methylphenidate hydrochloride

1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies ( 14 )] . Limitations of Use The use of methylphenidate hydrochloride extended-release capsules 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 ( 5.7 ), Use in Specific Populations ( 8.4 )] . Methylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. ( 1 ) Limitations of Use : The use of methylphenidate hydrochloride extended-release 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. ( 5.7 , 8.4 )

2 DOSAGE AND ADMINISTRATION Recommended starting dose for patients 6 years and older: 10 mg once daily with or without food in the morning. Dosage may be increased weekly in increments of 10 mg per day. Daily dosage above 60 mg is not recommended. ( 2.1 ) Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. ( 2.1 ) 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release capsules, 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 hydrochloride extended-release capsules [see Warnings and Precautions ( 5.10 )] . 2.2 Recommended Dosage The recommended starting dose of methylphenidate hydrochloride extended-release capsules in patients 6 years and older is 10 mg once daily orally in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient. The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended. 2.3 Administration Instructions Methylphenidate hydrochloride extended-release capsules may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, discontinue methylphenidate hydrochloride extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hydrochloride extended-release capsules.

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride extended-release, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release. ( 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 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 treatment interrupted. ( 5.7 ) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride extended-release-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 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: Before initiating methylphenidate hydrochloride extended-release, 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. ( 5.10 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release has a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release 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 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 hydrochloride extended-release, 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, 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 in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release to anyone else. Throughout methylphenidate hydrochloride extended-release 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 hydrochloride extended-release use in patients with known structural cardiac abnormal…

4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of the product. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions ( 6.1 )] . Concomitant treatment with monoamine oxidase inhibitors, and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of the risk of hypertensive crisis [see Drug Interactions ( 7.1 )] . Known hypersensitivity to methylphenidate or product components. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 )

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) 7.1 Clinically Important Interactions with Methylphenidate Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOIs) Do not administer methylphenidate hydrochloride extended-release capsules concomitantly or within 14 days after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Antihypertensive Drugs Methylphenidate hydrochloride extended-release capsules may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed [see Warnings and Precautions ( 5.3 )] . Halogenated Anesthetics Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of methylphenidate hydrochloride extended-release capsules in patients being treated with anesthetics on the day of surgery. 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 Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate hydrochloride extended-release during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Limited published studies report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at the highest dose of 60 mg/kg/day (6 times the MRHD given to adolescents) [see Data] . The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as methylphenidate hydrochloride extended-release, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (1.5 times the MRHD given to adolescents on a mg/m 2 basis).

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 ), and Drug Abuse and Dependence ( 9.2 , 9.3 )] Hypersensitivity to Methylphenidate [see Contraindications ( 4 )] Hypertensive Crisis with Concomitant Use of 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 )] 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 most common adverse reactions in double-blind clinical trials (> 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, decreased appetite, headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Studies with Other Methylphenidate Products in Children, Adolescents, and Adults with ADHD Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, increased blood pressure, increased heart rate, tachycardia, palpitations, hyperhidrosis, and pyrexia. Adverse Reactions in Studies with Methylphenidate Hydrochloride Extended-Release in Pediatric Patients with ADHD The safety data in this section is based on data from two one-week controlled clinical studies of methylphenidate hydrochloride extended-release in pediatric patients with ADHD, one in children ages 6 to 12 years (RP-BP-EF001, hereafter “Study 1”), and one in children and adolescents ages 6 to 17 years (RP-BP-EF002, hereafter “Study 2”). Two methylphenidate hydrochloride extended-release clinical studies evaluated a total of 256 patients with ADHD. Two hundred and forty-three (243) patients participated in the double-blind phase of these two clinical studies. Study 1 was a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over study to evaluate the time of onset, duration of efficacy, tolerability and safety of methylphenidate hydrochloride extended-release 15 mg, 20 mg, 30 mg, or 40 mg administered for one week in 26 pediatric patients aged 6 to 12 years who met DSM-IV criteria for ADHD [see Clinical Studies ( 14 )] . Most Common Adverse Reactions (incidence of ≥ 5% and at a rate at least twice placebo): abdominal pain, pyrexia and headache. Adverse Reactions Leading to Discontinuation: No subjects discontinued due to adverse reactions during the double-blind phase of this study. Study 2 was a randomized, double-blind, multicenter, placebo-controlled, parallel group, fixed-dose study of 10 mg, 15 mg, 20 mg, and 40 mg of methylphenidate hydrochloride extended-release administered for one week in 221 pediatric patients (6…