GAITHERSBURG, MD. — The lowest dose of a transdermal formulation of an MAO inhibitor could become available for treating depression, with no dietary restrictions, if the Food and Drug Administration follows the majority opinion of one of its advisory panels.
At a meeting in late October, the FDA's Psychopharmacologic Drugs Advisory Committee voted 7–4 that the available data supported the “reasonable safety” of the 20-mg formulation of a transdermal patch containing the irreversible MAO inhibitor selegiline without a recommendation to restrict aged cheeses and other tyramine-rich foods in the diet. The 20-mg strength is the lowest of three doses of a transdermal patch containing selegiline currently under review at the FDA for approval as a treatment for major depressive disorder. The FDA usually follows the advice of its advisory panels.
The selegiline patch would be the first transdermal medication approved to treat depression, and the 20-mg formulation would be the first MAO inhibitor approved for treating depression without dietary tyramine restrictions. If approved, the manufacturer, Somerset Pharmaceuticals, will market the patch under the trade name Emsam. An oral formulation of selegiline is approved and marketed as Eldepryl for Parkinson's disease, with no dietary restrictions recommended. Unlike the transdermal formulation, the oral formulation does not achieve antidepressant levels in the central nervous system, according to Somerset.
In three studies lasting 6, 8, or 52 weeks, treatment with 20 mg, 30 mg, and 40 mg of Emsam was significantly more effective than placebo in treating depression, based on different primary end points.
Thirty mg and 40 mg formulations of the patch are also under review at the FDA, but the company and agency have agreed that dietary restrictions would be recommended for those strengths.
Panel chair Wayne K. Goodman, M.D., who voted for approval with no dietary restrictions for the 20-mg dose, said he saw no signal of harmful effects of the 20-mg patch in clinical safety data presented by the manufacturer and in the more extensive database on Eldepryl.
“Benefit is clearly an issue here … we have other MAO inhibitors on the market, but it is clear to me that this is going to produce far less risk than the existing medications” in terms of hypertensive reactions, said Dr. Goodman, chair of the department of psychiatry at the University of Florida, Gainesville.
Based on safety data presented by the manufacturer, “it is abundantly clear” that all three doses were safer in terms of the risk of hypertensive reactions than the MAO inhibitor tranylcypromine (Parnate), said Dr. Goodman, also of the McKnight Brain Institute in Gainesville.
Carol A. Tamminga, M.D., pointed out while the patch does not provide a new mechanism of action for an antidepressant, “it is a mechanism of action that any psychiatrist would say is really woefully underused” and that the lack of a dietary restriction for the lower dose could encourage its use.
Those considerations did carry some weight on the safety issue.
The panelists voting no cited the small number of people in tyramine challenge studies and concern that patients might not understand that the dietary restrictions would continue to apply to the 30-mg and 40-mg strengths of the selegiline patch.
The FDA and the manufacturer have agreed that restrictions should be recommended for the two higher doses, based on the available data, but they did not agree on the need for such a restriction for the 20-mg dose.
The company believes that all three doses are safe without dietary restrictions, but fewer clinical trial data are available on the two higher doses.
When delivered transdermally, selegiline enters the systemic circulation directly and reaches the brain. The amount that reaches the intestine is only a fraction of the amount that reaches the GI tract when taken orally, according to Somerset. (The 20-mg patch delivers about 6 mg of selegiline over 24 hours; the 30-mg and 40-mg patches deliver 9 mg and 12 mg of selegiline, respectively.) A hypertensive crisis induced by tyramine occurs between 10 minutes and 2 hours after a high tyramine meal.
Among the main findings of 14 tyramine challenge studies conducted by the manufacturer was that the 20-mg strength of transdermal selegiline, 10 mg of oral selegiline, and 60 mg of fluoxetine resulted in similarly low levels of intestinal MAO inhibition, according to Somerset.
The challenge studies—conducted in 14 healthy people exposed to 20 mg, 30 mg, and 40 mg of transdermal selegiline for up to 96 days—included food challenges in which subjects who received 20 mg of transdermal selegiline were able to eat all the cheese they wanted without reaching the blood pressure end point (an increase of 30 mm Hg in systolic blood pressure).
Other safety data provided by the company looked at oral selegiline, which has been used to treat 1.6 million people since it was approved in 1989. Between 1997 and 2005, four cases of hypertensive crisis in patients on Eldepryl were reported to the FDA's Adverse Event Reporting System (AERS), a voluntary reporting system. Three of those cases were subsequently determined not to be related to tyramine. No details were available on the fourth report.
In another study of oral Eldepryl for treating parkinsonism in 800 patients, with 2,970 patient years of exposure, mortality among those on selegiline (2.1%) was similar to an age-matched population (2.7%), and the incidence of cardiovascular or cerebrovascular events was similar among treated patients and those on placebo.
And in studies of 2,503 patients with major depressive disorder evaluating the three selegiline patch strengths, with no dietary modifications, there were no cases of hypertensive crisis in treated patients and no deaths.
Gregory Dubitsky, M.D., of the FDA's division of psychiatry products, Rockville, Md., said that on average, a reasonable safety margin appeared to exist for the 20-mg patches, with no tyramine restrictions. But Dr. Dubitsky pointed out that it was possible that a small proportion of patients at all doses could experience an increase in tyramine sensitivity that could be potentially hazardous.
Among the FDA's concerns was that rare hypertensive reactions have been reported at recommended doses of oral selegiline, after eating tyramine-containing food, information that is included on the Eldepryl label.
Other concerns included the considerable variability in the pressor doses between subjects and within subjects in the studies, and the potential for misuse and confusion once Emsam was marketed—if one dose but not others were approved with no restrictions.
The company is planning an education program for physicians and patients about the proper use of the drug and the need for dietary modifications for the 30-mg and 40-mg strengths.
It also plans to look for cases of hypertensive crisis and other cardiovascular events in people prescribed the drug.
In 2005, 0.1% of all antidepressant prescriptions were for an MAO inhibitor, according to data from IMS provided by Somerset at the meeting.
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