1. What is carbadox?
Carbadox is an antibiotic used in swine (hogs and pigs) for production purposes (e.g., increased rate of weight gain and improved feed efficiency) and therapeutic purposes (e.g., to control swine dysentery and bacterial swine enteritis). While carbadox is an antimicrobial, it does not pose the same resistance issues as other antimicrobials and is not considered important to human medicine.
2. What are the approved animal drug products containing carbadox?
There are three approved New Animal Drug Applications (NADAs) for animal drug products containing carbadox, all held by Phibro Animal Health:
- Mecadox Premix 10 (NADA 041-061); contains carbadox alone
- Banminth/Mecadox (NADA 092-955); contains carbadox plus pyrantel tartrate
- Mecadox/Terramycin (NADA 141-211); contains carbadox plus oxytetracycline
3. Why does CVM want to remove carbadox from the market?
FDA’s Center for Veterinary Medicine (CVM) (the center within the FDA that approves new animal drugs) has questions about the safety of carbadox. To date, after requests for additional information from CVM, Phibro has not submitted information demonstrating that there is a safe way to use carbadox. Continued approval of carbadox could expose consumers to substances of carcinogenic concern.
4. Should consumers stop eating pork products treated with carbadox?
As a general matter, the FDA continues to advise all consumers to eat a well-balanced diet for good nutrition and to minimize potential adverse consequences from consuming an excess of any one food.
During the time that CVM is working to have carbadox removed from the market, the agency is not recommending that people make changes in their food choices. The potential cancer risks are based on an assumed lifetime of consuming pork containing carbadox residues, and short-term changes in diet are unlikely to affect anyone's lifetime risk. However, removal of the product from the market will reduce the lifetime risk to consumers, which is why CVM is taking this action.
The agency recognizes that pork is a common protein in American diets. Based on the FDA’s findings with respect to carbadox residues in pork products, the agency offers this advice to consumers: Pork is a good source of protein; however, protein can also be found in other meat, poultry, seafood, beans and peas, eggs, processed soy products, nuts and seeds. Select a variety of protein foods to improve nutrient intake and health benefits.
5. How can I tell which pork products come from pigs that were treated with carbadox?
The agency does not have information about which pork products come from pigs treated with carbadox. Producers are not required to report to the FDA which drugs they use, and drug sponsors are only required to report sales data, which does not reflect actual use. During the time that CVM is working to have carbadox removed from the market, the agency is not recommending that people make changes in their food choices. The potential cancer risks are based on a lifetime of consuming pork containing carbadox residues, and short-term changes in diet are unlikely to affect anyone's lifetime risk. However, removal of the product from the market will reduce the lifetime risk to consumers, which is why CVM is taking this action.
6. How will CVM remove carbadox from the market?
On April 8, 2016, CVM published a Notice of Opportunity for Hearing (NOOH) in the Federal Register announcing a proposal to withdraw the approval of the drug applications for products containing carbadox. The NOOH gives Phibro, the sponsor of all of the drug applications for carbadox, notice that they have an opportunity to request a hearing on whether the approvals should be withdrawn. Phibro has 30 days from the publication of the NOOH to request a hearing. If Phibro does request a hearing, the FDA Commissioner will then determine whether a hearing is justified, and if so, will publish a Notice of Hearing. This Notice of Hearing will include, among other things, the reasons for the hearing and the timeframe for the hearing process.
If Phibro does not request a hearing, CVM may then withdraw the approvals for carbadox and it would no longer be legal to market the drug in the United States. Any new animal drug marketed without an approval or other legal marketing status (i.e., index listing) is subject to enforcement action at any time.
7. How does the FDA regulate carcinogenic animal drugs?
Under the Delaney Clause in section 512 of the Federal Food, Drug, & Cosmetic Act (FD&C Act), the FDA cannot approve a new animal drug application if it “is found to induce cancer when ingested by man or animal…” An exception to this general rule, referred to as the DES Proviso, allows for the approval of a carcinogenic drug if the FDA finds that, under the approved conditions of use, the drug will not adversely affect treated animals and no residues of the drug will be found by an approved regulatory method in any edible tissues of or foods from the animal. All animal drugs must also meet the standards of the General Safety Clause in 512 of the FD&C Act, which requires the agency to find that the drug is safe for both the animal it is intended for and humans who consume food products derived from that animal.
8. Why was carbadox approved for use in swine?
Carbadox was approved for therapeutic (e.g., control of swine dysentery) and production (e.g., increased rate of weight gain, improved feed efficiency) purposes in 1972. At the time the drug was approved, information indicated that, under the approved conditions of use, carbadox did not result in unsafe quantities of carcingogenic residues, and that use of carbadox met the exception to the Delaney Clause prohibition on carcinogenic animal drugs.
The FDA approved carbadox under the conditions that no carcinogenic residues of carbadox and its metabolite, quinoxaline-2-carboxylic acid or “QCA,” are found in the uncooked edible tissues of swine. At the time, CVM determined that when QCA was at or below the tolerance of 30 ppb, there would be no detectable carcinogenic residues —of carbadox in the edible tissues (i.e., meat) of treated pigs. Use limitations also restricted the administration of carbadox to young pigs to ensure an adequate withdrawal time.
9. Why is CVM questioning the safety of carbadox?
Data from the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2003, in conjunction with new publications in 1990, 1991 and 2009, raised questions about the safety of carbadox. CVM requested additional information from the manufacturer of Phibro to address these concerns.
From 2012 to 2014, the FDA’s Center for Veterinary Medicine (CVM) conducted a preliminary risk characterization, which determined that the lifetime cancer risk from the consumption of pork liver containing carcinogenic carbadox residues is higher than that allowed under the FDA’s current framework for regulating carcinogenic new animal drugs.
Also in 2014, the Codex Alimentarius Commission provided the risk management recommendation, “In view of the JECFA conclusions on the available scientific information, there is no safe level of residues of carbadox or its metabolites in food that represents an acceptable risk to consumers. For this reason, competent authorities should prevent residues of carbadox in food. This can be accomplished by not using carbadox in food producing animals.”
CVM had discussions with the drug’s sponsor, Phibro Animal Health, in 2015 about their plans to generate safety data. The plans did not sufficiently address FDA’s questions.
In order to remove carbadox from the market, CVM must propose withdrawing approval of the drug by filing a Notice of Opportunity for a Hearing (NOOH). The notice gives the manufacturer of the drug an opportunity to request a hearing on whether the approvals should be withdrawn. In 2016, CVM completed its determination that, based on the new information, evaluated together with the information available at the time of the approvals, carbadox is not shown to be safe, and filed a NOOH to remove carbadox from the market.
10. What is the expected impact of this action on the swine industry?
Alternative drugs to carbadox are available for controlling swine dysentery and bacterial swine enteritis. Pork producers can also work with their veterinarian to implement preventative measures that reduce the need for a drug like carbadox, such as vaccination or changes in husbandry practices. The FDA is committed to working with producers in an effort to minimize impacts on the swine industry to the extent possible while ensuring the safety of the food supply.