Benefits and Side Effects of the Selegeline Transdermal System

Donald S. Robinson, MD

Consultant, Worldwide Drug Development

Introduction

A new formulation of the monoamine oxidase inhibitor (MAOI) selegiline was recently approved for the treatment of major depressive disorder (MDD). This once-daily transdermal patch known as the selegiline transdermal system (STS) offers an important advantage over existing MAOIs. STS carries significantly lower liability for tyramine-induced acute hypertensive reactions, allowing much more dietary latitude than is possible with the oral MAOIs. While MAOIs were the first antidepressants and have sustained a reputation of unsurpassed efficacy,¹ their clinical utility has been markedly restricted by the liability for severe and sometimes fatal hypertensive reactions resulting from ingesting a meal of high tyramine content.²

Dosage Forms of Selegiline Transdermal System

STS (EMSAM) is supplied in three different doses for the treatment of MDD. Depending on the size, a patch delivers on average either 6 mg (20 cm²), 9 mg (30 cm²), or 12 mg (40 cm²) of selegiline to the systemic circulation over a 24-hour period (patch size differs by dose). The Food and Drug Administration requires standard nomenclature for dermal drug formulations that specify the quantity of drug systemically delivered over a 24-hour period rather than the drug content of the patch. The recommended initial dose is STS 6 mg/24-hour, with subsequent titration to higher doses if indicated, depending on clinical response of the patient. While patients treated with STS 6 mg/24-hour are allowed an unrestricted diet, higher STS doses will require a patient to observe dietary modifications.

Gastrointestinal Barrier to Tyramine Absorption

Selegiline is an irreversible MAOI with relative selectivity for the MAO-B isoenzyme; however, at higher concentrations selegiline also inhibits the MAO-A isoenzyme. This latter attribute is necessary for antidepressant efficacy. Oral selegiline, approved as adjunct treatment for late-stage Parkinson’s disease at a dose of 5 mg BID, does not require a special diet. However, an oral dose of 30–60 mg/day required for antidepressant efficacy because of the poor oral bioavailability of selegiline necessitates dietary restrictions.¹ By delivering drug via the skin directly into the systemic circulation and avoiding exposure of gastrointestinal tissues to high selegiline concentrations, STS achieves therapeutic brain concentrations while preserving the monoamine oxidase barrier in intestinal mucosa and liver to the systemic absorption of tyramine. Tyramine, an indirectly acting sympathomimetic amine, acts on sympathetic nerves to raise blood pressure (BP) by displacing stored norepinephrine in nerve endings.

Tyramine Sensitivity

Extensive tyramine sensitivity studies conducted by the manufacturer of STS show that there is minimal change in sensitivity to an oral dose of tyramine when administered to subjects treated with the STS 6 mg/24-hour, the recommended initial dose.³ Quantities of tyramine (administered fasting as capsules to maximize bioavailability) averaged in excess of 200 mg to produce a detectable increase in BP (30 mm Hg) in subjects treated at this STS dose. By comparison, typical sample meals consisting of tyramine rich substances have an estimated tyramine content of ≤40 mg.⁴ As a positive control, the MAOI tranylcypromine, in contrast to STS, produced marked BP elevations in all subjects at a tyramine dose of 10 mg, and tyramine sensitivity of subjects was increased more than 40-fold.

Several placebo-controlled trials employing an STS 6 mg/24-hour fixed-dose have demonstrated efficacy in the treatment of MDD.^5-7 Except for the initial trial conducted before tyramine sensitivity data were available, patients in all subsequent STS clinical studies were allowed unrestricted diets without being advised to modify their diet. Based on the findings of the tyramine sensitivity studies and the extensive safety data accrued in clinical trials, the FDA approved product labeling⁸ that allows STS 6 mg/24-hour to be prescribed without the dietary precautions required of other MAOIs.

Effects of higher doses (STS 9 mg/24-hour, 12 mg/24-hour) on tyramine sensitivity have been extensively investigated in clinical pharmacology studies. The safety and efficacy of these higher STS doses were also assessed in phase III clinical trials. While tyramine sensitivity was found to be increased 4.5-fold (average) at a STS 12 mg/24-hour dose, it was necessary for subjects to ingest a minimum of 75 mg of tyramine with a meal before detecting a BP increase. This quantity of tyramine remains considerably higher than the amount consumed in sample meals that included tyramine rich foods.⁴ Clinical trials without dietary restrictions employing dose titration over a range of STS 6–12 mg/24-hour have similarly found these higher doses to be safe and well tolerated without a single occurrence of acute hypertensive crisis in spite of the unrestricted diet.

Dietary Tyramine Modifications at STS 9 mg/Day and 12 mg/Day

In concurrence with the FDA, until more extensive safety data become available at higher doses, the drug manufacturer recommends that patients treated with STS at 9 mg/24-hour and 12 mg/24-hour doses observe dietary modifications to avoid potential sources of excessive tyramine content. Protein food substances subjected to fermentation processes can contain high levels of tyramine and should be avoided.⁹ Examples are unpasteurized and tap beers, aged meats and cheeses, sauerkraut, fava bean pods, and most soybean products such as soy sauce and tofu. Nutritional supplements containing tyramine should also be avoided. All fresh meats, poultry, fish, vegetables, and dairy products are acceptable, as are soy milk, brewer’s and baker’s yeast, wines, and canned beers. While it is unlikely that a typical meal would exceed 40 mg of tyramine, and even though tyramine sensitivity tests found that no STS 12 mg/24-hour–treated subjects had BP increases at a dose <75 mg of tyramine ingested with a meal, it is advisable that patients treated with STS 9 or 12 mg/24-hour avoid potentially rich sources of tyramine. It is similarly recommended that STS-treated patients follow dietary recommendations for 2 weeks following reduction in dose to STS 6 mg/24-hour, or following discontinuation.

Drug Interactions with STS

The clinical syndrome referred to as the “serotonin syndrome” is a manifestation of untoward drug interactions with an MAOI. This potentially fatal central nervous system (CNS) toxicity has been reported with co-administration of non-selective MAOIs and various CNS-active drugs, including antidepressants, amphetamines and other sympathomimetic agents, meperidine, and pentazocine. The pharmacologic mechanism of this reaction is not well understood but appears to involve enhanced serotonergic and noradrenergic activity of the CNS due to the combined effects of these agents with an MAOI. In the clinical program, a single case of serotonin syndrome has been reported in a patient who surreptitiously self-medicated with multiple prohibited drugs during STS treatment. To avoid this drug interaction, it is recommended that prohibited CNS-active drugs be washed out for 4–5 half-lives (usually 1 week, except for fluoxetine) before starting treatment with STS. When switching from STS to other agents, a 2-week washout is recommended to allow sufficient time for regeneration of tissue MAO to occur.

Side Effects of STS

Adverse effects (AE) incidence data from controlled trials in depression show that the two principal AEs associated with STS at a 6 mg/24-hour dose in comparison with placebo are local skin reactions (22% versus 12%) and insomnia (10% versus 7%). These side effects are dose-related: patients treated with STS 9–12 mg/24-hour had higher incidences of skin reactions (44%) and insomnia (32%). Other AEs in placebo-controlled trials that appear to be dose-related were dry mouth, dizziness, and nervousness. These STS side effects are consistent with those reported for other MAOIs. Side effects were an infrequent reason for premature discontinuation from study treatment in the STS clinical trials. The majority of application site reactions required no treatment, and the skin reactions gradually faded as the sites were rotated. Skin reactions warranting treatment responded to topical corticosteroids, usually over-the-counter hydrocortisone. Insomnia was often managed with standard hypnotic agents if the side effect was severe.

Side effects proven to be particularly troublesome with other MAOIs include orthostatic hypotension, sexual dysfunction, excessive weight gain, and peripheral edema. However, for the STS patch, these side effects seem to be either minimal or of lower incidence than expected for this class of antidepressant. Orthostatic hypotension was dose-related and more frequent in STS-treated patients but generally not symptomatic. Symptoms of sexual dysfunction had low AE incidences in STS and placebo-treated patients, and sexual questionnaire data from controlled trials¹⁰ showed no evidence of drug-induced impairment of sexual functioning for either men or women. Excessive weight gain and peripheral edema with long-term treatment were not encountered during STS therapy.

Conclusion

STS, a transdermal patch formulation of the MAOI selegiline, has been recently approved for the treatment of MDD. STS represents a therapeutic advance over existing MAOIs because of its low liability for tyramine-induced hypertensive reactions. Although studied over a dose range of STS 6–12 mg/24-hour in treating patients on unrestricted diets with no occurrences of hypertensive episodes, safety data currently support the safe use of STS 6 mg/24-hour without dietary modifications. At higher STS doses, it is prudent to observe dietary precautions to avoid foods high in tyramine, although compared with the oral MAOIs, STS at all therapeutic doses appears to be considerably safer.

STS was well tolerated in clinical depression studies, with the principal side effects noted being local dermal reactions and insomnia, both of which were dose-related. Other side effects commonly encountered with MAOIs, such as postural hypotension, sexual dysfunction, excessive weight gain, and peripheral edema were either infrequent or not evident. STS represents a useful addition to the existing array of antidepressants.

References

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7. Robinson DS, Moonsammy G, Azzaro AJ. Relapse prevention study shows the long-term safety and efficacy of transdermal selegiline, a new generation MAOI. Poster presented at: the 41st Annual Meeting of the American College of Neuropsychopharmacology; December 11, 2002; San Juan, Puerto Rico.

8. EMSAM [package insert]. New York, NY: Bristol-Myers Squibb; 2006.

9. Shulman KI, Walker SE. A reevaluation of dietary restrictions for irreversible monoamine oxidase inhibitors. Psychiatr Ann. 2001;31(6):378-384.

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