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FDA Halts Marketing of Off-Label Ergotamine Therapies for Migraine

Stepping up its efforts to go after the illegal marketing of off-label drugs, the FDA warned 20 companies last month to stop marketing unapproved ergotamine drugs for migraine. Ergotamine, a vasoconstrictor, is derived from a rye fungus, ergot, from which LSD also can be synthesized. The list of companies and products is posted online at www.fda.gov/CDER/drug/unapproved_drugs/ergotamine_WL.htm.

The FDA said the 20 drug companies failed to warn consumers against using such products when taking CYP 3A4 inhibitors, including macrolide antibiotics (erythromycin, troleandomycin, clarithromycin); HIV protease or reverse transcriptase inhibitors (ritonavir, indinavir, nelfinavir, delavirdine); or azole antifungals (kenoconazole, intraconazole, voriconazole). Less potent inhibitors include grapefruit juice, fluoxetine, fluvoxamine, saquinavir, nefazodone, zileuton, and clotrimazole.

CYP 3A4 is a metabolic enzyme that helps the body eliminate drugs or other chemicals. Serious and life-threatening ischemia, including death and gangrene, have occurred when the products are used together.

Five ergotamine-containing products are approved for marketing in the US: Migergot suppository; Ergotamine tartrate with caffeine tablets; Cafergot tablets; and Ergomar sublingual tablets

These products are indicated for the treatment of vascular headaches, including migraine, and labeling for them carries a black-box warning — the FDA's strongest caution — alerting prescribers to the dangers of taking them with CYP 3A4 inhibitors.

But it's not clear how often neurologists prescribe ergotamine therapies for migraine these days. “Prior to the advent of the triptans for migraine, many patients regularly used ergotamine-containing medications for acute migraine headache,” Gretchen Tietjen, MD, professor and chair of the department of neurology at the University of Toledo Medical Center in OH, told Neurology Today in an e-mail.

“The ergotamine products had to be paired with anti-emetics, because nausea is a prominent side effect,” she said. “Overuse, particularly of those preparations paired with caffeine, frequently leads to rebound headache, and more rarely to pain or coolness in the distal extremities (‘ergotism’) secondary to vasoconstriction.

“Although, I frequently use intravenous or intramuscular dihydroergotamine for intractable migraine, it has been many years since I have prescribed any other ergotamine-containing products,” Dr. Tietjen said.

“Until reading the FDA announcement I was not aware that these and similar products were even available,” she continued. “I support the FDA effort to ensure that available medications are both safe and effective, and that product information is correct and regularly updated.”

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