Emsam (Selegiline Transdermal) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Alcohol

The pharmacokinetics and pharmacodynamics of alcohol (0.75 mg/kg) alone or in combination with EMSAM 6 mg/24 hours for 7 days of treatment was examined in 16 healthy volunteers. No clinically significant differences were observed in the pharmacokinetics or pharmacodynamics of alcohol or the pharmacokinetics of selegiline during co-administration. Although EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg/kg) and failed to alter the pharmacokinetic properties of alcohol, patients should be advised that the use of alcohol is not recommended while taking EMSAM.

Alprazolam

In subjects who had received EMSAM 6 mg/24 hours for 7 days, co-administration with alprazolam (15 mg/day), a CYP3A4/5 substrate, did not affect the pharmacokinetics of either selegiline or alprazolam.

Carbamazepine

Carbamazepine is an enzyme inducer and typically causes decreases in drug exposure; however, slightly increased levels of selegiline and its metabolites were seen after single application of EMSAM 6 mg/24 hours in subjects who had received carbamazepine (400 mg/day) for 14 days. Changes in plasma selegiline concentrations were nearly two-fold, and variable across the subject population. The clinical relevance of these observations is unknown. Carbamazepine is contraindicated with MAOIs, including selegiline (see CONTRAINDICATIONS).

Ibuprofen

In subjects who had received EMSAM 6 mg/24 hours for 11 days, combined administration with the CYP2C9 substrate ibuprofen (800 mg single dose) did not affect the pharmacokinetics of either selegiline or ibuprofen.

Ketoconazole

Seven-day treatment with ketoconazole (200 mg/day), a potent inhibitor of CYP3A4, did not affect the steady-state pharmacokinetics of selegiline in subjects who received EMSAM 6 mg/24 hours for 7 days and no differences in the pharmacokinetics of ketoconazole were observed.

Levothyroxine

In healthy subjects who had received EMSAM 6 mg/24 hours for 10 days, single dose administration with levothyroxine (150 µg) did not alter the pharmacokinetics of either selegiline or levothyroxine (as judged by T₃ and T₄ plasma levels).

Olanzapine

In subjects who had received EMSAM 6 mg/24 hours for 10 days, co-administration with olanzapine, a substrate for CYP1A2, CYP2D6, and possibly CYP2A6, did not affect the pharmacokinetics of either selegiline or olanzapine.

Phenylpropanolamine (PPA)

In subjects who had received EMSAM 6 mg/24hours for 9 days, co-administration with PPA (25 mg every 4 hours for 24 hours) did not affect the pharmacokinetics of PPA. There was a higher incidence of significant blood pressure elevations with the co-administration of EMSAM and PPA than with PPA alone, suggesting a possible pharmacodynamic interaction. It is prudent to avoid the concomitant use of sympathomimetic agents with EMSAM.

Pseudoephedrine

EMSAM 6 mg/24 hours for 10 days, co-administered with pseudoephedrine (60 mg, 3 times a day) did not affect the pharmacokinetics of pseudoephedrine. The effect of pseudoephedrine on EMSAM was not examined. There were no clinically significant changes in blood pressure during pseudoephedrine administration alone, or in combination with EMSAM. Nonetheless, it is prudent to avoid the concomitant use of sympathomimetic agents with EMSAM.

Risperidone

In subjects who had received EMSAM 6 mg/24 hours for 10 days, co-administration with risperidone (2 mg per day for 7 days), a substrate for CYP2D6, did not affect the pharmacokinetics of either selegiline or risperidone.

Tyramine

Selegiline (the drug substance of EMSAM) is an irreversible inhibitor of monoamine oxidase (MAO), a ubiquitous intracellular enzyme. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline shows greater affinity for MAO-B; however, as selegiline concentration increases, this selectivity is lost with resulting dose-related inhibition of MAO-A. Intestinal MAO is predominantly type A, while in the brain both isoenzymes exist.

MAO plays a vital physiological role in terminating the biological activity of both endogenous and exogenous amines. In addition to their role in the catabolism of monoamines in the CNS, MAOs are also important in the catabolism of exogenous amines found in a variety of foods and drugs. MAO in the gastrointestinal tract (primarily type A) provides protection from exogenous amines with vasopressor actions, such as tyramine, which if absorbed intact can cause a hypertensive crisis, the so-called "cheese reaction." If a large amount of tyramine is absorbed systemically, it is taken up by adrenergic neurons and causes norepinephrine release from neuronal storage sites with resultant elevation of blood pressure. While most foods contain negligible amounts or no tyramine, a few food products (see WARNINGS) may contain large amounts of tyramine that represent a potential risk for patients with significant inhibition of intestinal MAO-A resulting from administration of MAOIs. Tyramine-containing nutritional supplements should be avoided by patients taking EMSAM (selegiline transdermal system).

Animal studies have indicated the transdermal administration of selegiline via EMSAM 6 mg/24 hours allows for critical levels of MAO inhibition to be achieved in the brain while avoiding levels of gastrointestinal inhibition. To further define the risk of hypertensive crises with use of EMSAM, several Phase I tyramine challenge studies were conducted both with and without food.

Fourteen tyramine challenge studies including 214 healthy subjects (age range 18 - 65; 31 subjects > 50 years of age) were conducted to determine the pressor effects of oral tyramine with concurrent EMSAM treatment (6 mg/24 hours - 12 mg/24 hours), measured as the dose of tyramine required to raise systolic blood pressure by 30 mmHg (TYR30). Studies were conducted with and without concomitant administration of food. Studies conducted with food are most relevant to clinical practice since tyramine typically will be consumed in food. A high-tyramine meal is considered to contain up to 40 mg of tyramine.

One study using a crossover design in 13 subjects investigated tyramine pressor doses (TYR30) after administration of EMSAM 6 mg/24 hours and oral selegiline (5 mg twice daily) for 9 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 338 mg and 385 mg in subjects treated with EMSAM and oral selegiline, respectively.

Another study using a crossover design in 10 subjects investigated tyramine pressor doses after administration of EMSAM 6 mg/24 hours or tranylcypromine 30 mg/day for 10 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 270 mg in subjects treated with EMSAM 6 mg/24 hours and 10 mg in subjects treated with tranylcypromine.

In a third crossover study, tyramine without food was administered to 12 subjects. The mean tyramine pressor doses (TYR30) after administration of EMSAM 6 mg/24 hours for 9 and 33 days were 292 mg and 204 mg, respectively. The lowest pressor dose was 50 mg in one subject in the 33-day group.

Tyramine pressor doses were also studied in 11 subjects after extended treatment with EMSAM 12 mg/24 hours. At 30, 60, and 90 days, the mean pressor doses (TYR30) of tyramine administered without food were 95 mg, 72 mg, and 88 mg, respectively. The lowest pressor dose without food was 25 mg in 3 subjects at day 30 while on EMSAM 12 mg/24 hours. Eight subjects from this study, with a mean tyramine pressor dose of 64 mg at 90 days, were subsequently administered tyramine with food, resulting in a mean pressor dose of 172 mg (2.7 times the mean pressor dose observed without food, p < 0.003).

With the exception of one study (N = 153), the Phase III clinical development program was conducted without requiring a modified diet (N = 2553, 1606 at 6 mg/24 hours, and 947 at 9 mg/24 hours or 12 mg/24 hours). No hypertensive crises were reported in any patient receiving EMSAM.

In its entirety, the data for EMSAM 6 mg/24 hours support the recommendation that a modified diet is not required at this dose. Due to the more limited data available for EMSAM 9 mg/24 hours and 12 mg/24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours. (See WARNINGS.)

Warfarin

Warfarin is a substrate for CYP2C9 and CYP3A4 metabolism pathways. In healthy volunteers titrated with Coumadin^® (warfarin sodium) to clinical levels of anticoagulation (INR of 1.5 to 2), co-administration with EMSAM 6 mg/24 hours for 7 days did not affect the pharmacokinetics of the individual warfarin enantiomers. EMSAM did not alter the clinical pharmacodynamic effects of warfarin as measured by INR, Factor VII or Factor X levels.

OVERDOSAGE

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.

CONTRAINDICATIONS

EMSAM (selegiline transdermal system) is contraindicated in patients with known hypersensitivity to selegiline or to any component of the transdermal system.

EMSAM (selegiline transdermal system) is contraindicated with selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, and paroxetine); dual serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine); tricyclic antidepressants (TCAs, e.g., imipramine and amitriptyline); bupropion hydrochloride; meperidine and analgesic agents such as tramadol, methadone, and propoxyphene; the antitussive agent dextromethorphan; St. John's wort; mirtazapine; and cyclobenzaprine. EMSAM should not be used with oral selegiline or other MAO inhibitors (MAOIs e.g., isocarboxazid, phenelzine, and tranylcypromine) (see WARNINGS).

Carbamazepine and oxcarbazepine are contraindicated in patients taking selegiline (see PRECAUTIONS, Drug Interactions).

As with other MAOIs, EMSAM is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).

As with other MAOIs, patients taking EMSAM should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. EMSAM should be discontinued at least 10 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may be used cautiously.

As with other MAOIs, EMSAM is contraindicated for use in patients with pheochromocytoma.

EMSAM is an irreversible MAO inhibitor. As a class, these compounds have been associated with hypertensive crises caused by the ingestion of foods containing high amounts of tyramine. In its entirety, the data for EMSAM 6 mg/24 hours support the recommendation that a modified diet is not required at this dose. Due to the more limited data available for EMSAM 9 mg/24 hours and 12 mg/24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours. (See WARNINGS and PRECAUTIONS, Drug Interactions, Tyramine.)