Methylphenidate Hydrochloride

1 INDICATIONS AND USAGE Methylphenidate HCl Extended-Release Tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see Clinical Studies (14) ] . Limitations of Use The use of Methylphenidate HCl Extended-Release Tablets is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.8) , Use in Specific Populations (8.4) ]. Methylphenidate HCl Extended-Release Tablets is a CNS stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65. ( 1 ) Limitations of Use The use of Methylphenidate HCl Extended-Release Tablets is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.8 , 8.4 ).

2 DOSAGE AND ADMINISTRATION Methylphenidate HCl Extended-Release Tablets should be taken once daily in the morning and swallowed whole with the aid of liquids. Methylphenidate HCl Extended-Release Tablets should not be chewed or crushed. Methylphenidate HCl Extended-Release Tablets may be taken with or without food. ( 2.2 ) For children and adolescents new to methylphenidate, the recommended starting dosage is 18 mg once daily. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 54 mg/day in children and 72 mg/day in adolescents. ( 2.3 ) For adult patients new to methylphenidate, the recommended starting dose is 18 or 36 mg/day. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 72 mg/day for adults. ( 2.3 ) For patients currently using methylphenidate, dosing is based on current dose regimen and clinical judgment. ( 2.4 ) 2.1 Pretreatment Screening Prior to treating patients with Methylphenidate HCl Extended-Release Tablets, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2) ] . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Methylphenidate HCl Extended-Release Tablets [see Warnings and Precautions (5.13) ] . 2.2 Recommended Dosage Methylphenidate HCl Extended-Release Tablets should be administered orally once daily in the morning with or without food. Methylphenidate HCl Extended-Release Tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17) ] . 2.3 Patients New to Methylphenidate The recommended starting dose of Methylphenidate HCl Extended-Release Tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1 ). Table 1 . Methylphenidate HCl Extended-Release Tablets Recommended Starting Doses and Dose Ranges Patient Age Recommended Starting Dose Dose Range Children 6-12 years of age 18 mg/day 18 mg - 54 mg/day Adolescents 13-17 years of age 18 mg/day 18 mg - 72 mg/day not to exceed 2 mg/kg/day Adults 18-65 years of age 18 or 36 mg/day 18 mg - 72 mg/day 2.4 Patients Currently Using Methylphenidate The recommended dose of Methylphenidate HCl Extended-Release Tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily. Table 2 . Recommended Dose Conversion from Methylphenidate Regimens to Methylphenidate HCl Extended-Release Tablets Previous Methylphenidate Daily Dose Recommended Methylphenidate HCl Extended-Release Tablets Starting Dose 5 mg Methylphenidate twice daily or three times daily 18 mg every morning 10 mg Methylphenidate twice daily or three times daily 36 mg every morning 15 mg Methylphenidate twice daily or three times daily 54 mg every morning 20 mg Methylphenidate twice daily or three times daily 72 mg every morning Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose. 2.5 Dose Titration Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended. A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages. 2.6 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue Methylphenidate HCl E…

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 i…

4 CONTRAINDICATIONS Known hypersensitivity to the product ( 4.1 ) Do not use Methylphenidate HCl Extended-Release Tablets in patients currently using or within 2 weeks of using an MAO inhibitor ( 4.2 ) 4.1 Hypersensitivity to Methylphenidate Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with Methylphenidate HCl Extended-Release Tablets. Therefore, Methylphenidate HCl Extended-Release Tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.5) ] . 4.2 Monoamine Oxidase Inhibitors Methylphenidate HCl Extended-Release Tablets are contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions (7.1) ] .

7 DRUG INTERACTIONS Methylphenidate HCl Extended-Release Tablets may increase blood pressure; use cautiously with vasopressors ( 7.2 ) Inhibition of metabolism of coumarin anticoagulants, anticonvulsants, and some antidepressants ( 7.3 ) 7.1 MAO Inhibitors Methylphenidate HCl Extended-Release Tablets should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.2) ] . 7.2 Vasopressor Agents Because of possible increases in blood pressure, Methylphenidate HCl Extended-Release Tablets should be used cautiously with vasopressor agents [see Warnings and Precautions (5.3) ] . 7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. 7.4 Halogenated Anesthetics Concomitant use of halogenated anesthetics and Methylphenidate HCl Extended-Release Tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Monitor blood pressure and avoid use of Methylphenidate HCl Extended-Release Tablets in patients being treated with anesthetics on the day of surgery. 7.5 Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

8.1 Pregnancy Pregnancy Category C Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of Methylphenidate HCl Extended-Release Tablets on a mg/kg and mg/m 2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1-2 times that seen in trials in volunteers and patients with the maximum recommended dose of Methylphenidate HCl Extended-Release Tablets based on the AUC. The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. Methylphenidate HCl Extended-Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Methylphenidate HCl Extended-Release Tablets are administered to a nursing woman. In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.

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 clinica…