EMSAM

1 INDICATIONS AND USAGE EMSAM (selegiline transdermal system) is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies (14) ] . EMSAM ® (selegiline transdermal system) is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of major depressive disorder (MDD) ( 1 ).

2 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 ). 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 Clinical Studies (14) ] . 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 [see Drug Interactions (7.2) ] . 2.4 Screen for Bipolar Disorder Prior to Starting EMSAM Prior to initiating treatment with EMSAM or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4) ] .

3 DOSAGE FORMS AND STRENGTHS EMSAM (selegiline transdermal system) is supplied as 6 mg per 24 hours (20 mg per 20 cm 2 ), 9 mg per 24 hours (30 mg per 30 cm 2 ) and 12 mg per 24 hours (40 mg per 40 cm 2 ) 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’. Transdermal System: 6 mg per 24 hours, 9 mg per 24 hours and 12 mg per 24 hours ( 3 ).

4 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. • 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 ).

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1) ] . • Serotonin Syndrome [see Contraindications (4) and Warnings and Precautions (5.2) ] . • Blood Pressure Elevation [see Warnings and Precautions (5.3) ] . • Activation of Mania/Hypomania [see Warnings and Precautions (5.4) ] . • External Heat [see Warnings and Precautions (5.5) ] . • 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 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-4-INFO-RX (1-877-446-3679) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patient Exposure The premarketing development program for EMSAM included selegiline exposures in patients and/or normal subjects from two different groups of studies: 702 healthy subjects in clinical pharmacology/pharmacokinetics studies and 2,036 exposures from patients in controlled and uncontrolled major depressive disorder clinical trials. The conditions and duration of treatment with EMSAM varied and included double-blind, open-label, fixed-dose, and dose titration studies of short-term and longer-term exposures. Safety was assessed by monitoring adverse reactions, physical examinations, vital signs, body weights, laboratory analyses, and ECGs. Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions Leading To Discontinuation of Treatment Among 817 MDD patients treated with EMSAM at doses of either 3 mg per 24 hours (151 patients), 6 mg per 24 hours (550 patients) or 6 mg per 24 hours, 9 mg per 24 hours, and 12 mg per 24 hours (116 patients) in placebo-controlled trials of up to 8 weeks in duration, 7.1% discontinued treatment due to an adverse reaction as compared with 3.6% of 668 patients receiving placebo. The only adverse reaction associated with discontinuation, in at least 1% of EMSAM-treated patients at a rate at least twice that of placebo, was application site reaction (2% EMSAM vs. 0% placebo). Adverse Reactions Occurring at an Incidence of 2% or More Among EMSAM-Treated Patients Table 2 enumerates adverse reactions that occurred at an incidence of 2% or more (rounded to the nearest percent) among 817 MDD patients treated with EMSAM in doses ranging from 3 to 12 mg per 24 hours in placebo-controlled trials of up to 8 weeks in duration. Reactions included are those occurring in 2% or more of patients treated with EMSAM and for which the incidence in patients treated with EMSAM was greater than the incidence in placebo-treated patients. One adverse reaction was associated with a reporting of at least 5% in the EMSAM group, and a rate at least twice that in the placebo group, in the pool of short-term, placebo-controlled studies: application site reactions ( see Application Site Reactions , below ). In one such study which utilized higher mean doses of EMSAM than that in the entire study pool, the following reactions met these criteria: application site reactions, insomnia, di …

7 DRUG INTERACTIONS 7.1 Serotonergic Drugs 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. Use of EMSAM with these drugs is contraindicated [see Contraindications (4) and Warnings and Precautions (5.2) ] . 7.2 Tyramine 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2) ] . A diet low in tyramine content may be necessary to avoid this interaction. Studies to evaluate the potential for EMSAM to inhibit tyramine metabolism have been conducted and, 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 below [see Clinical Pharmacology (12.2) ] . Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours 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. Table 5. Food and Beverages to Avoid and Those which are Acceptable [see References (15) ] Class of Food and Beverage Tyramine-Rich Foods and Beverages to Avoid Acceptable Foods and Drinks, Containing No or Little Tyramine Meat, Poultry, and Fish Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham) Vegetables Broad bean pods (fava bean pods) All other vegetables Dairy Aged cheeses Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt Beverages All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation Concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.) Miscellaneous Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine 7.3 Sympathomimetic Amines and Buspirone The use of EMSAM with sympathomimetic amines or buspirone may produce substantial elevations in blood pressure. Therefore, monitor blood pressure if EMSAM is used with any of the following drugs: buspirone, amphetamines, and cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). 7.4 Effect of Other Drugs on EMSAM Carbamazepine is contraindicated with MAOIs, including selegiline [see Contraindications (4) , Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . 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) …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm ( 8.1 ). • Lactation: Breastfeeding is not recommended ( 8.2 ). • Pediatrics: EMSAM is contraindicated in patients under age 12 years and is not recommended in patients 12 to 17 years of age ( 4 , 8.4 ). 8.1 Pregnancy Risk Summary The available data on EMSAM use in pregnant women are not sufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. In animal embryo-fetal development studies, transdermal administration of selegiline to rats and rabbits at doses up to 60 and 64 times the maximum recommended human dose (MRHD) respectively, produced slight increases in malformations in both rats and rabbits, and decreased fetal weight, delayed ossification, and embryo-fetal post-implantation loss in rats. Most of these effects were seen at the high dose in both rats and rabbits. These effects were not seen at 8 times and 16 times the MRHD in rats and rabbits, respectively. In a pre-natal and post-natal development study, transdermal administration of selegiline in rats at doses 8, 24, and 60 times MRHD produced a decrease in pup weight and survival at the medium and high doses, an increase in the number of stillborn pups at the high dose, and delayed neurobehavioral and sexual development in pups at all doses. A persistent effect on reproductive performance of pups born to mothers treated at the high dose was evident (see Data ). When treating a pregnant woman with EMSAM, the physician should carefully consider both the potential risks of taking an MAOI, particularly the risk of hypertensive crisis during pregnancy, along with the established benefits of treating depression with an antidepressant. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. Data Animal Data In an embryofetal development study, rats were treated with transdermal selegiline during the period of organogenesis at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the MRHD of EMSAM [12 mg/24 hours] on a mg/m 2 basis). At the highest dose there was a decrease in fetal weight and slight increases in malformations, delayed ossification (also seen at the mid dose), and embryofetal post-implantation loss. Concentrations of selegiline and its metabolites in fetal plasma were generally similar to those in maternal plasma. In an embryofetal development study, rabbits were treated with transdermal selegiline during the period of organogenesis at doses of 2.5, 10, and 40 mg/kg/day (4, 16, and 64 times the MRHD on a mg/m 2 basis). A slight increase in visceral malformations was seen at the high dose. In a prenatal and postnatal development study, rats were treated with transdermal selegiline at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the MRHD on a mg/m 2 basis) on days 6 to 21 of gestation and days 1 to 21 of the lactation period. An increase in post-implantation loss was seen at the mid and high doses, and an increase in stillborn pups was seen at the high dose. Decreases in pup weight (throughout lactation and postweaning periods) and survival (throughout lactation period), delayed pup physical development, and …

12.1 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).

11 DESCRIPTION EMSAM ® contains selegiline, a MAOI antidepressant. When applied to intact skin, EMSAM is designed to transdermally deliver selegiline over a 24-hour period. Selegiline base is a colorless to yellow liquid, chemically described as (-)-( N )-Methyl- N -[(1 R )-1-methyl-2-phenylethyl]prop-2-yn-1-amine. It has a molecular formula of C 13 H 17 N and a molecular weight of 187.30. The structural formula is: EMSAM transdermal systems are available in three strengths that deliver approximately 6 mg, 9 mg, or 12 mg of selegiline over 24 hours. Each corresponding system has an active surface area of 20 cm 2 , 30 cm 2 , or 40 cm 2 containing 20, 30, or 40 mg of selegiline, respectively. The composition of the systems per unit area is identical. EMSAM is a matrix-type transdermal system composed of three layers as illustrated in Figure 1 below. Layer 1 is the Backing Film that provides occlusivity, physical integrity and protects the adhesive/drug layer. Layer 2 is the Adhesive/Drug Layer. Layer 3 consists of side-by-side release liners that are peeled off and discarded by the patient prior to applying EMSAM. The inactive ingredients are acrylic adhesive, ethylene vinyl acetate/polyethylene, polyester, polyurethane, and silicone coated polyester. Figure 1: Side view of EMSAM system. (Not to scale.) Selegiline Structural Formula Figure 1: Side view of EMSAM

10 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied EMSAM (selegiline transdermal system) is a transdermal system with the following strengths, sizes, color, backing film printing and presentation: Features Strengths 6 mg per 24 hours 9 mg per 24 hours 12 mg per 24 hours EMSAM Size 20 mg per 20 cm 2 30 mg per 30 cm 2 40 mg per 40 cm 2 Color Translucent Translucent Translucent Backing Film Printing EMSAM ® 6mg/24h EMSAM ® 9mg/24h EMSAM ® 12mg/24h NDC number NDC 49502-900-30 NDC 49502-901-30 NDC 49502-902-30 Presentation Box of 30 transdermal systems Box of 30 transdermal systems Box of 30 transdermal systems Storage and Handling Store at 20° to 25° C (68° to 77° F). [See USP Controlled Room Temperature.] Do not store outside of the sealed pouch. Apply immediately upon removal from the protective pouch. Discard used EMSAM in household trash in a manner that prevents accidental application or ingestion by children, pets or others.