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Drug combo for migraines too risky for approval.

ROCKVILLE, MD. -- At a meeting last month, members of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee agreed that the risk of tardive dyskinesia associated with the metoclopramide component of a fixed-dose combination pill outweighed the product's benefits for treating migraines.

All 12 panel members found that there was not enough evidence to assume that the intermittent chronic use of the product, which combines metoclopramide with naproxen, did not cause tardive dyskinesia (TD) and that it was not possible to determine a maximum number of monthly doses that could be recommended to avoid the risk of TD.

TD is a well-known side effect of metoclopramide, a neuroleptic dopamine receptor antagonist, although the incidence is unclear, said Eric Bastings, M.D., clinical team leader in the FDA's division of neurology products, Rockville. Although no cases were reported in trials of the fixed-dose combination of 16 mg of metoclopramide with 500 mg of naproxen, called MT 100, the database was too small to detect rare events, he told the panel.

In May 2004, the FDA sent the company a "not approvable" letter, stating that the company had not established that MT 100 was effective for acute treatment of migraine or that the metoclopramide component contributed to the effectiveness, and that there was no evidence to support the company's argument that intermittent long-term use for migraines would not be associated with TD.

The meeting was held to discuss the TD risk associated with the addition of metoclopramide, which is approved in the United States for short-term treatment of gastroesophageal reflux disease and diabetic gastroparesis. The label warns about the risk of TD, which increases with the duration of treatment but may occur after brief periods of treatment at low doses.

The day after the meeting, Pozen Inc., a Chapel Hill, N.C.-based pharmaceutical company, announced in a statement that it would no longer pursue approval of the combination product in the United States, "based on a thoughtful review of the outcome" of the meeting. Contributing to the decision was the company's plan to file an application for approval of another product to treat acute migraines, a combination formulation of sumatriptan and naproxen. Several days later, the company announced that it had submitted the new drug application to the FDA for the sumatriptan-naproxen combination.

In two phase III trials of over 2,000 patients with moderate or severe migraine, the sustained pain response at 24 hours associated with one dose of MT 100 was 4% and 6% above the level achieved with naproxen alone (36% and 32% among MT 100 users vs. 30% and 28% on naproxen alone), which the FDA said was not significant. There were no significant differences in the 2-hour pain response.

Although there were no TD cases reported in trials, the company estimated that the annual incidence of TD at a daily metoclopramide dose of 30-40 mg for 72 days a year would be up to 0.038%. All but 1 of the 12 panelists agreed this was not a reasonable estimate.

Metoclopramide enhances the absorption of naproxen and counteracts gastric stasis associated with migraines, with antinausea and antiemetic effects, according to Pozen.

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Title Annotation:Clinical Rounds; risk of tardive dyskinesia
Author:Mechcatie, Elizabeth
Publication:Family Practice News
Geographic Code:1USA
Date:Sep 15, 2005
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