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 a higher dosage 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 methylphenidate hydrochloride extended-release tablets, 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) , Drug Abuse and Dependence ( 9.2 , 9.3 )] . 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 methylphenidate hydrochloride extended-release tablets, 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 N/A • 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: 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: Carefully assess for digital changes 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 height or weight as expected may need to have their Methylphenidate hydrochloride extended-release tablets treatment interrupted. ( 5.7 ) • 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. ( 5.8 ) • 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. ( 5.9 ) • Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Regularly monitor patients for the emergence or Methylphenidate hydrochloride extended-release tablets worsening of tics or Tourette's syndrome. Discontinue Methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate. ( 5.10 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets has 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 [see Drug Abuse and Dependence ( 9.1 , 9.2 )] . 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 dosage 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 treated with CNS stimulants at the recommended ADHD dosage. Prior to treating patients with methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). 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 may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6) ] . 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 Preexisting Psychosis in Patients with a Psychotic Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may induce a manic or mixed mood episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets), 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 hydrochloride extended-release tablets. 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 but developed after some time., often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 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, including methylphenidate hydrochloride extended-release tablets used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions (6) ] . 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 postmarketing reports at different times and at a therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of these cases of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation of drug. During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. 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 non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients treated with methylphenidate (i.e., treatment for 7 days per week throughout the year) have 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 period of development. Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release tablets-treated pediatric patients. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 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. 5.9 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 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. 5.10 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 methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette' syndrome 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 methylphenidate hydrochloride extended-release tablets 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) ] Hypertensive crisis with Concomitant Use of 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) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.10) ] The following adverse reactions associated with the use of methylphenidate were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with Methylphenidate Hydrochloride Extended-Release Tablets • Infections and Infestations: nasopharyngitis • Blood and the Lymphatic System Disorders : leukopenia, thrombocytopenia, anemia • Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis • Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients • Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood • Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs • Eye Disorders: blurred vision, difficulties in visual accommodation • Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris • Respiratory, Thoracic and Mediastinal Disorders: cough • Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia • Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury • Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura • Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis • Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions reported with other methylphenidate-containing products. • Blood and Lymphatic Disorders: pancytopenia • Immune System Disorders: hypersensitivity reactions such as auricular swelling, bullous conditions, eruptions, exanthemas • Psychiatric Disorders: affect lability, mania, disorientation and libido changes • Nervous System Disorders: migraine • Eye Disorders: diplopia, mydriasis • Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole • Vascular Disorders: peripheral coldness, Raynaud's phenomenon • Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea • Gastrointestinal Disorders: diarrhea, constipation • Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption • Musculoskeletal, Connective Tissue and bone Disorders: myalgia, muscle twitching • Renal and Urinary Disorders: hematuria • Reproductive System and Breast Disorders: gynecomastia • General Disorders: fatigue, hyperpyrexia • Urogenital Disorders : priapism Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc. at 1-877-770-3138 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.