The U.S. Food and Drug Administration (FDA) granted final approval February
28 to market the skin-patch formulation of the monoamine oxidase inhibitor
(MAOI) selegiline for the treatment of major depression.
The new skin patch, developed by Somerset Pharmaceuticals, will be marketed
in the U.S. by Bristol-Myers Squibb Company under the brand name Emsam.
In announcing the approval, Steven Galson, M.D., M.P.H., director of the
FDA's Center for Drug Evaluation and Research, noted, "Emsam provides a
significant advance because, at least in the lowest dose, patients can use the
drug without the usual dietary restrictions associated with these types of
MAOIs have long been considered highly effective, particularly in patients
with atypical depression, which DSM-IV-TR characterizes as presenting
with "mood reactivity, increased appetite or weight gain, hypersomnia,
leaden paralysis, and a long-standing pattern of extreme sensitivity to
perceived interpersonal rejection."
However, use of MAOIs has also been limited by the drugs' ability to block
the monoamine oxidase enzyme (MAO) not only in the central nervous system, but
throughout the body.
The highest concentrations of MAO are found in the liver, kidney, stomach,
intestinal wall, and brain. MAOs are subclassified into two types, A and B,
which differ in their specificity and actions, as well as where each is found
in the body. In humans, most of the MAO in the brain is type B, while in the
digestive tract, for example, MAO is predominantly type A.
In brain neurons, MAO plays an important role in the metabolism of the
catecholamines dopamine, norepinephrine, and epinephrine, and to a lesser
extent serotonin. As such, MAOIs are commonly referred to as "triple
amine drugs." MAOs are also important in the metabolism of various
amines found in a variety of foods and drugs.
MAO in the GI tract and liver (primarily type A), for example, is thought
to provide protection from high blood levels of the amine, tyramine. Tyramine
has the capacity, if absorbed intact, to cause a "hypertensive
crisis," also known as the "cheese reaction," because
tyramine is found in large amounts in fermented cheese, red wine, herring, and
over-the-counter cough/cold medications. High amounts of tyramine lead to the
release of excessive amounts of norepinephrine from adrenergic neurons
throughout the body. It is this release of norepinephrine that causes the rise
in systemic blood pressure.
In theory, at the doses of selegiline used therapeutically in the skin
patch (for example, 10 mg a day), MAO-A in the gut is not inhibited, which
would free patients from having to watch diet and other medications that could
also increase tyramine levels or stimulate release of norepinephrine. At
higher doses, selegiline inhibits both MAO-A and MAO-B.
The Emsam patch will be available in doses equivalent to 6 mg, 9 mg, and 12
mg absorbed in a 24-hour period. Clinical trials data on the 6 mg dose showed
no inhibition of MAO-A, and therefore the lowest dose will not be labeled with
patient warnings regarding diet. However, both the 9 mg and 12 mg patches will
carry dietary warnings.
In addition, Somerset and BMS have agreed to develop a patient-education
campaign regarding dietary modifications necessary when using the two higher
doses. The companies have pledged to monitor reports of adverse events.
In clinical trials, the most common treatment-emergent adverse events
included skin reaction to the patch (24 percent with Emsam, 12 percent with
placebo), headache (18 percent versus 17 percent), insomnia (12 percent versus
7 percent), and diarrhea (9 percent versus 7 percent).
Alexander Bodkin, M.D., chief of the Clinical Psychopharmacology Research
Program at Harvard University/McLean Hospital, noted that the need for other
treatment options "is indeed great: some 30 percent of all patients who
seek treatment and receive SSRIs or SNRIs do not respond to the medication.
Many then end up taking combinations of two or more antidepressants in an
attempt to get an effect on all three monoamines, such as an SSRI plus
bupropion or CNS stimulants. With selegiline, all three monoamines are
covered, and the data show onset of action is very quick—within the
first day to seven days." Bodkin was a principal investigator on several
clinical trials of the Emsam patch.
More information is posted at<www.bms.com>.▪