Drug Facts
Composition & Profile
Identifiers & Packaging
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.; PRINCIPAL DISPLAY PANEL - 6 mg/24 h NDC-49502-900-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 6 mg/24 h FOR TRANSDERMAL USE ONLY Patient: Read enclosed Medication Guide. Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 6 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S033:93:30C:R10 Dosage application 6 mg/24 h Emsam Transdermal 6 mg/24 hour Carton Label; PRINCIPAL DISPLAY PANEL - 9 mg/24 h NDC-49502-901-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 9 mg/24 h Important: Do not eat certain foods. Read enclosed Medication Guide. FOR TRANSDERMAL USE ONLY Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2 . Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 9 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S044:93:30C:R10 Dosage application 9 mg/24 h Emsam Transdermal 9 mg/24 hour Carton Label; PRINCIPAL DISPLAY PANEL - 12 mg/24 h NDC-49502-902-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 12 mg/24 h Important: Do not eat certain foods. Read enclosed Medication Guide. FOR TRANSDERMAL USE ONLY Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 12 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S055:93:30C:R10 Dosage application 12 mg/24 h Emsam Transdermal 12 mg/24 hour Carton Label
- 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.
- PRINCIPAL DISPLAY PANEL - 6 mg/24 h NDC-49502-900-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 6 mg/24 h FOR TRANSDERMAL USE ONLY Patient: Read enclosed Medication Guide. Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 6 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S033:93:30C:R10 Dosage application 6 mg/24 h Emsam Transdermal 6 mg/24 hour Carton Label
- PRINCIPAL DISPLAY PANEL - 9 mg/24 h NDC-49502-901-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 9 mg/24 h Important: Do not eat certain foods. Read enclosed Medication Guide. FOR TRANSDERMAL USE ONLY Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2 . Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 9 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S044:93:30C:R10 Dosage application 9 mg/24 h Emsam Transdermal 9 mg/24 hour Carton Label
- PRINCIPAL DISPLAY PANEL - 12 mg/24 h NDC-49502-902-30 EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only EMSAM ® (selegiline transdermal system) 12 mg/24 h Important: Do not eat certain foods. Read enclosed Medication Guide. FOR TRANSDERMAL USE ONLY Pharmacist: Dispense with enclosed Medication Guide. 30 TRANSDERMAL SYSTEMS INSTRUCTIONS FOR APPLICATION 1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide. 2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system. 3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers. For more detailed instructions, read enclosed Medication Guide. Dosage: Apply one (1) transdermal system every 24 hours. Read enclosed Medication Guide. Each transdermal system has a release rate of 12 mg selegiline per 24 hour period. Wear only one transdermal system at a time. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A. Rx only S055:93:30C:R10 Dosage application 12 mg/24 h Emsam Transdermal 12 mg/24 hour Carton Label
Overview
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
Indications & 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 ).
Dosage & 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) ] .
Warnings & 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 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing EMSAM, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with concomitant use of MAOIs, such as EMSAM, with serotonergic drugs. These reactions have also been reported in patients who have discontinued serotonergic drugs and then subsequently started an MAOI [see Contraindications (4) ] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. Treatment with EMSAM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive treatment should be initiated. 5.3 Blood Pressure Elevation Tyramine-Induced Hypertensive Crisis EMSAM inhibits the catabolism of dietary amines, such as tyramine, and has the potential to produce a hypertensive crisis following the ingestion of tyramine-rich foods or beverages [see Drug Interactions (7.2) and Clinical Pharmacology (12.2) ] . Hypertensive crises, which in some cases may be fatal, are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. Intracranial bleeding has been reported in association with the increase in blood pressure. Patients should be instructed as to the signs and symptoms of severe hypertension and advised to seek immediate medical attention if these signs or symptoms are present. If a hypertensive crisis occurs, EMSAM should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. Fever should be managed by means of external cooling. Patients must be closely monitored until symptoms have stabilized. To prevent a hypertensive crisis, patients receiving treatment with EMSAM 9 mg per 24 hours or EMSAM 12 mg per 24 hours should follow the advice regarding a low tyramine diet described in Table 5 under Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours [see Drug Interactions (7.2) ] . Blood Pressure Elevation Related to Concomitant Medication Carbamazepine is contraindicated with EMSAM because carbamazepine has been shown to significantly elevate selegiline levels, which may increase the risk of a hypertensive crisis [see Contraindications (4) and Drug Interactions (7.4) ] . The use of EMSAM with adrenergic drugs or buspirone may produce substantial increases in blood pressure. Therefore, 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). 5.4 Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with EMSAM or another antidepressant may precipitate a mixed/manic episode. During Phase III trials, a manic reaction occurred in 8 out of 2,036 (0.4%) patients treated with EMSAM. Prior to initiating treatment with EMSAM, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.5 External Heat The effect of direct heat applied to EMSAM on the bioavailability of selegiline has not been studied. However, in theory, heat may result in an increase in the amount of selegiline absorbed from EMSAM and produce elevated serum levels of selegiline. Patients should be advised to 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.
Boxed Warning
SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1) ] . EMSAM is contraindicated in patients less than 12 years of age because of an increased risk of hypertensive crisis [see Contraindications (4) and Use in Specific Populations (8.4) ] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ). • EMSAM is contraindicated in patients less than 12 years of age ( 4 , 8.4 ).
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 ).
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, diarrhea, and pharyngitis. Table 2. Treatment-Emergent Adverse Reactions: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder with EMSAM Reactions reported by at least 2% of patients treated with EMSAM are included, except the following reactions, which had an incidence on placebo treatment greater than or equal to EMSAM: infection, nausea, dizziness, pain, abdominal pain, nervousness, back pain, asthenia, anxiety, flu syndrome, accidental injury, somnolence, rhinitis, and palpitations. Body System/Preferred Term EMSAM (N = 817) Placebo (N = 668) (% of Patients Reporting Reaction) Body as a Whole Headache 18 17 Digestive Diarrhea 9 7 Dyspepsia 4 3 Nervous Insomnia 12 7 Dry Mouth 8 6 Respiratory Pharyngitis 3 2 Sinusitis 3 1 Skin Application Site Reaction 24 12 Rash 4 2 Application Site Reactions In the pool of short-term, placebo-controlled major depressive disorder studies, application site reactions (ASRs) were reported in 24% of EMSAM-treated patients and 12% of placebo-treated patients. Most ASRs were mild or moderate in severity. ASRs led to dropout in 2% of EMSAM-treated patients and no placebo-treated patients. In one such study which utilized higher mean doses of EMSAM, ASRs were reported in 40% of EMSAM-treated patients and 20% of placebo-treated patients. Most of the ASRs in this study were described as erythema and most resolved spontaneously, requiring no treatment. When treatment was administered, it most commonly consisted of dermatological preparations of corticosteroids. Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 shows that the incidence rates of sexual side effects in patients with major depressive disorder are comparable to the placebo rates in placebo-controlled trials. Table 3. Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials with EMSAM Adverse Reaction EMSAM Placebo IN MALES ONLY (N = 304) (N = 256) Abnormal Ejaculation 1.0% 0.0% Decreased Libido 0.7% 0.0% Impotence 0.7% 0.4% Anorgasmia 0.2% 0.0% IN FEMALES ONLY (N = 513) (N = 412) Decreased Libido 0.0% 0.2% There are no adequately designed studies examining sexual dysfunction with EMSAM treatment. Vital Sign Changes EMSAM and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure), and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. In the pool of short-term, placebo-controlled major depressive disorder studies, 3.0% of EMSAM-treated patients and 1.5% of placebo-treated patients experienced a low systolic blood pressure, defined as a reading less than or equal to 90 mmHg with a change from baseline of at least 20 mmHg. In one study which utilized higher mean doses of EMSAM, 6.2% of EMSAM-treated patients and no placebo-treated patients experienced a low standing systolic blood pressure by these criteria. In the pool of short-term major depressive disorder trials, 9.8% of EMSAM-treated patients and 6.7% of placebo-treated patients experienced a notable orthostatic change in blood pressure, defined as a decrease of at least 10 mmHg in mean blood pressure with postural change. Weight Changes In placebo-controlled studies (6 to 8 weeks), the incidence of patients who experienced at least 5% weight gain or weight loss is shown in Table 4. Table 4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials with EMSAM Weight Change EMSAM Placebo (N = 757) (N = 614) Gained at least 5% 2.1% 2.4% Lost at least 5% 5.0% 2.8% In these trials, the mean change in body weight among EMSAM-treated patients was a 1.2 lbs loss compared to 0.3 lbs gain in placebo-treated patients. Laboratory Changes EMSAM and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with EMSAM. Electrocardiogram Changes Electrocardiograms (ECGs) from EMSAM (N = 817) and placebo (N = 668) groups in controlled studies were compared with respect to (1) mean change from baseline in various ECG parameters, and (2) the incidence of patients meeting criteria for clinically significant changes from baseline in these variables. No clinically meaningful changes in ECG parameters from baseline to final visit were observed for patients in controlled studies. Other Reactions Observed During the Premarketing Evaluation of EMSAM The following listing does not include reactions: 1) already listed elsewhere in labeling, 2) for which a causal relationship to drug was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Cardiovascular System: Tachycardia. Digestive System: Anorexia. Nervous System: Agitation, amnesia, tremor, twitching. Skin and Appendages: Pruritus. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of EMSAM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System: Convulsion and hypoesthesia. Psychiatric System: Disorientation, hallucination (visual), and tension.
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). 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) ] . 7.5 Effect of EMSAM on Other Drugs Use of alcohol while taking EMSAM is not recommended, even though EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg) [see Clinical Pharmacology (12.3) ] . Monitor blood pressure if sympathomimetic agents (e.g., phenylpropanolamine (PPA) or pseudoephedrine) are used with EMSAM, even though selegiline does not appear to affect the pharmacokinetics of PPA or pseudoephedrine [see Clinical Pharmacology (12.3) ] . No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, 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.
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