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FDA Warned 20 Companies for Unapproved Ergotamine Containing Drug Products

Ergotamine is a vasoconstrictor used for migraine prevention and is sometimes mixed with caffeine. It is part of the ergot family of alkaloids and closely related to ergoline.Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result.
Although signs and symptoms of ergotism rarely develop even after long term intermittent use of the rectally administered drug, care should be exercised to remain within the limits of recommended dosage.

Use with sympathomimetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of CAFERGOT by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.

The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with these antibiotics. Many of the prescription medications for migraines narrow your blood vessels. Therefore, these drugs should not be used if you have heart disease, unless specifically instructed by your doctor.

The Federal Food, Drug, and Cosmetic Act generally requires that drugs marketed in the United States be shown to be both safe and effective prior to marketing and widespread use in the general population. Drugs that are marketed without required FDA approval may not meet modern standards for safety, effectiveness, quality, and labeling.

However, for a variety of historical reasons, some drugs, mostly older products, continue to be marketed illegally in the United States without required FDA approval. Many healthcare providers are unaware of the unapproved status of some drugs and have continued to unknowingly prescribe unapproved drugs because the drugs’ labels do not disclose that they lack FDA approval. Often these drugs are advertised in reputable medical journals or are included in widely used pharmaceutical references such as the Physicians’ Desk Reference (PDR).

While some unapproved drugs may have benefits, there may also be risks. Patients and health professionals should carefully consider the medical condition being treated, the patient’s previous response to the drug, and the availability of approved alternatives as part of discussing the benefits and risks of any unapproved treatment.

Recently,The Food and Drug Administration (FDA) today told 20 companies to cease marketing unapproved drug products containing ergotamine tartrate. Ergotamine tartrate products are used to treat vascular headaches, including migraines. As part of the FDA’s continued efforts to combat the marketing of unapproved drugs, the agency sent warning letters to eight manufacturers and 12 distributors warning them that they are subject to further enforcement action if they do not stop manufacturing and distributing these products.

The agency urges consumers who are using ergotamine products and have questions or concerns to contact their health care provider. This action does not affect FDA-approved products containing ergotamine, which will remain on the market.

“Unapproved drugs pose real risks to the American public,” said Steven Galson, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “Because they have not been subject to FDA review, the safety, effectiveness, and quality of such products are unknown. We remain dedicated to tackling this problem through education and outreach, as well as enforcement actions like these. It is central to our mission to ensure a safe and effective drug supply for the American public.”

In addition to marketing these products without FDA approval, most of the companies receiving warning letters have omitted from their drugs’ labeling critical warnings regarding the potential for serious, possibly fatal, interactions with certain other drugs. Based on recent scientific information, the five marketed, approved versions of ergotamine-containing products have updated their labeling to include a box warning (the strongest agency warning) against using such products when also taking potent CYP 3A4 inhibitors, including some antifungal agents, protease inhibitors, and certain antibiotics. CYP 3A4 is a metabolic enzyme that helps the body eliminate drugs or other chemicals. Serious and life-threatening ischemia (a restriction in blood supply), including death and gangrene, have resulted when such products are used together. Most unapproved versions of the drug do not carry these warnings.

“The warning letters we issued are another example of our commitment to the Unapproved Drugs Initiative. We are taking a sensible, risk-based approach to the problem, and remain dedicated to the goal of getting unapproved drugs off the market,” said CDER’s Director of Compliance, Deborah M. Autor. “Doctors and patients often do not realize that not all drugs that are available on the market are backed by FDA approval. We estimate that less than 2% of prescribed drugs are unapproved. This lack of approval undermines FDA’s drug safety efforts. Drugs that skirt the approval process may be unsafe, may not work, and in our experience, often have inadequate labeling.”

Companies have 15 days to respond to the FDA with a discontinuation plan for their products. Manufacturers have 60 days to cease manufacturing of new product, and distributors have 180 days to cease further shipment of existing products. Previously manufactured unapproved ergotamine products may still be found on pharmacy shelves for a short period of time.

FDA’s actions against unapproved drugs are part of the agency’s broader initiative, announced in June 2006, to ensure that consumers and the health care community are provided with established and emerging drug safety information so that they can make the best possible medical decisions about the safe and effective use of drugs.