Medications: Emsam^® – selegiline

EMSAM® (selegiline transdermal system) is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of major depressive disorder (MDD) (1).

DOSAGE AND ADMINISTRATION

EMSAM should be applied to dry, intact skin on the upper torso (below the neck and above the waist), upper thigh or the outer surface of the upper arm once every 24 hours (2.1).

• Initial Treatment: The recommended starting dose and target dose for EMSAM is 6 mg per 24 hours (2.1). Based on clinical judgment, dose increases should occur in increments of 3 mg per 24 hours (up to a maximum dose of 12 mg per 24 hours) at intervals of no less than 2 weeks (2.1).
• Geriatric Use: The recommended dose for elderly patients (65 years and older) is EMSAM 6 mg per 24 hours daily (8.5).
• Dietary Modifications with EMSAM 9 mg per 24 hours and 12 mg per 24 hours: Tyramine-rich foods and beverages should be avoided beginning on the first day of EMSAM 9 mg per 24 hours or 12 mg per 24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours (2.3).

Adverse Reactions occurring at an incidence of 2% or More Among EMSAM-Treated Patients and greater than placebo: Application site reaction, headache, insomnia, diarrhea, dry mouth, dyspepsia, rash, pharyngitis, sinusitis (6.1).

• Serotonergic drugs: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), clomipramine and imipramine, meperidine, tramadol, methadone, pentazocine, and propoxyphene; and the antitussive agent dextromethorphan should not be used with EMSAM because of a risk of serotonin syndrome (4, 5.2).
• Carbamazepine should not be used with EMSAM (4, 5.3).
• After stopping treatment with contraindicated medication, a time period equal to 4 to 5 half-lives (approximately one week) of the drug or any active metabolite should elapse before starting therapy with EMSAM. Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with EMSAM (4).
• At least 2 weeks should elapse after stopping EMSAM before starting therapy with a drug that is contraindicated with EMSAM (4).
• EMSAM is contraindicated in patients less than 12 years of age (4, 8.4).
• Pheochromocytoma (4).

WARNINGS AND PRECAUTIONS:

• Tyramine-Induced Hypertensive Crisis: Patients receiving EMSAM 9 mg per 24 hours and 12 mg per 24 hours should follow the recommended dietary modifications (5.3).
• Blood Pressure Elevation Related to Concomitant Medication: monitor blood pressure if EMSAM is used with any of the following drugs: buspirone, amphetamines, or cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). If a hypertensive crisis occurs, EMSAM should be discontinued immediately and therapy to lower blood pressure should be instituted immediately (5.3).
• Activation of Mania/Hypomania: Screen patients for bipolar disorder (5.4).
• External Heat: Avoid exposing the EMSAM application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight (5.5).

• Serious, sometimes fatal, central nervous system (CNS) toxicity referred to as the “serotonin syndrome” has been reported with the combination of nonselective MAOIs and serotonergic drugs.
• EMSAM has the capacity to inhibit intestinal MAO, which is responsible for the catabolism of tyramine in food and beverages. As a result of this inhibition, large amounts of tyramine may enter the systemic circulation and precipitate a sudden, large rise in blood pressure or hypertensive crisis
• The use of EMSAM with sympathomimetic amines or buspirone may produce substantial elevations in blood pressure.
• No dose adjustment for EMSAM is needed when EMSAM is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4 inhibitors (e.g., ketoconazole). No clinically meaningful change in selegiline exposure was seen when EMSAM was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole [see Clinical Pharmacology (12.3)].
• No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperdione, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with EMSAM. EMSAM had no clinically relevant effect on pharmacokinetics of these drugs.

EMSAM overdosage may resemble overdosage with other nonselective, oral MAOI antidepressants and present with any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

Management of Overdose: There are no specific antidotes for EMSAM. If symptoms of overdosage occur, immediately remove the EMSAM system and institute appropriate supportive therapy. For contemporary information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur, and peak effects may not be observed for 24 to 48 hours. Since death has been reported following overdosage with MAOI agents, hospitalization with close monitoring during this period is strongly recommended. In order to avoid the occurrence of hypertensive crisis (“cheese reaction”), dietary tyramine should be restricted for several weeks beyond recovery to permit regeneration of the peripheral MAO-A isoenzyme.There are no specific antidotes for EMSAM. If symptoms of overdosage occur, immediately remove the EMSAM system and institute appropriate supportive therapy. For contemporary consultation on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222- 1222.

EMSAM is considered to be an irreversible MAOI at therapeutic doses and, in overdosage, is likely to cause excessive MAO-A inhibition, and may result in the signs and symptoms resembling overdosage with other non-selective, oral MAOI antidepressants [e.g., tranylcypromine (Parnate^®), phenelzine (Nardil^®), or isocarboxazide (Marplan^®)].

Overdosage with Non-Selective MAO Inhibition

NOTE: The following is provided for reference only; it does not describe events that have actually been observed with selegiline in overdosage. No information regarding overdose by ingestion of EMSAM is available.

Typical signs and symptoms associated with overdosage of non-selective MAOI antidepressants may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur, and peak effects may not be observed for 24 – 48 hours. Since death has been reported following overdosage with MAOI agents, hospitalization with close monitoring during this period is essential.

Overdosage with MAOI agents is typically associated with CNS and cardiovascular toxicity. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Type and intensity of symptoms may be related to extent of the overdosage.

Treatment should include supportive measures, with pharmacological intervention as appropriate. Symptoms may persist after drug washout because of the irreversible inhibitory effects of these agents on systemic MAO activity. With overdosage, in order to avoid the occurrence of hypertensive crisis (“cheese reaction”), dietary tyramine should be restricted for several weeks beyond recovery to permit regeneration of the peripheral MAO-A isoenzyme.