt explains. Even approved drugs at different routes have different disposition.

"Drugs may be absorbed at different rates in different tissues, so changing the route of administration from what is on the drug label is a crap shoot, unless you have the benefit of published or labeled pharmacokinetic comparisons," Fajt adds. "Following the label will keep you on the right path and will also help you if there should be a residue resulting from an on-label dosing regimen."

Flunixin meglumine is one example. Its only current approved route of administration in the United States in cattle is intravenous. The FDA-CVM reports it is important for veterinarians to prescribe and use flunixin meglumine and other drugs for food animals according to directions on the label so that adulterating residues are avoided. The intramuscular administration of flunixin meglumine has the potential to cause violative drug residues, since it requires a longer withdrawal period to deplete the drug-related residue in the animal than does the
approved intravenous route of administration.

"Therefore, administration requires the animal to be adequately restrained and the operator to be proficient in IV administration," Coetzee says. "Similar issues are encountered with epidural analgesic drug administration and administration of local anesthesia into the scrotum." The latter procedure is also considered especially hazardous by many livestock handlers.

Coetzee adds that in addition, the majority of analgesic drugs that are available in the U.S. have a short elimination half-life necessitating frequent administration in order to be effective. This increases the stress on the individual animal and increases labor and drug costs. Another challenge to providing effective analgesia in cattle is that there is often a delay between the time of drug administration and the onset of analgesic activity. For example, local anesthetics require 5–10 minutes before a maximal effect is achieved. "This may slow animal processing and that may serve as a disincentive to producers to provide routine preemptive analgesia," Coetzee notes. "Furthermore, this may result in procedures being initiated before optimal analgesia is achieved."

BQA can help

One way to help ensure proper drug use and prevent residues is through Beef Quality Assurance (BQA) training and/or certification by producers and veterinarians. "BQA certification may provide a good faith immersion in a veterinarian's clients" production practices, but the most important thing is to understand BQA principles, since many producers will try to follow them," Fajt says. "If your clients are not following BQA guidelines, you can play a role in improving the quality of the products they produce and in keeping them out of trouble." 

Your clients will do what you do, Fajt adds. "So if the industry thinks it is important to stay in front of the shoulder to improve beef quality, you need to model good drug administration practices. If you don't think BQA matters, then perhaps you need to consider how to educate yourself." 

Fajt believes FDA-CVM and USDA are looking more closely at residues and at who is responsible. "Anecdotal reports from veterinarians in the field suggest that even when the veterinarians did not authorize a drug, if they are veterinarians of record for the farm, they will be drawn into an investigation and their drug prescription practices will be scrutinized." 

OTCs can be an extralabel risk

If an over-the-counter (OTC) medication is used in an extralabel manner, it becomes like a prescription drug and must be used only by or under the direction of a licensed veterinarian.  Once something is used extralabel, the veterinarian must also establish an extended withdrawal time. "OTC drugs used extralabel without veterinary involvement, even when a producer has seen the use previously, could be used inappropriately (for the wrong condition, at the wrong dose, etc.), is illegal, and could result in a residue," says Virginia Fajt, DVM, PhD, Dipl. ACVCP. 

Fajt adds that many of the violative tissue residues in recent months have been from drugs that have OTC approvals, and it is likely that these may have been used without veterinary involvement to assist with proper diagnosis, treatment selection, and withdrawal time estimation. 

Using OTC medications extralabel moves them into the territory of AMDUCA, meaning that all the conditions apply, including a valid veterinarian-client-patient-relationship.  It also requires a label from the veterinarian (or the pharmacy dispensing the prescription) which includes the following requirements (from the AMDUCA regulations):

Sec. 530.12  Labeling.

Any human or animal drug prescribed and dispensed for extralabel use by a veterinarian or dispensed by a pharmacist on the order of a  veterinarian shall bear or be accompanied by labeling information adequate to assure the safe and proper use of the product. Such information shall include the following:

    (a) The name and address of the prescribing veterinarian. If the drug is dispensed by a pharmacy on the order of a veterinarian, the labeling shall include the name of the prescribing veterinarian and the name and address of the dispensing pharmacy, and may include the address of the prescribing veterinarian;

    (b) The established name of the drug or, if formulated from more than one active ingredient, the established name of each ingredient;

    (c) Any directions for use specified by the veterinarian, including the class/species or identification of the animal or herd, flock, pen, lot, or other group of animals being treated, in which the drug is intended to be used; the dosage, frequency, and route of administration; and the duration of therapy;

    (d) Any cautionary statements; and

    (e) The veterinarian's specified withdrawal, withholding, or discard time for meat, milk, eggs, or any other food which might be derived from the treated animal or animals.

"Veterinarians are involved all the time in helping producers make good decisions about drugs, nutrition, disease control, and so on, so just because they do not write a prescription does not mean that they cannot be involved in drug decision-making," Fajt says. "Helping your clients provide a healthy wholesome product to the market seems like an easy sell." 

The liability of the veterinarian for producers using OTC antimicrobials is certainly not clear; however, if you work with a farm on other issues, or if you have treated animals with prescription products previously, your practice is likely to be scrutinized, whether or not legal action follows.

Why aren't pain medications approved?

While there is increasing pressure to provide pain control, relief and mitigation during and after a variety of industry practices such as dehorning and castration, the approved (in the United States) analgesics that are needed to do the job – in food animals – just aren't there.

The use of analgesics at the time of dehorning is only routinely performed on less than 20% of operations, explains Hans Coetzee, BVSc, Cert CHP, PhD, Dipl. ACVCP. "For a pharmaceutical company to approve a new product for this size market may not seem cost-effective. A company will be responsible for largely establishing a new market which may be challenging."

Many of the compounds that may be approved for pain relief have generic formulations available. "Companies may be reluctant to approve a drug for this purpose if the market is not protected from generic competition and if an extended period of marketing exclusivity cannot be assured," Coetzee adds.

Other aspects of the drug approval process such as establishing an appropriate tissue withhold period in food animals are very time consuming and costly studies for a company to undertake. "Companies may be reluctant to invest time and capital into developing a product for use in a market that has not yet been established without assurance of sales and marketing exclusivity," Coetzee says.

VCPR is critical

The FDA considers a valid Veterinary-Client-Patient Relationship (VCPR) to exist when:

a) the licensed veterinarian has assumed clinical responsibility for the animals and the owner of the animals has agreed to follow the veterinarian's instructions

b) the veterinarian has sufficient direct knowledge of the animal(s) condition and their care

c) the veterinarian is available for follow-up evaluation.


www.FDA.gov/cvm Food and Drug Administration Center for Veterinary Medicine

www.avma.org AVMA has information about prescribing practices, an AMDUCA flowchart to review the conditions for ELDU, and policies on antimicrobial drugs. 

www.aabp.org American Association of Bovine Practitioners

www.bqa.org Beef Quality Assurance

www.bqa.org/dairybqa.aspx Dairy Quality Assurance