Methylphenidate Hydrochloride

1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 15 years of age. 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 pediatric patients 6 to 15 years of age. (1) 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 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 Take orally once daily in the morning, before breakfast. Swallow whole with the aid of liquids, or sprinkle contents onto a small amount of applesauce and give immediately. Do not crush or chew the capsule or capsule contents. (2.1) Recommended starting dose is 20 mg once daily. Dosage may be increased 10 mg to 20 mg at weekly intervals; do not exceed 60 mg per day. (2.2) 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 (5.10) ] . 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 Dosage Recommendations The recommended starting dose of methylphenidate hydrochloride extended-release capsules is 20 mg once daily. Dosage may be adjusted in weekly 10 mg to 20 mg increments to the maximum recommended dose of 60 mg per day. Dosage should be individualized according to the needs and responses of the patient. 2.3 Administration Instructions Administer methylphenidate hydrochloride extended-release capsules orally once daily in the morning, before breakfast. Swallow the capsule whole with the aid of liquids. Alternatively, open the capsule and sprinkle the contents onto a small amount (tablespoon) of applesauce and administer immediately. Do not store for future use. Drink fluids following the intake of the sprinkled capsule contents with applesauce. The capsules and the capsule contents must not be crushed or chewed. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage 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 dosage. Avoid methylphenidate hydrochloride extended-release use in patients with known structural cardiac abnormalities, cardiomyopathy, se…

4 CONTRAINDICATIONS Methylphenidate hydrochloride extended-release capsules are contraindicated in patients with: known hypersensitivity to methylphenidate or other component of methylphenidate hydrochloride extended-release capsules. Angioedema has been reported in patients treated with methylphenidate hydrochloride extended-release capsules. Anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions (6) ] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crisis [see Drug Interactions (7) ] . Methylphenidate hydrochloride extended-release capsules contain sucrose. Therefore, patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine. Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release capsules. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 ) Use in patients with patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency. ( 4 )

7 DRUG INTERACTIONS Table 3 presents clinically important drug interactions with methylphenidate hydrochloride extended-release. Table 3: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4) ] . Intervention: Concomitant use of methylphenidate hydrochloride extended-release with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate hydrochloride extended-release may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3) ] . Intervention: Adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Monitor blood pressure and avoid use of methylphenidate hydrochloride extended-release in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: 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). Intervention: Monitor for signs of EPS. Antihypertensive Drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 )

8.1 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including 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 Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations ) . 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 53 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 doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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. 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 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 adults 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 (3 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 adults 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 (~2 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 Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2, 9.3) ] Hypersensitivity to Methylphenidate and Other Component of Methylphenidate Hydrochloride Extended-Release Capsules [see Contraindications (4) ] Hypertensive Crisis when Used Concomitantly with MAOIs [see Contraindications (4) and 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 most common adverse reactions (≥ 5% and twice the rate of placebo) were anorexia and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 practice. Clinical trials experience with methylphenidate hydrochloride extended-release included 188 pediatric patients 6 to 15 years old with ADHD exposed to methylphenidate hydrochloride extended-release. Patients received methylphenidate hydrochloride extended-release 20 mg, 40 mg, and/or 60 mg per day. The 188 patients were evaluated in the following studies: Study 1, a 3-week placebo-controlled clinical study consisting of a total of 314 pediatric patients (ages 6 to 15 years; methylphenidate hydrochloride extended-release n=155); Study 2, a placebo-controlled, crossover clinical study consisting of 25 pediatric patients (ages 7 to 12 years); and Study 3, an uncontrolled clinical study consisting of 8 pediatric patients (ages 6 to 10 years). Adverse Reactions Leading to Discontinuation of Treatment In the 3-week placebo-controlled, parallel-group trial, two methylphenidate hydrochloride extended-release-treated patients (1%) and no placebo-treated patients discontinued due to an adverse reaction (rash and pruritus; and headache, abdominal pain, and dizziness, respectively). Most Common Adverse Reactions The most common adverse reactions that occurred in 5% or more of patients treated with methylphenidate hydrochloride extended-release in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate hydrochloride extended-release was at least twice the incidence in placebo-treated patients were anorexia and insomnia. Adverse reactions that occurred in ≥ 5% of patients treated with methylphenidate hydrochloride extended-release and greater than placebo in pooled Studies 1, 2, and 3 are presented in Table 2: Table 2: Adverse Reactions (≥ 5% and Greater than Placebo) in Pediatric Patients Ages 6 to 15 Years Receiving Methylphenidate Hydrochloride Extended-Release in Pooled Three to Four Week Trials Body System Preferred Term Methylphenidate Hydrochloride Extended-Release (n=188) % Placebo (n=190) % General Headache 12 8 Abdominal Pain (stomachache) 7 4 Digestive System Anorexia 9 2 Nervous System Insomnia 5 2 6.2 Post-marketing Experience The following adverse reactions have been identified during post-marketing use of methylphenidate hydrochloride extended-release and other methylphenidate hydrochloride produ…