Questions and Answers on Health Canada's Policy on Extra-Label Drug Use (ELDU) in food-producing animals

1. What is ELDU in animals?
2. What is considered a "drug label" by Health Canada?
3. How could I verify if a drug product is approved by Health Canada?
4. How could one identify the DIN on the label of a drug product?
5. How important is it to use Health Canada-approved drug products?
6. What is the impact of ELDU on public health and animal health?
7. What are violative drug residues?
8. Who practices ELDU in animals in Canada?
9. Why has ELDU become an issue for Health Canada?
10. How does Canada mitigate the risks to public health from ELDU practice in animals?
11. Why is the current ELDU policy directed toward food-producing animals?
12. Which animals are considered food-producing animals in Canada?
13. Who is qualified to practice ELDU in animals in Canada?
14. What does "valid VCPR" mean?
15. Who assumes the risks of using drugs in an extra-label manner?
16. How important is the list of Category I Antimicrobials and why is Health Canada recommending against their use in an ELDU manner?
17. Why should anyone avoid the extra-label use of banned substances in Canada?
18. What types of drugs are prohibited for sale for administration to food-producing animals in Canada?
19. What do I need to know about ELDU in medicated feeds?
20. How do I know if I am engaged in ELDU practice?

1. What is ELDU in animals?

Extra-Label Drug Use (ELDU) is often referred to as "off-label use" in human medicine. In animals, ELDU refers to the actual use or intended use of any drug, whether it is a prescription drug or over-the-counter drug, in an animal in a manner that is not in accordance with the approved label or the package insert of the drug licensed by Health Canada. This definition includes the use of all unlicensed drugs, including unapproved bulk active pharmaceutical ingredients (APIs) and compounded drugs.

2. What is considered a "drug label" by Health Canada?

The labels for drug products include package labels such as package inserts, prescribing information, fact sheets, or other materials containing drug product- specific information, whether included in packaging or supplied to the end user at the time of purchase or after purchase.

3. How could I verify if a drug product is approved by Health Canada?

On each drug product approved by Health Canada, whether human or veterinary, there is a Drug Identification Number (DIN) specific to that drug product.

The Drug Identification Number (DIN) is the number located on the label of prescription and over-the-counter drug products that have been evaluated by Health Canada and approved for sale in Canada. Once a drug has been approved, Health Canada issues a DIN, which permits the manufacturer to market the drug in Canada. A DIN lets the user know that the product has undergone and passed a review of its safety, efficacy and quality. It also shows that Health Canada has verified and approved the formulation, labelling and instructions for use of the approved drug product. Any drug product sold in Canada without a DIN is not in compliance with the Canadian law. The DIN provides a tool to help in the follow-up of products on the market, recall of products, inspections, and quality monitoring.

4. How could one identify the DIN on the label of a drug product?

The DIN is an eight-digit numerical code assigned to each drug product and it is preceded by three capital letters, DIN. An approved drug product should have a DIN clearly displayed on the drug label.

5. How important is it to use Health Canada-approved drug products?

The drug review process at Health Canada ensures that new drug products undergo rigorous scientific scrutiny and fully satisfy all requirements and criteria that are prescribed by the Food and Drug Regulations. Drug sponsors must meet these criteria in order to have their drug products approved for sale in Canada. Health Canada's authorization is granted upon satisfactory review of the safety, efficacy and quality of the drug products. Throughout the process, the safety and well-being of Canadians, their animals and the environment are of paramount concern.

6. What is the impact of ELDU on public health and animal health?

When an individual makes a decision to administer a drug product on animal(s) in an extra-label manner, there are potential public health and food safety risks involved. Some of the implications of ELDU practice are as follows:

• Violative drug residues may be present in food products derived from ELDU-treated animals consumed by humans or in feed by-products fed to other animals;
• Violative residues may be present in the environment;
• ELDU may lead to the emergence of antimicrobial resistance (AMR), which presents a risk to public health;
• Adverse reactions may arise in treated animals since these products may not have been tested appropriately for these new conditions of use;
• Drugs used in this manner may have reduced or uncertain efficacy for the conditions being treated in animals;
• There may be ethical and liability considerations for veterinarians prescribing extra-label drugs that do not have proven safety or efficacy characteristics;
• ELDU may potentially initiate trade restrictions.
  

7. What are violative drug residues?

The Food and Drug Regulations specify a "Maximum Residue Limit (MRL)" or the amount of residue that could remain in the tissue or food product derived from a food producing animal that has been treated with a veterinary drug. The presence of trace amount of administered drug product, in animal-derived food products, that is beyond the established MRL (expressed in p.p.m) for the specific veterinary drug constitutes violative drug residues. MRLs are established only after the Health Canada's Veterinary Drugs Directorate has conducted extensive reviews of data submitted by manufacturers and determined that foods containing these veterinary drug residues up to the recommended levels are safe for human consumption. In cases where MRLs have not been established for the specific veterinary drugs, no detectable residues are permitted in animal-derived food products. Health Canada is actively working to have MRLs established for drug products that could be used in food-producing animals.

8. Who practices ELDU in animals in Canada?

Evidence has shown that the practice of ELDU in Canada is not restricted to veterinarians. It is being practiced by a variety of people, including laypersons, feed mill operators, feedlot managers, wildlife officers, animal breeders, pet owners, pet shop owners and employees, and by intermediate professionals such as pharmacists and animal health technicians.

9. Why has ELDU become an issue for Health Canada?

In Canada, the federal legislative authority for regulating the approval, sale and labelling of veterinary drugs is the responsibility of Health Canada. The Canadian Food Inspection Agency (CFIA) is responsible for enforcing the health and safety standards set by Health Canada. In the case of veterinary drugs, this is done through the residue monitoring program and, specifically, sampling and testing of food products of animal origin. The authority and accountability for the prescribing and use of veterinary drugs falls under provincial and territorial jurisdiction.

In recent years, increased attention has been focussed on ELDU in Canada partly as a result of concerns about the potential for ELDU abuse and/or misuse and the potential public health risks relating to the uncontrolled practice of ELDU in Canada. These concerns were also highlighted in the European Commission's (EC) 2007 audit report on the evaluation of the Canadian control of residues and contaminants in live animals and animal products, including the control of veterinary medicinal products. In order to address these concerns, a comprehensive action plan aimed at ensuring a national approach for the effective control of extra label use of veterinary drugs was deemed imperative. Health Canada's policy on ELDU will is construed to set a national standard for the effective control of ELDU in food-producing animals in Canada. Health Canada's primary goal is to maintain the safety of our food system.

10. How does Canada mitigate the risks to public health from ELDU practice in animals?

In Canada, the use of drugs is a complex multi-jurisdictional issue involving the federal government and the various provinces and territories. Health Canada regulates the sale but not the use of drugs. The use of veterinary drugs per se comes under the "practice of veterinary medicine", a provincial jurisdiction. Currently, there are no federal Canadian regulations defining the requirements for the practice of ELDU, with the exception of medicated feeds, whose requirements are described in the ELDU policy and could also be found in the Food and Drug regulations C.08.012.

11. Why is the current ELDU policy directed toward food-producing animals?

The use of drugs in food-producing animals can lead to potentially harmful residues in the edible products harvested from these animals. Since human food safety is an important aspect that is considered in the review of veterinary drugs that would be administered to food-producing animals, Health Canada considers it a priority to focus only on food-producing animals.

12. Which animals are considered food-producing animals in Canada?

As defined in the Meat Regulations of Canada, "food animal" includes animals in the class of mammals or birds that are slaughtered and processed as meat products for human consumption and for which inspection systems have been established. In the context of the ELDU policy, food-producing animals refer to animals that could be slaughtered and processed as meat products for human consumption in Canada.

13. Who is qualified to practice ELDU in animals in Canada?

Consistent with international direction, Health Canada takes the following view on the practice of ELDU:

ELDU in food producing animals by persons other than licensed veterinarians is not recommended except when such use is conducted under the supervision of a veterinarian within the context of a "valid Veterinarian-Client-Patient Relationship "(VCPR).

This approach is universal and should be applied for the benefit of public health and animal safety.

14. What does "valid VCPR" mean?

Health Canada considers a "valid VCPR" to exist when the following conditions apply:

1. The client [Owner or owner's agent of the animal(s)] has given the responsibility of medical care to the veterinarian and has agreed to follow the instructions of the veterinarian; and
2. the veterinarian has assumed the responsibility from the client for making clinical judgment regarding the health of the animal(s), the need for medical treatment, and for ensuring the provision of ongoing medical care for the animal(s); and
3. the veterinarian has sufficient knowledge of the health status of the animal(s) and the care received. The knowledge has been obtained through a recent examination of the animal(s) and the premises where it is (they are) kept or through a history of medically appropriate and timely examinations and interventions; and
4. the veterinarian is readily available or has made the necessary arrangements with another veterinarian, for ongoing medical care in case of adverse reactions or therapy failure.

These four elements need to be present in order to establish a "valid VCPR".

15. Who is assuming the risks when they are using a drug in an extra-label manner?

The entire responsibility is assumed by the individual who is practicing ELDU.

16. How important is the list of Category I Antimicrobials and why is Health Canada recommending against their use in an ELDU manner?

The antimicrobials in Category I are considered of "very high importance" or "critically important" in human medicine as they are essential for the treatment of serious bacterial infections and there are limited or no availability of alternative antimicrobials in case of resistance to these antimicrobials. Health Canada is recommending against their use in an ELDU manner because it is essential that we protect the efficacy of these drugs by using them prudently and judiciously, as indicated on the approved label.

The current list of Category I antimicrobials includes the following examples:

• Carbapenems
• Cephalosporins - the third and fourth generations
• Fluoroquinolones
• Glycopeptides
• Glycylcyclines
• Ketolides
• Lipopeptides
• Monobactams
• Nitroimidazoles (metronidazole)
• Oxazolidinones
• Penicillin - β-lactamase inhibitor combinations
• Polymyxins (colistin)
• Streptogramins
• Therapeutic agents for tuberculosis (e.g. ethambutol, isoniazid, pyrazinamide and rifampin)

17. Why should anyone avoid the extra-label use of banned substances in Canada?

Banned substances should never be used in food-producing animals because residues of these substances in food could cause fatal diseases in humans, if ingested.

18. What types of drugs are prohibited for sale for administration to food-producing animals in Canada?

The list of substances prohibited for sale for administration to food-producing animals in Canada is as follows:

C.01.610.1 (Banned Substances):

• Chloramphenicol or its salts or derivatives;
• 5-nitrofuran compound;
• Clenbuterol or its salts or derivatives;
• 5-nitroimidazole compound;
• Diethylstilbesterol or other stilbene compounds.

19. What do I need to know about ELDU in medicated feeds?

There are multiple requirements by the Food and Drug Regulations (C.08.012). However here are the most important that you should always consider and respect when you are preparing a medicated feeds different than what is prescribed in the MIB.

• You need to have a prescription signed by a licensed veterinarian ; and
• You should use only drug products that have DINs/ or have been obtained via EDR or ESC; and
• The preparation should be for therapeutic purpose under a "valid VCPR".

20. How do I know if I am engaged in ELDU practice?

Extra label use of a drug may take many forms. Below is a list of examples of ELDU which all require a valid VCPR.

• The use of a drug product (that has a DIN):
  • in a different dosage than what is approved on the label;
  • with a greater or lesser frequency of administration than what is approved on the label;
  • for a different indication (ie., different disease or condition) that was stated on the label;
  • for a longer or shorter duration of treatment than what is indicated on the label;
  • by different routes of administration (e.g. oral versus injectable);
  • in a different species than what is indicated on the label (e.g. a drug approved in cattle administered to sheep);
  • in a different age group;
  • in a different stage of the animal's production cycle (e.g. dried out cows versus lactating dairy cows);
  • in a different dosage form (e.g. a tablet may be crushed into powder and incorporated into a gel i.e., by "Compounding");
  • that has been approved for human use, to treat an animal;
  • in a medicated feed outside of Medicated Ingredient Brochure (MIB) listing;
  • in a different formulation e.g. two drugs being mixed in the same syringe i.e., by "Compounding";

• The use of drug product ( with no DIN)
  • The use of unapproved drugs (no DIN) in animals, or the use of bulk pharmaceutical substances (with no DIN), also called Active Pharmaceutical Ingredients (APIs), which have been formulated by compounding or administered as is.