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Questions and Answers About FDA's Enforcement Action Against
Unapproved Injectable Colchicine Products
1. What action is FDA taking concerning injectable drugs containing colchicine?
The U.S. Food and Drug Administration (FDA) has ordered companies to stop marketing unapproved drug products that contain colchicine in an injectable dosage form. Injectable colchicine is used for the intravenous administration of the drug. The action does not affect colchicine tablets, and they will remain on the market at this time. FDA took this action as part of its effort to ensure that all drugs marketed in the United States have the required FDA approval and that they are safe, effective, of good quality, and appropriately labeled. Individuals and firms must stop making these products within 30 days and stop shipping the product within 180 days. After these dates, all injectable colchicine drug products must have FDA approval to be manufactured or shipped interstate.
2. What is colchicine?
Colchicine is a drug with anti-inflammatory properties that is most commonly used for the treatment of gout. The oral dosage form of colchicine is typically used to prevent gout attacks. Colchicine for injection has been available in the United States since the 1950s and administered intravenously for the treatment of acute attacks of gout. Due to serious toxicities associated with the use of intravenous colchicine and the emergence of safer alternative therapies, intravenous colchicine is rarely used in current practice for acute gout treatment.
3. Why is FDA taking this action?
Drug products containing colchicine for intravenous use have been marketed without approval. Colchicine is a drug which, when not properly dosed, can produce harmful or fatal effects including abdominal pain, vomiting, seizures, lack of blood cell production, and organ failure. Because injectable colchicine is a toxic drug, and also a drug with a narrow margin between an effective dose and a toxic dose, proper manufacturing and dosing recommendations are essential. These can only be assured by making certain that the products are held to the rigorous safety and efficacy standards of the FDA approval process. This action affects all injectable colchicine products, as none currently have FDA approval. There was one manufacturer of injectable colchicine, but that firm voluntarily discontinued manufacture of injectable colchicine in October 2007.
4. What risks are associated with injectable colchicine-containing drugs?
Serious safety concerns, including fatalities, associated with intravenous colchicine drug products are well-documented in the literature and in adverse drug events reported to the agency. FDA is aware of 50 reports of adverse events associated with intravenous (i.v.) colchicine use, including 23 deaths, through June 2007. Three of these deaths occurred in March and April of 2007 and were associated with the use of compounded i.v. colchicine. Among the commonly reported events were neutropenia (low number of white blood cells), acute renal (kidney) failure, thrombocytopenia (low number of platelets), congestive heart failure, and pancytopenia (low number of all types of blood cells). Many of these adverse events are caused by colchicine toxicity, which can have serious and potentially fatal consequences.
As mentioned, colchicine is known to have a narrow therapeutic index, or a narrow margin of safety between doses that are therapeutic and doses that are toxic. Many of the adverse events associated with colchicine are dose-related.
5. Are there approved drug products containing colchicine?
The approved versions of colchicine are tablets that also contain the active ingredient probenecid. There are two such approved products: Col-Probenecid from Watson Laboratories, and Probenecid and Colchicine from Ivax Pharmaceuticals. There are no approved products that contain only colchicine as an active ingredient. FDA is not taking any orally administered colchicine products off the market at this time, whether approved or unapproved.
6. Why is the FDA taking the injectable form of colchicine off the market at this time but not the oral forms?
There is an increased likelihood of colchicine toxicity when the drug is administered intravenously. For oral dosing in the treatment of acute gout, the dose is usually titrated by administering the drug over time until symptoms resolve or the patient begins to experience side effects, which are typically gastrointestinal. This emergence of side effects when the drug is taken orally provides a margin of safety that often prevents serious and fatal overdoses. In the case of intravenous administration, side effects are generally not experienced until the patient has already received toxic levels of colchicine. Therefore, extreme care must be exercised when colchicine is administered by this route.
FDA is not taking action at this time against those colchicine tablets that are marketed without FDA approval because the risks are less acute for colchicine tablets than they are for injectable colchicine. Like all other unapproved drugs, colchicine tablets that are marketed without FDA approval could be subject to FDA enforcement at any time. Accordingly, FDA strongly encourages the manufacturers of those products to pursue FDA approval.
7. Why does FDA caution against using intravenous colchicine to treat back pain?
In recent years, intravenous colchicine has gained popularity within the alternative medicine community as a treatment for back pain. FDA has not approved colchicine in any dosage form for this indication. Because of the toxicity of colchicine, the potential for serious adverse events and the availability of safer therapies for the treatment of back pain, FDA believes that the safety risks associated with injectable colchicine outweigh any potential benefit in using the drug for back pain. As a matter of policy, FDA does not ordinarily interfere with the practice of medicine. In the exercise of their professional judgment, physicians may generally prescribe approved drugs for unapproved uses. These warnings regarding colchicine do not change that policy.
8. Why does FDA caution against compounding colchicine for injection products and using compounded colchicine for injection?
In addition to being manufactured by pharmaceutical companies, injectable colchicine products are sometimes formulated by compounding pharmacies. There are serious risks associated with the compounding of injectable colchicine products because there is a limited margin of safety due to the narrow therapeutic index and serious toxicities associated with colchicine. Any concentration errors that occur within the course of compounding injectable colchicine can have potentially serious and fatal consequences. FDA is aware of a number of deaths attributed to improperly compounded injectable colchicine products and discourages the compounding of these products due to the serious safety risks.
9. Does FDA want to prevent pharmacy compounding?
No. FDA believes that pharmacists engaging in traditional compounding provide a valuable medical service that is important to patient health. FDA has no interest in ending traditional pharmacy compounding. FDA regards traditional pharmacy compounding as the combining or altering of ingredients by a pharmacist, in response to a licensed practitioner’s prescription, to produce a drug tailored to an individual patient’s special medical needs. In its simplest form, traditional compounding may involve reformulating a drug, for example, by removing a dye or preservative in response to a patient allergy. Instead, FDA focuses on the subset of inappropriate compounding described in FDA’s Pharmacy Compounding CPG. The CPG is available on FDA’s pharmacy compounding Web page at http://www.fda.gov/cder/pharmcomp/default.htm.
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Date created: February 6, 2008
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