EMSAM is here!

Let us begin with a question that has been on everybody’s mind: Why is it named “EMSAM?"

It required several phone calls to Bristol-Myers Squibb, but we finally have our answer. Somerset Pharmaceuticals, the original developer of the formulation, held a company-wide contest to see who could come up with the best name for their new product. One employee offered a name that combined the names of his two children, Emily and Sam. The company vetted the name through its branding consultants and focus groups, eventually deciding that EMSAM (in all caps, for unclear reasons) was the winner. We hope the children will get a cut of the profits!

But before shaking your head and saying, “I don’t prescribe this class of drugs, they’re too complicated, they’re too dangerous,” consider that this medication offers patients a potentially valuable therapeutic option with less of the difficulty and potential dangers associated with the other available MAOIs.

As you’ve read elsewhere in this issue, the use of oral MAOIs requires our patients to follow a low tyramine diet to prevent a potentially dangerous hypertensive reaction. What makes EMSAM unique is that it does not require this restrictive diet when prescribed at the lowest dose, the 6 mg patch. (The 9 and 12 mg patches do require the usual MAOI dietary restrictions – more on that later.)

The Early History
EMSAM is the reformulation of an oral MAOI, selegiline, into a skin patch form. Selegiline was discovered in the 1960’s and has been available in the U.S. since 1989 through Somerset Pharmaceuticals under the brand name Eldepryl, approved to treat Parkinson’s Disease. Although selegiline was never FDA-approved as an antidepressant in this country, there has been ample clinical experience and research data demonstrating that it is an effective antidepressant at doses between 30 and 60 mg a day (Bodkin et al, Psychiatric Annals 2001; 31:385-391). In fact, those of us who have prescribed it for depression have found it to be a useful drug with fewer nuisance side effects such as weight gain, sexual dysfunction and edema than other MAOIs such as Nardil (phenelzine). Consistent with this more benign side effect profile was a study by Sunderland et al (Arch Gen Psychiatry 1994;51:607-15) in which selegiline successfully treated major depression in treatment-refractory geriatric patients.

So why wasn’t oral selegiline marketed to psychiatrists? At low doses, up to 10 mg/day (the dose used to treat Parkinson’s Disease), selegiline inhibits only one of the two isoforms of monoamine oxidase enzymes, MAOI-B. Most research has shown that MAO-A inhibition is also necessary to treat depression, and while at higher doses selegeline does inhibit MAO-A, this comes with the disadvantage of requiring the same MAOI dietary limitations as conventional MAOIs. Therefore, there was little economic incentive for Somerset Pharmaceuticals to seek a depression indication for a “me-too” MAOI drug that would likely be prescribed by few psychiatrists.

The MAOI diet and EMSAM
So why does the EMSAM 6 mg patch not require the MAOI diet? And why are low doses in patch form therapeutic when higher doses are required when taken orally? Absorption through the skin sends selegiline directly into the blood stream and toward the brain, sidestepping the liver, where some of the oral MAOI is spent in blocking the breakdown of ingested tyramine. Thus, the patch is able to generate higher levels of MAO-A and MAO-B inhibition in the brain at lower doses with much less inhibition of gut and liver MAO-A. There is enough inhibition of MAO in the brain to produce a therapeutic antidepressant effect, and the absence of MAOI in the liver allows tyramine to be inactivated by intestinal MAO, thereby minimizing the danger of a hypertensive reaction.

The FDA Ruling
Let’s return to the FDA decision to limit the removal of MAOI dietary restrictions for the 6 mg patch only, thus creating the complicating situation for clinicians in which pushing the dose to 9 mg or 12 mg requires instructing patients to initiate the MAOI diet. (The FDA hearings on this issue, in all of its 243-page glory, can be viewed at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4186T2.pdf)

How did the FDA determine that 6 mg was the only safe dose? Somerset presented results of a “tyramine pressor test” in which patients were fed tyramine under experimentally controlled research conditions. (In one study, research subjects were asked to eat a few pounds of cheddar and blue cheese over a two hour period!) The increase in blood pressure was only slightly greater for subjects gorging on tyramine with the 6 mg EMSAM patch than for those who ingested tyramine while taking the control drugs, 20 mg fluoxetine or 10 mg oral selegiline. There was enough research data and patient experience to satisfy the FDA that subjects on the 6 mg patch could eat all the tyramine they wanted without incurring any hypertensive risk.

But what did the research data say about the risk of tyramine at the higher doses of EMSAM, such as 9 mg? While there was evidence of a greater potential of a hypertensive effect, the tyramine risk was still much less than found with the comparator classic MAOI, Parnate. However, far fewer subjects were tested at this higher dose than at the 6 mg dose. Thus the manufacturer opted to play it safe in not requesting the lifting of dietary restrictions on the 9 mg dose, even though their naturalistic data set included about 800 people who were on either the 9 or 12 mg patch, had not followed an MAOI diet, and had no problems with hypertension.

From a medico-legal perspective, pending more data, we clinicians may feel equally compelled to recommend an MAOI diet for patients on the 9 and 12 mg patches.

At all doses, EMSAM carries the same medication restrictions as other MAOIs. But here as well some data endorses the cardiovascular safety of sympathomimetics combined with EMSAM (Feinberg, J Clin Psychiatry 2004; 65:1520-1524) and, in particular, Sudafed (pseudoephedrine) in combination with the 6 mg dose of EMSAM (Patkur et al, CNS Spectr 2006;11:363-375).

Efficacy, Side Effects
T hus far, all of the EMSAM efficacy studies have compared it to placebo, so we have no head-to-head data versus other antidepressants. Using the research studies done with oral MAOIs as a guide, we would assume that EMSAM might yield some advantages over tricyclics and possibly other classes (for instance in treating atypical or treatment-resistant ment-resistant depression) but we’ll need more studies to know just how effective EMSAM is, and to convince us that its high cost ($14/patch) is worth the investment.

n the FDA studies and early clinical experience, side effects of EMSAM have included local skin irritation, requiring the daily rotation of the patch site, as well as insomnia (patients sleep better when they remove the patch prior to bed time). Orthostatic hypotension, which is a far more common problem with previous MAOIs than hypertensive crisis, appears to be less problematic with EMSAM. Other common MAOI related side effects such as weight gain and sexual side effects also do not appear to be as common with EMSAM. Again we await more experience and data but this side effect profile certainly appears more user-friendly.

TCPR Verdict:
EMSAM: Could be time to conquer your MAOI phobia!