CONCERTA

WARNING: ABUSE, MISUSE, AND ADDICTION CONCERTA has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of CONCERTA, and proper disposal of any unused drug. Throughout CONCERTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1 , 9.2) ]. WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. CONCERTA has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of CONCERTA, and proper disposal of any unused drug. Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse ( 5.3 ). Psychiatric Adverse Reactions : Prior to initiating CONCERTA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing CONCERTA. ( 5.4 ) Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ) Peripheral Vasculopathy, including Raynaud's Phenomenon : Carefully assess for digital changes during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ) Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their CONCERTA treatment interrupted. ( 5.7 ) Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing: Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing. ( 5.8 ) Acute Angle Closure Glaucoma: CONCERTA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.9 ) Increased Intraocular Pressure (IOP) and Glaucoma : Prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. ( 5.10 ) Motor and Verbal Tics, and Worsening of Tourette's Syndrome : Before initiating CONCERTA, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue CONCERTA treatment if clinically appropriate. ( 5.11 ) 5.1 Abuse, Misuse, and Addiction CONCERTA has a high potential for abuse and misuse. The use of CONCERTA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1 , 9.2) ] . Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store CONCERTA in a safe place, preferably locked, and instruct patients to not give CONCERTA to anyone else. Throughout CONCERTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid CONCERTA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6) ] . Some patients may have larger increases. Monitor all CONCERTA-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Psychosis in Patients with a Psychotic Disorder CNS stimulants, including CONCERTA, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants, including CONCERTA, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating CONCERTA treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder CNS stimulants (including CONCERTA), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing CONCERTA. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6) ] . Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). CONCERTA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including CONCERTA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon [see Adverse Reactions (6.2) ] . Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation. During CONCERTA treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for CONCERTA-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients CONCERTA is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4) ] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in CONCERTA-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing Because CONCERTA extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, CONCERTA should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. CONCERTA should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration (2.2) ] . 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, CONCERTA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6) ]. Prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor CONCERTA-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.11 Motor and Verbal Tics, and Worsening of Tourette's Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6) ] . Worsening of Tourette's syndrome has also been reported . Before initiating CONCERTA, assess the family history for tics or Tourette' syndrome and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor CONCERTA-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue CONCERTA treatment if clinically appropriate.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) ] Hypersensitivity Reactions [see Contraindications (4) ] Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7) ] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2) ] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions (5.8) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.11) ] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain. ( 6.1 ) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received CONCERTA. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3 ]. Table 3: CONCERTA-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4 ] . Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5 ] . The most common adverse reactions associated with CONCERTA discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure . Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of CONCERTA-treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials. Table 4: Most Common Adverse Reactions Reported in ≥ 2% of CONCERTA-treated patients in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials CONCERTA (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia Initial insomnia (CONCERTA=0.6%) and insomnia (CONCERTA=2.2%) terms were combined into Insomnia. 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of CONCERTA-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials. Table 5: Most Common Adverse Reactions Reported in ≥ 2% of CONCERTA-treated patients in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials CONCERTA Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage). (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% Other Adverse Reactions Observed in Clinical Trials of CONCERTA The following adverse reactions occurred in less than 2% of CONCERTA-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials. Blood and Lymphatic System Disorders : Leukopenia Cardiac Disorders : Cardiac murmur, Hypertension, Heart rate increased Ear and Labyrinth Disorders : Vertigo Eye Disorders : Accommodation disorder, Dry eye, Vision blurred Gastrointestinal Disorders : Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting General Disorders and Administration Site Conditions : Asthenia, Fatigue, Feeling jittery, Thirst Hepatobiliary Disorders : Hepatic enzymes increased Infections and Infestations : Sinusitis Metabolism and Nutrition Disorders : Anorexia Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness Nervous System Disorders : Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache Psychiatric Disorders : Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic Reproductive System and Breast Disorders : Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders : Cough, Dyspnea, Oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Rash Vascular Disorders : Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) CONCERTA-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the CONCERTA group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%). In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) CONCERTA-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Blood Pressure and Heart Rate Increases In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies (14.2) ] , both the CONCERTA once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo. In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies (14.3) ] , mean increases from baseline in resting pulse rate were observed with CONCERTA and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for CONCERTA and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4) ] , mean changes from baseline in resting pulse rate were 3.6 in CONCERTA-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment. Mean changes from baseline in blood pressure after 7 weeks of treatment in CONCERTA-treated and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3) ] . In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [ see Clinical Studies (14.4) ] , dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with CONCERTA-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks. Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for CONCERTA-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of CONCERTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Blood and Lymphatic System Disorders : Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders : Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders : Diplopia, Increased intraocular pressure, Mydriasis General Disorders and Administration Site Conditions : Chest pain, Drug effect decreased, Hyperpyrexia Hepatobiliary Disorders : Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC Investigations : Blood alkaline phosphatase increased, Platelet count decreased, Musculoskeletal and Connective Tissue Disorders : Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders : Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders : Disorientation, Hallucination, Mania, Logorrhea Reproductive System and Breast Disorders : Priapism Skin and Subcutaneous Tissue Disorders : Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias Vascular Disorders : Raynaud's phenomenon

<table width="80%" ID="table3"><caption>Table 3: CONCERTA-treated Patients in Double-Blind and Open-Label Clinical Studies</caption><col width="34%" align="left" valign="bottom"/><col width="33%" align="left" valign="bottom"/><col width="33%" align="left" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule">Patient Population</th><th styleCode="Rrule">N</th><th styleCode="Rrule">Dosage Range</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pediatric patients 6 to 12 years of age</td><td styleCode="Rrule" valign="top">2,216</td><td styleCode="Rrule" valign="top">18 to 54 mg once daily</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Adolescents</td><td styleCode="Rrule">502</td><td styleCode="Rrule">18 to 72 mg once daily</td></tr><tr><td styleCode="Lrule Rrule">Adults up to 65 years of age</td><td styleCode="Rrule">1,188</td><td styleCode="Rrule">18 to 108 mg once daily</td></tr></tbody></table>

<table width="80%" ID="table4"><caption>Table 4: Most Common Adverse Reactions<footnote>Reported in &#x2265; 2% of CONCERTA-treated patients</footnote> in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials</caption><col width="34%" align="left" valign="bottom"/><col width="33%" align="center" valign="bottom"/><col width="33%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">CONCERTA (n=321)</th><th styleCode="Rrule">Placebo (n=318)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper abdominal pain </td><td styleCode="Rrule">6%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia<footnote>Initial insomnia (CONCERTA=0.6%) and insomnia (CONCERTA=2.2%) terms were combined into Insomnia.</footnote></td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr></tbody></table>

<table width="80%" ID="table5"><caption>Table 5: Most Common Adverse Reactions<footnote>Reported in &#x2265; 2% of CONCERTA-treated patients</footnote> in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials</caption><col width="50%" align="left" valign="bottom"/><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">CONCERTA<footnote>Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage).</footnote> (n=415)</th><th styleCode="Rrule">Placebo (n=212) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">25%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">22%</td><td styleCode="Rrule">16%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry mouth</td><td styleCode="Rrule">14%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anxiety</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased weight</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Irritability</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tachycardia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperhidrosis</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Depressed mood</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Initial insomnia</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Restlessness</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Palpitations</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nervousness</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tremor</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Agitation</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule Rrule">Dyspepsia </td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr></tbody></table>