The lowest dose of a new transdermal formulation of selegiline, a
monoamine oxidase inhibitor (MAOI) antidepressant, should not be required to
carry long-standing warnings about avoiding dietary intake of foods high in
tyramine, an advisory panel of the U.S. Food and Drug Administration (FDA)
told the agency.
Joseph Berger, M.D. (left), discusses an action paper with colleague Ray
Freebury, M.D., at last month's meeting of the APA Assembly. Berger and
Freebury are the representatives from the Ontario District Branch. See page
9 for coverage of the
By a vote of 7-4, members of the FDA's Psychopharmacologic Drugs Advisory
Committee (PDAC) recommended in October that the 20 mg skin patch be marketed
without the restrictions found on all MAOIs marketed to date. In a second vote
by the same count, PDAC members said it was permissible to market the 20 mg
patch without dietary restrictions, even if two higher doses carried the
warnings. Final approval is expected in the first half of 2006.
The selegiline transdermal patch—to be marketed by Somerset
Pharmaceuticals under the trade name Emsam—will be available in 20 mg,
30 mg, and 40 mg strengths. Somerset had already reached agreement with the
FDA that the two higher doses will carry the standard dietary warning;
however, the company said the lowest dose was safe and should be marketed
without any need for patients to watch their diets.
Because an internal FDA review of the data concluded that all three doses
should carry dietary restrictions, the agency chose to put the issue before
the advisory committee.
The PDAC's recommendations are not binding on the agency, which will make a
final decision on the labeling for the patches within the next few months.
Somerset (a joint venture of Mylan and Watson Pharmaceuticals) received
tentative FDA marketing approval for 20 mg, 30 mg, and 40 mg doses of selegine
in January 2004; however, the agency expressed concern about the safety of the
drug and the need for dietary restrictions. Somerset filed its response to
those concerns this past May 26.
Selegiline is a nonselective MAOI, inhibiting not only the MAO-B enzyme in
the central nervous system, but also MAO-A elsewhere in the body. In the
digestive tract, MAO-A normally metabolizes tyramine, a dietary amine that is
found in high concentrations in foods such as aged cheese and red wine.
The breakdown of tyramine in the gut prevents significant amounts of it
from being absorbed and circulated throughout the body. Tyramine is a potent
pressor— leading to constriction of blood vessels— which
ultimately results in increased blood pressure. High amounts of tyramine can
lead to hypertensive crises, resulting in stroke, heart attack, and even
Because the medication is absorbed from the skin patch and bypasses the gut
wall, it is thought that transdermal selegiline will have a significantly
reduced effect on MAO-A in the digestive tract. In addition, at lower doses,
selegiline is thought to inhibit MAO-B preferentially, while at higher doses
both A and B isoenzymes are effected. With significantly reduced inhibition of
digestive tract MAO-A, dietary restrictions would not be necessary, the
Thomas Laughren, M.D., head of psychiatry products at the FDA, wrote in a
memo to PDAC members, "Having to worry about diet is a major
disincentive to using the orally available MAOIs in the U.S."
Appearing before the committee, FDA staff reviewer Greg Dubitsky, M.D.,
strongly argued that the clinical trial data regarding tyramine sensitivity in
patients wearing selegiline patches was highly variable, and for that reason
said he could not conclude that it was safe to market the 20 mg dose without
dietary restrictions. He urged that dietary warnings be put on the labels of
all three doses of the patch.
In the end, though, the majority of PDAC members were not swayed by
"I am convinced that there is no harm signal in either the clinical
trials data that were represented or the more extensive database for the use
of Eldepryl [selegiline in pill form]," said Wayne Goodman, M.D., PDAC
chair and a professor of psychiatry at the University of Florida.
Goodman said that "benefit is clearly an issue here," noting
the unique new dose formulation will present patients with an entirely new
option. "We do have other MAOIs on the market," he said,"
but it's clear to me that this is going to produce far less risk than
our existing medications."
More information on the PDAC's consideration of Emsam is posted at<www.fda.gov/ohrms/dockets/ac/05/briefing/disclaimer.htm>.▪