Selegiline (transdermal)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
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Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
EMSAM (selegiline transdermal system) is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of major depressive disorder (MDD). The efficacy of EMSAM in the treatment of major depressive disorder was established in two short term (6-week and 8-week) trials of outpatients with major depressive disorder. Efficacy was studied in two short term studies and one maintenance study
Dosage
2.1 Initial Treatment 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. The recommended starting dose and target dose for EMSAM is 6 mg per 24 hours. EMSAM has been systematically evaluated and shown to be effective in a dose range of 6 mg per 24 hours to 12 mg per 24 hours. However, the trials were not designed to assess if higher doses are more effective than the lowest effective dose of 6 mg per 24 hours. Based on clinical judgment, if dose increases are indicated for individual patients, they should occur in dose 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. Full antidepressant effect may be delayed.
Patients should be informed that 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 [see WARNINGS AND PRECAUTIONS (5.3)].
2.2 Maintenance Treatment It is generally agreed that episodes of depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in depressed patients on therapy with EMSAM at a dose of 6 mg per 24 hours after achieving a responder status for an average duration of about 25 days was demonstrated in a controlled trial [see INDICATIONS AND USAGE (1) and CLINICAL STUDIES (14.1)].
The physician who elects to use EMSAM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
2.3 Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours EMSAM (selegiline transdermal system) contains a monoamine oxidase inhibitor (MAOI). MAOIs including EMSAM combined with a high tyramine diet may cause a hypertensive crisis. A hypertensive crisis can be a life-threatening condition [see WARNINGS AND PRECAUTIONS (5.3)].
The foods and beverages listed in Table 5 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.
DOSAGE FORMS AND STRENGTHS
EMSAM (selegiline transdermal system) is supplied as 6 mg per 24 hours (20 mg per 20 cm2), 9 mg per 24 hours (30 mg per 30 cm2) and 12 mg per 24 hours (40 mg per 40 cm2) transdermal systems (TDS).
EMSAM 6 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 6mg/24h’. EMSAM 9 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 9mg/24h’. EMSAM 12 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 12mg/24h’.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Selegiline (transdermal) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Selegiline (transdermal) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Selegiline (transdermal) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Selegiline (transdermal) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Selegiline (transdermal) in pediatric patients.
Contraindications
EMSAM (selegiline transdermal system) is contraindicated with selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, and paroxetine); serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine); the tricyclic antidepressants clomipramine and imipramine, the opiate analgesics meperidine, tramadol, methadone, pentazocine, and propoxyphene; and the antitussive agent dextromethorphan because of a risk of serotonin syndrome when EMSAM is used with these agents [see WARNINGS AND PRECAUTIONS (5.2) and DRUG INTERACTIONS (7.1)]. Carbamazepine is contraindicated with EMSAM because of a possible increased risk of hypertensive crisis [see WARNINGS AND PRECAUTIONS (5.3) and CLINICAL PHARMACOLOGY (12.3)]. After stopping treatment with drugs contraindicated with EMSAM, 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. At least 2 weeks should elapse after stopping EMSAM before starting therapy with any drug that is contraindicated with EMSAM. EMSAM is contraindicated in patients less than 12 years of age because of the potential for a hypertensive crisis [see USE IN SPECIFIC POPULATIONS (8.4) and CLINICAL PHARMACOLOGY (12.3)]. EMSAM is contraindicated in patients with pheochromocytoma because MAOIs may precipitate a hypertensive crisis in such patients.
Warnings
There is limited information regarding Selegiline (transdermal) Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Selegiline (transdermal) Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Selegiline (transdermal) Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Selegiline (transdermal) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Selegiline (transdermal) in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Selegiline (transdermal) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Selegiline (transdermal) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Selegiline (transdermal) in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Selegiline (transdermal) in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Selegiline (transdermal) in geriatric settings.
Gender
There is no FDA guidance on the use of Selegiline (transdermal) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Selegiline (transdermal) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Selegiline (transdermal) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Selegiline (transdermal) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Selegiline (transdermal) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Selegiline (transdermal) in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Selegiline (transdermal) Administration in the drug label.
Monitoring
There is limited information regarding Selegiline (transdermal) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Selegiline (transdermal) and IV administrations.
Overdosage
10.1 Signs and Symptoms 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.
10.2 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.
Pharmacology
There is limited information regarding Selegiline (transdermal) Pharmacology in the drug label.
Mechanism of Action
The mechanism of action of selegiline (the drug substance of EMSAM) as an antidepressant is not fully understood, but is presumed to be linked to potentiation of monoamine neurotransmitter activity in the central nervous system (CNS) resulting from its irreversible inhibition of the enzyme monoamine oxidase (MAO).
Structure
There is limited information regarding Selegiline (transdermal) Structure in the drug label.
Pharmacodynamics
MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline has a greater affinity for MAO-B, compared to MAO-A. However, at antidepressant doses, selegiline inhibits both isoenzymes. In an in vivo animal model used to test for antidepressant activity (Forced Swim Test), selegiline administered by transdermal system exhibited antidepressant properties only at doses that inhibited both MAO-A and MAO-B activity in the brain. In the CNS, MAO-A and MAO-B play important roles in the catabolism of neurotransmitter amines such as norepinephrine, dopamine, and serotonin, as well as neuromodulators such as phenylethylamine.
Receptor Binding
In in vitro receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic α2B receptor (Ki = 0.3 mcM). No affinity [Ki greater than 10 mcM] was noted at dopamine receptors, adrenergic β3, glutamate, muscarinic M1-M5, nicotinic, or rolipram receptor/sites.
Interaction with 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, certain food products may contain large amounts of tyramine that represent a potential risk for hypertensive crisis [see WARNINGS AND PRECAUTIONS (5.3)].
To 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 to 65; 31 subjects greater than 50 years of age) were conducted to determine the pressor effects of oral tyramine with concurrent EMSAM treatment (6 mg per 24 hours to 12 mg per 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 per 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 per 24 hours or tranylcypromine 30 mg per day for 10 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 270 mg in subjects treated with EMSAM 6 mg per 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 per 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 per 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 three subjects at day 30 while on EMSAM 12 mg per 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 less than 0.003).
With the exception of one study (N = 153), the Phase III clinical development program was conducted without requiring a modified diet (N = 2,553, 1,606 at 6 mg per 24 hours, and 947 at 9 mg per 24 hours or 12 mg per 24 hours). No hypertensive crises were reported in any patient receiving EMSAM.
Overall, the data for EMSAM 6 mg per 24 hours support a recommendation that a modified diet is not required at this dose. Due to the more limited data available for EMSAM 9 mg per 24 hours and the results from the Phase I tyramine challenge study in fed volunteers administered EMSAM 12 mg per 24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours [see WARNINGS AND PRECAUTIONS (5.3)].
Pharmacokinetics
There is limited information regarding Selegiline (transdermal) Pharmacokinetics in the drug label.
Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis
In a dermal carcinogenicity study in CD-1 mice, selegiline (the drug substance of EMSAM) was administered daily for 2 years at the same skin site at dose levels of 20, 70, and 200 mg per kg per day (dissolved in acetone). The incidence of systemic tumors was not increased and the high dose provided systemic exposures to selegiline and its three metabolites in mice that were greater than 40 times the exposures in humans at the maximum recommended human dose (MRHD). The incidence of squamous cell carcinoma was slightly increased on treated skin of mice administered the high dose. This finding was associated with an increased incidence of epithelial hyperplasia, dyskeratosis/hyperkeratosis and inflammation.
In an oral carcinogenicity study in rats, selegiline given in the diet for 104 weeks was not carcinogenic up to the highest evaluable dose tested (3.5 mg per kg per day), which exposed rats to systemic levels of selegiline and its three metabolites that were comparable to those in humans at the MRHD.
Mutagenesis
Selegiline induced mutations and chromosomal damage when tested in the in vitro mouse lymphoma assay with and without metabolic activation. Selegiline was negative in the Ames assay, the in vitro mammalian chromosome aberration assay in human lymphocytes, and the in vivo oral mouse micronucleus assay.
Impairment of Fertility
A mating and fertility study was conducted in male and female rats at transdermal doses of 10, 30, and 75 mg per kg per day of selegiline (8, 24, and 60 times the maximum recommended human dose of EMSAM [12 mg per 24 hours] on a mg per m2 basis). Slight decreases in sperm concentration and total sperm count were observed at the high dose; however, no significant adverse effects on fertility or reproductive performance were observed.
Clinical Studies
There is limited information regarding Selegiline (transdermal) Clinical Studies in the drug label.
How Supplied
There is limited information regarding Selegiline (transdermal) How Supplied in the drug label.
Storage
There is limited information regarding Selegiline (transdermal) Storage in the drug label.
Images
Drug Images
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Patient Counseling Information
There is limited information regarding Selegiline (transdermal) Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Selegiline (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Selegiline (transdermal) Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Selegiline (transdermal) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.