Methylphenidate Hydrochloride

WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride extended-release tablets have 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 methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride extended-release tablets 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 ( 9.2 )] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride extended-release tablets have 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 methylphenidate hydrochloride extended-release tablets, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, 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 serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride extended-release tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. ( 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: Careful observation for digital changes is necessary during methylphenidate hydrochloride extended-release tablets 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 weight as expected may need to have their treatment interrupted. ( 5.7 ) Gastrointestinal Obstruction: Avoid use with preexisting GI narrowing. ( 5.8 ) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride extended-release tablets-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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets, 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 treatment if clinically appropriate. ( 5.11 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride extended-release tablets can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 , 9.3 )]. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, 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 methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride extended-release tablets 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 taking CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride extended-release tablets 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 cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm) [see Adverse Reactions ( 6.1 )]. Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms, a family history of suicide, bipolar disorder, and depression). New Psychotic or Manic Symptoms CNS stimulants, 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 to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use, including another formulation of methylphenidate hydrochloride extended-release tablets, in both adult and pediatric male patients [see Adverse Reactions ( 6.2 )] . Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during a methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-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, such as methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are 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 dosage in all age groups throughout the course of treatment. Signs and symptoms generally improved after reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride extended-release tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and are 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. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year 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 methylphenidate hydrochloride extended-release tablets-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 Potential for Gastrointestinal Obstruction Because the methylphenidate hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the GI tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the extended-release design of the tablet, methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the tablet whole [see Patient Counseling Information ( 17 )] . 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release tablets-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 ( 6.2 )] . Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release tablets-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. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions ( 6.2 )] . Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue 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 Box Warning, Warnings and Precautions ( 5.1 ), and Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients [see Contraindications ( 4 )] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.1 )] 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 )] Potential for Gastrointestinal Obstruction [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%) were: Pediatric patients 6 to 17 years: abdominal pain upper ( 6.1 ) Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Trigen Laboratories, LLC at 1-800-444-5164 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 safety of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. Below is a display of adverse reactions from those adequate and well-controlled studies in ADHD. Adults and pediatric patients 6 to 17 years with ADHD were evaluated in six controlled clinical studies and eleven open-label clinical studies (see Table 3). Safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ECGs), and by performing physical examinations and laboratory analyses. A total of 3,906 patients participated in the clinical trials. Table 3: Exposure in Double-Blind and Open-Label Clinical Studies of Another Formulation of Methylphenidate Hydrochloride Extended-Release Tablets Patient Population N Dosage Range Pediatric patients 6 to 12 years 2216 18 mg to 54 mg once daily Pediatric patients 13 to 17 years 502 18 mg to 72 mg once daily Adults 1188 18 mg to 108 mg* once daily * 108 mg is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets. The most common adverse reactions in double-blind clinical trials (>5%) were: Pediatric patients 6 to 17 years: abdominal pain upper (see Table 4). Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see Table 5). The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased . Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Pediatric Patients 6 to 17 Years Table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials. Table 4: Adverse Reactions Reported by ≥1% of Pediatric Patients (6 to 17 years) Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Four Placebo-Controlled, Double-Blind Clinical Trials System/Organ Class Adverse Reaction Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=321) % Placebo (n=318) % Gastrointestinal Disorders Abdominal pain upper 6.2 3.8 Vomiting 2.8 1.6 General Disorders and Administration Site Conditions Pyrexia 2.2 0.9 Infections and Infestations Nasopharyngitis 2.8 2.2 Nervous System Disorders Dizziness 1.9 0 Psychiatric Disorders Insomnia * 2.8 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 0.9 Oropharyngeal pain 1.2 0.9 * Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia. Adults Table 5 lists the adverse reactions reported in 1% or more of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials. Table 5: Adverse Reactions Reported by ≥1% of Adults Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Two Placebo-Controlled, Double-Blind Clinical Trials * System/Organ Class Adverse Reaction Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=415) % Placebo (n=212) % Cardiac Disorders Tachycardia 4.8 0 Palpitations 3.1 0.9 Ear and Labyrinth Disorders Vertigo 1.7 0 Eye Disorders Vision blurred 1.7 0.5 Gastrointestinal Disorders Dry mouth 14.0 3.8 Nausea 12.8 3.3 Dyspepsia 2.2 0.9 Vomiting 1.7 0.5 Constipation 1.4 0.9 General Disorders and Administration Site Conditions Irritability 5.8 1.4 Infections and Infestations Upper respiratory tract infection 2.2 0.9 Investigations Weight decreased 6.5 3.3 Metabolism and Nutrition Disorders Decreased appetite 25.3 6.6 Anorexia 1.7 0 Musculoskeletal and Connective Tissue Disorders Muscle tightness 1.9 0 Nervous System Disorders Headache 22.2 15.6 Dizziness 6.7 5.2 Tremor 2.7 0.5 Paresthesia 1.2 0 Sedation 1.2 0 Tension headache 1.2 0.5 Psychiatric Disorders Insomnia 12.3 6.1 Anxiety 8.2 2.4 Initial insomnia 4.3 2.8 Depressed mood 3.9 1.4 Nervousness 3.1 0.5 Restlessness 3.1 0 Agitation 2.2 0.5 Aggression 1.7 0.5 Bruxism 1.7 0.5 Depression 1.7 0.9 Libido decreased 1.7 0.5 Affect lability 1.4 0.9 Confusional state 1.2 0.5 Tension 1.2 0.5 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 1.7 1.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 5.1 0.9 * Included doses up to 108 mg (1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets). Adverse Reactions Observed in Clinical Trials with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets This section includes adverse reactions reported with use of another formulation of methylphenidate hydrochloride extended-release tablets in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by the other formulation of methylphenidate hydrochloride extended-release tablets-treated patients who participated in open-label and postmarketing clinical trials. Blood and Lymphatic System Disorders: Leukopenia Eye Disorders: Accommodation disorder, Dry eye Vascular Disorders: Hot flush Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst Infections and Infestations: Sinusitis Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased Musculoskeletal and Connective Tissue Disorders: Muscle spasms Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Rash, Rash macular Vascular Disorders: Hypertension Discontinuation Due to Adverse Reactions Adverse reactions in the four placebo-controlled studies of pediatric patients (6 to 17 years) leading to discontinuation occurred in 2 patients (0.6%) treated with another formulation of methylphenidate hydrochloride extended-release tablets including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%). In the two placebo-controlled studies of adults, 25 patients (6.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Incidence of >0.5% in patients treated with another formulation of methylphenidate hydrochloride extended-release tablets included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). In the eleven open-label studies of pediatric patients and adults, 266 patients (7.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets discontinued due to an adverse reaction. Incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Tics In a long-term uncontrolled study (n=432 pediatric patients 6 to 12 years), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with another formulation of methylphenidate hydrochloride extended-release tablets. In a second uncontrolled study (n=682 pediatric patients 6 to 12 years) the cumulative incidence of new-onset tics was 1% (9/682). The treatment period was up to 9 months with mean treatment duration of 7.2 months. Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in pediatric patients 6 to 12 years (Studies 1 and 2), both another formulation of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled trial in pediatric patients 13 to 17 years (Study 4), mean increases from baseline in resting pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for another formulation of methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for another formulation of methylphenidate hydrochloride extended-release tablets 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 )] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of another formulation of methylphenidate hydrochloride extended-release tablets. 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. Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes Reproductive System and Breast Disorders: Priapism Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud's phenomenon

<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col width="81pt"/><col width="193.5pt"/><tbody><tr><td><paragraph><content styleCode="bold">Patient Population</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">N</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Dosage Range</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pediatric patients 6 to 12 years</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2216</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18 mg to 54 mg once daily</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pediatric patients 13 to 17 years</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>502</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18 mg to 72 mg once daily</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adults</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1188</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18 mg to 108 mg* once daily</paragraph></td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0"><col width="265.05pt"/><col width="90.45pt"/><col width="85.5pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=321) %</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (n=318) %</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td><paragraph>Abdominal pain upper</paragraph></td><td><paragraph>6.2</paragraph></td><td><paragraph>3.8</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>2.8</paragraph></td><td><paragraph>1.6</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">General Disorders and Administration Site Conditions</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph>2.2</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Nasopharyngitis</paragraph></td><td><paragraph>2.8</paragraph></td><td><paragraph>2.2 </paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Dizziness</paragraph></td><td><paragraph>1.9</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Insomnia^*</paragraph></td><td><paragraph>2.8</paragraph></td><td><paragraph>0.3</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Cough</paragraph></td><td><paragraph>1.9</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Oropharyngeal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.9</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia.</paragraph></td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0"><col width="299.95pt"/><col width="109.05pt"/><col width="45.5pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=415) %</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (n=212) %</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td><paragraph>Tachycardia</paragraph></td><td><paragraph>4.8</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Palpitations</paragraph></td><td><paragraph>3.1</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Ear and Labyrinth Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Vertigo</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Vision blurred</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Dry mouth</paragraph></td><td><paragraph>14.0</paragraph></td><td><paragraph>3.8</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>12.8</paragraph></td><td><paragraph>3.3</paragraph></td></tr><tr><td><paragraph>Dyspepsia</paragraph></td><td><paragraph>2.2</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Constipation</paragraph></td><td><paragraph>1.4</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">General Disorders and Administration Site Conditions</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Irritability</paragraph></td><td><paragraph>5.8</paragraph></td><td><paragraph>1.4</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Upper respiratory tract infection</paragraph></td><td><paragraph>2.2</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Weight decreased</paragraph></td><td><paragraph>6.5</paragraph></td><td><paragraph>3.3</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td><paragraph>Decreased appetite</paragraph></td><td><paragraph>25.3</paragraph></td><td><paragraph>6.6</paragraph></td></tr><tr><td><paragraph>Anorexia</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td><paragraph>Muscle tightness</paragraph></td><td><paragraph>1.9</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph>22.2</paragraph></td><td><paragraph>15.6</paragraph></td></tr><tr><td><paragraph>Dizziness</paragraph></td><td><paragraph>6.7</paragraph></td><td><paragraph>5.2</paragraph></td></tr><tr><td><paragraph>Tremor</paragraph></td><td><paragraph>2.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Paresthesia</paragraph></td><td><paragraph>1.2</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Sedation</paragraph></td><td><paragraph>1.2</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Tension headache</paragraph></td><td><paragraph>1.2</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td/><td/></tr><tr><td><paragraph>Insomnia</paragraph></td><td><paragraph>12.3</paragraph></td><td><paragraph>6.1</paragraph></td></tr><tr><td><paragraph>Anxiety</paragraph></td><td><paragraph>8.2</paragraph></td><td><paragraph>2.4</paragraph></td></tr><tr><td><paragraph>Initial insomnia</paragraph></td><td><paragraph>4.3</paragraph></td><td><paragraph>2.8</paragraph></td></tr><tr><td><paragraph>Depressed mood</paragraph></td><td><paragraph>3.9</paragraph></td><td><paragraph>1.4</paragraph></td></tr><tr><td><paragraph>Nervousness</paragraph></td><td><paragraph>3.1</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Restlessness</paragraph></td><td><paragraph>3.1</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Agitation</paragraph></td><td><paragraph>2.2</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Aggression</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Bruxism</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Depression</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph>Libido decreased</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Affect lability</paragraph></td><td><paragraph>1.4</paragraph></td><td><paragraph>0.9</paragraph></td></tr><tr><td><paragraph>Confusional state</paragraph></td><td><paragraph>1.2</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Tension</paragraph></td><td><paragraph>1.2</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td></tr><tr><td><paragraph>Oropharyngeal pain</paragraph></td><td><paragraph>1.7</paragraph></td><td><paragraph>1.4</paragraph></td></tr><tr><td colspan="3"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hyperhidrosis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.9</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Included doses up to 108 mg (1.5 times the maximum recommended dosage of methylphenidate hydrochloride</paragraph><paragraph>extended-release tablets).</paragraph></td></tr></tbody></table>