EMSAM

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 ).

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

<table ID="_RefID0ENNAE" width="100%"><caption>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</caption><col width="17%"/><col width="83%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Age Range (years)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Increases Compared to Placebo</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&lt;18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14 additional patients</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18-24</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>5 additional patients</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Decreases Compared to Placebo</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25-64</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1 fewer patient</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>&#x2265;65</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>6 fewer patients</paragraph></td></tr></tbody></table>

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, 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.

<table ID="_RefID0EDXAE" cellpadding="0pt" width="100%"><caption>Table 2. Treatment-Emergent Adverse Reactions: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder with EMSAM<footnote ID="_Ref398291025">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.</footnote></caption><col width="46%"/><col width="26%"/><col width="27%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Body System/Preferred Term</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">EMSAM</content></paragraph><paragraph><content styleCode="bold">(N = 817)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N = 668)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">(% of Patients Reporting Reaction)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>17</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Digestive</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Nervous</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Dry Mouth</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Pharyngitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Sinusitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Skin</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Application Site Reaction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2</paragraph></td></tr></tbody></table>

<table ID="_RefID0EEAAG" cellpadding="0pt" width="100%"><caption>Table 3. Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials with EMSAM</caption><col width="36%"/><col width="32%"/><col width="32%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">EMSAM</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>IN MALES ONLY</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 304)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 256)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Abnormal Ejaculation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.0%</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Decreased Libido</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.0%</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Impotence</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.4%</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Anorgasmia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.0%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>IN FEMALES ONLY</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 513)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 412)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Decreased Libido</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0.0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0.2%</paragraph></td></tr></tbody></table>

<table ID="_RefID0ELGAG" cellpadding="0pt" width="100%"><caption>Table 4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials with EMSAM</caption><col width="39%"/><col width="33%"/><col width="28%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Weight Change</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">EMSAM</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 757)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(N = 614)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Gained at least 5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.4%</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Lost at least 5%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>5.0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>2.8%</paragraph></td></tr></tbody></table>