Methylphenidate Hydrochloride

WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate HCl 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 HCl 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 HCl 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 HCl 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 HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets, can result in overdose and death ( 5.1 , 9.2 , 10 ): • Before prescribing Methylphenidate HCl 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 in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increase in Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating Methylphenidate HCl Extended-Release Tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing Methylphenidate HCl Extended-Release Tablets. ( 5.4 ) Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.5 ) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.6 ) Peripheral Vasculopathy, including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during Methylphenidate HCl Extended-Release Tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 ) 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 treatment interrupted. ( 5.8 ) Gastrointestinal obstruction with preexisting GI narrowing. ( 5.9 ) Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ( 5.10 ) Acute Angle Closure Glaucoma: Methylphenidate HCl 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. ( 5.11 ) Increased Intraocular Pressure and Glaucoma: Prescribe Methylphenidate HCl 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. ( 5.12 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating Methylphenidate HCl 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. ( 5.13 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate HCl Extended-Release Tablets have a high potential for abuse and misuse. The use of Methylphenidate HCl Extended-Release Tablets expose individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate HCl Extended-Release Tablets can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ] . Misuse and abuse of CNS stimulants, including Methylphenidate HCl 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 HCl 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 HCl Extended-Release Tablets in a safe place, preferably locked, and instruct patients to not give Methylphenidate HCl Extended-Release Tablets to anyone else. Throughout Methylphenidate HCl 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 treated with CNS stimulants at the recommended ADHD dosage. Avoid Methylphenidate HCl 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 may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all Methylphenidate HCl 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 pre-existing 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 HCl Extended-Release Tablets treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or 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 with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Methylphenidate HCl Extended-Release Tablets. 5.5 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. 5.6 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients [see Adverse Reactions (6.5) ] . 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 methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate HCl Extended-Release Tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.7 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including Methylphenidate HCl 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 dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during Methylphenidate HCl Extended-Release Tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Methylphenidate HCl Extended-Release Tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.8 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate HCl 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 children 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 children 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 HCl 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. 5.9 Potential for Gastrointestinal Obstruction Because the Methylphenidate HCl Extended-Release Tablet is nondeformable and does not appreciably change in shape in the GI tract, Methylphenidate HCl 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 controlled-release design of the tablet, Methylphenidate HCl Extended-Release Tablets should only be used in patients who are able to swallow the tablet whole [see Patient Counseling Information (17) ] . 5.10 Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy. 5.11 Acute Angle Closure Glaucoma There have been rare reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, Methylphenidate HCl 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. 5.12 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.5) ] . Prescribe Methylphenidate HCl 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 HCl Extended-Release Tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.13 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 (6.2 , 6.5 )] . Worsening of Tourette’s syndrome has also been reported. Before initiating Methylphenidate HCl Extended-Release Tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor Methylphenidate HCl 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 Boxed Warning , Warnings and Precautions (5.1) ] Hypersensitivity to Methylphenidate [see Contraindications (4.1) ] Monoamine Oxidase Inhibitors [see Contraindications (4.2) 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) ] Seizures [see Warnings and Precautions (5.5) ] Priapism [see Warnings and Precautions (5.6) ] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.7) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.8) ] Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.9) ] Hematologic Monitoring [see Warnings and Precautions (5.10) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.11) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.12) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.13) ] The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Adverse Reactions (6.1) ] . The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3) ] . The development program for Methylphenidate HCl Extended-Release Tablets included exposures in a total of 3906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3 ). Safety was assessed by collecting adverse events, vital signs, weights, ECGs, and by performing physical examinations and laboratory analyses. Table 3. Methylphenidate HCl Extended-Release Tablets Exposure in Double-Blind and Open-Label Clinical Studies Patient Population N Dose Range Children 2216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults 1188 18 to 108 mg once daily Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Methylphenidate HCl Extended-Release Tablets based on the comprehensive assessment of the available adverse event information. A causal association for Methylphenidate HCl Extended-Release Tablets often cannot be reliably established in individual cases. Further, 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 majority of adverse reactions were mild to moderate in severity. The most common adverse reaction in double-blind clinical trials (>5%) in children and adolescents was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis. ( 6.1 and 6.2 ) The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased. ( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Kremers Urban Pharmaceuticals Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Commonly Observed 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. Children and Adolescents Table 4 lists the adverse reactions reported in 1% or more of Methylphenidate HCl Extended-Release Tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials. Table 4. Adverse Reactions Reported by ≥1% of Methylphenidate HCl Extended-Release Tablets-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate HCl Extended-Release Tablets System/Organ Class Adverse Reaction Methylphenidate HCl 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 Terms of Initial insomnia (Methylphenidate=0.6%) and Insomnia (Methylphenidate=2.2%) are combined into Insomnia. 2.8 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 0.9 Oropharyngeal pain 1.2 0.9 The majority of adverse reactions were mild to moderate in severity. Adults Table 5 lists the adverse reactions reported in 1% or more of Methylphenidate HCl Extended-Release Tablets-treated adults in 2 placebo-controlled, double-blind clinical trials. Table 5. Adverse Reactions Reported by ≥1% of Methylphenidate HCl Extended-Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials Included doses up to 108 mg. System/Organ Class Adverse Reaction Methylphenidate HCl 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 The majority of ADRs were mild to moderate in severity. 6.2 Other Adverse Reactions Observed in Methylphenidate HCl Extended-Release Tablets Clinical Trials This section includes adverse reactions reported by Methylphenidate HCl Extended-Release Tablets-treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by Methylphenidate HCl Extended-Release Tablets -treated subjects 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 6.3 Discontinuation Due to Adverse Reactions Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 Methylphenidate HCl Extended-Release Tablets patients (0.6%) 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 2 placebo-controlled studies of adults, 25 Methylphenidate HCl Extended-Release Tablets patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the Methylphenidate HCl Extended-Release Tablets patients 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 11 open-label studies of children, adolescents, and adults, 266 Methylphenidate HCl Extended-Release Tablets patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). 6.4 Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in children (Studies 1 and 2), both Methylphenidate HCl 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 adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with Methylphenidate HCl 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 Methylphenidate HCl 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 Methylphenidate HCl 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 Methylphenidate HCl 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 Methylphenidate HCl 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 Methylphenidate HCl 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) ] . 6.5 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of Methylphenidate HCl 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: 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><caption>Table 3. Methylphenidate HCl Extended-Release Tablets Exposure in Double-Blind and Open-Label Clinical Studies</caption><col width="1px"/><col width="1px"/><col/><thead><tr><th valign="top" styleCode=" Rrule">Patient Population</th><th valign="top" styleCode=" Rrule">N</th><th valign="top">Dose Range</th></tr></thead><tbody><tr><td valign="top" styleCode=" Rrule"> Children</td><td valign="top" styleCode=" Rrule"> 2216</td><td valign="top" styleCode=" Botrule"> 18 to 54 mg once daily</td></tr><tr><td valign="top" styleCode=" Rrule"> Adolescents</td><td valign="top" styleCode=" Rrule"> 502</td><td valign="top" styleCode=" Botrule"> 18 to 72 mg once daily</td></tr><tr><td valign="top" styleCode=" Rrule"> Adults</td><td valign="top" styleCode=" Rrule"> 1188</td><td valign="top"> 18 to 108 mg once daily</td></tr></tbody></table>

<table><caption>Table 4. Adverse Reactions Reported by &#x2265;1% of Methylphenidate HCl Extended-Release Tablets-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate HCl Extended-Release Tablets</caption><col width="1px"/><col width="1px"/><col width="1px"/><tbody><tr><td styleCode=" Rrule"><content styleCode="bold">System/Organ Class </content> Adverse Reaction</td><td align="center" valign="top" styleCode=" Rrule"><content styleCode="bold">Methylphenidate HCl Extended-Release Tablets (n=321) % </content></td><td align="center" valign="top" styleCode=" Botrule"><content styleCode="bold">Placebo (n=318) % </content></td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Abdominal pain upper</td><td align="center" valign="top" styleCode=" Rrule"> 6.2</td><td align="center" valign="top"> 3.8</td></tr><tr><td valign="top" styleCode=" Rrule"> Vomiting</td><td align="center" valign="top" styleCode=" Rrule"> 2.8</td><td align="center" valign="top"> 1.6</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Pyrexia</td><td align="center" valign="top" styleCode=" Rrule"> 2.2</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Infections and Infestations</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Nasopharyngitis</td><td align="center" valign="top" styleCode=" Rrule"> 2.8</td><td align="center" valign="top"> 2.2</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Nervous System Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Dizziness</td><td align="center" valign="top" styleCode=" Rrule"> 1.9</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Insomnia<footnote ID="FOOT_5597">Terms of Initial insomnia (Methylphenidate=0.6%) and Insomnia (Methylphenidate=2.2%) are combined into Insomnia.</footnote></td><td align="center" valign="top" styleCode=" Rrule"> 2.8</td><td align="center" valign="top"> 0.3</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Cough</td><td align="center" valign="top" styleCode=" Rrule"> 1.9</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"> Oropharyngeal pain</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0.9</td></tr></tbody></table>

<table><caption>Table 5. Adverse Reactions Reported by &#x2265;1% of Methylphenidate HCl Extended-Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials<footnote ID="FOOT_5598">Included doses up to 108 mg.</footnote></caption><col width="1px"/><col width="1px"/><col width="1px"/><tbody><tr><td styleCode=" Rrule"><content styleCode="bold">System/Organ Class </content> Adverse Reaction</td><td align="center" valign="top" styleCode=" Rrule"><content styleCode="bold">Methylphenidate HCl Extended-Release Tablets (n=415) %</content></td><td align="center" valign="top" styleCode=" Botrule"><content styleCode="bold">Placebo (n=212) %</content></td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Cardiac Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Tachycardia</td><td align="center" valign="top" styleCode=" Rrule"> 4.8</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"> Palpitations</td><td align="center" valign="top" styleCode=" Rrule"> 3.1</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Ear and Labyrinth Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Vertigo</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Eye Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Vision blurred</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Dry mouth</td><td align="center" valign="top" styleCode=" Rrule"> 14.0</td><td align="center" valign="top"> 3.8</td></tr><tr><td valign="top" styleCode=" Rrule"> Nausea</td><td align="center" valign="top" styleCode=" Rrule"> 12.8</td><td align="center" valign="top"> 3.3</td></tr><tr><td valign="top" styleCode=" Rrule"> Dyspepsia</td><td align="center" valign="top" styleCode=" Rrule"> 2.2</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"> Vomiting</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Constipation</td><td align="center" valign="top" styleCode=" Rrule"> 1.4</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Irritability</td><td align="center" valign="top" styleCode=" Rrule"> 5.8</td><td align="center" valign="top"> 1.4</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Infections and Infestations</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Upper respiratory tract infection</td><td align="center" valign="top" styleCode=" Rrule"> 2.2</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Investigations</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Weight decreased</td><td align="center" valign="top" styleCode=" Rrule"> 6.5</td><td align="center" valign="top"> 3.3</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Decreased appetite</td><td align="center" valign="top" styleCode=" Rrule"> 25.3</td><td align="center" valign="top"> 6.6</td></tr><tr><td valign="top" styleCode=" Rrule"> Anorexia</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Muscle tightness</td><td align="center" valign="top" styleCode=" Rrule"> 1.9</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Nervous System Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Headache</td><td align="center" valign="top" styleCode=" Rrule"> 22.2</td><td align="center" valign="top"> 15.6</td></tr><tr><td valign="top" styleCode=" Rrule"> Dizziness</td><td align="center" valign="top" styleCode=" Rrule"> 6.7</td><td align="center" valign="top"> 5.2</td></tr><tr><td valign="top" styleCode=" Rrule"> Tremor</td><td align="center" valign="top" styleCode=" Rrule"> 2.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Paresthesia</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"> Sedation</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"> Tension headache</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Insomnia</td><td align="center" valign="top" styleCode=" Rrule"> 12.3</td><td align="center" valign="top"> 6.1</td></tr><tr><td valign="top" styleCode=" Rrule"> Anxiety</td><td align="center" valign="top" styleCode=" Rrule"> 8.2</td><td align="center" valign="top"> 2.4</td></tr><tr><td valign="top" styleCode=" Rrule"> Initial insomnia</td><td align="center" valign="top" styleCode=" Rrule"> 4.3</td><td align="center" valign="top"> 2.8</td></tr><tr><td valign="top" styleCode=" Rrule"> Depressed mood</td><td align="center" valign="top" styleCode=" Rrule"> 3.9</td><td align="center" valign="top"> 1.4</td></tr><tr><td valign="top" styleCode=" Rrule"> Nervousness</td><td align="center" valign="top" styleCode=" Rrule"> 3.1</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Restlessness</td><td align="center" valign="top" styleCode=" Rrule"> 3.1</td><td align="center" valign="top"> 0</td></tr><tr><td valign="top" styleCode=" Rrule"> Agitation</td><td align="center" valign="top" styleCode=" Rrule"> 2.2</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Aggression</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Bruxism</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Depression</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"> Libido decreased</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Affect lability</td><td align="center" valign="top" styleCode=" Rrule"> 1.4</td><td align="center" valign="top"> 0.9</td></tr><tr><td valign="top" styleCode=" Rrule"> Confusional state</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"> Tension</td><td align="center" valign="top" styleCode=" Rrule"> 1.2</td><td align="center" valign="top"> 0.5</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Oropharyngeal pain</td><td align="center" valign="top" styleCode=" Rrule"> 1.7</td><td align="center" valign="top"> 1.4</td></tr><tr><td valign="top" styleCode=" Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td align="center" valign="top" styleCode=" Rrule"/><td align="center" valign="top"/></tr><tr><td valign="top" styleCode=" Rrule"> Hyperhidrosis</td><td align="center" valign="top" styleCode=" Rrule"> 5.1</td><td align="center" valign="top"> 0.9</td></tr></tbody></table>