methylphenidate hydrochloride extended release

1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of: • Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults • Narcolepsy Limitations of Use: The use of Methylphenidate hydrochloride 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 tablet is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy (1). Limitations of Use: The use of Methylphenidate hydrochloride 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 and 8.4).

2 DOSAGE AND ADMINISTRATION Methylphenidate hydrochloride extended-release tablets (2.2): • May switch to Methylphenidate hydrochloride extended-release tablets when the 8-hour dosage of Methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. • Must be swallowed whole and never crushed or chewed. 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including Methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)] . Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for Methylphenidate hydrochloride extended-release tablets use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)] . 2.2 General Dosing Information Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, Methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of Methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Methylphenidate hydrochloride extended-release tablets, and adjust dosage as needed. 2.3 Dose Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue Methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

3 DOSAGE FORMS AND STRENGTHS • 10 mg extended-release tablets, white to off-white, round, biconvex tablets debossed “K75” on one side and plain on the other side. • 20 mg extended-release tablets, white to off-white, round, biconvex tablets debossed “K76” on one side and plain on the other side. • Extended-Release Tablets: 10 mg and 20 mg (3)

4 CONTRAINDICATIONS • Hypersensitivity to methylphenidate or other components of Methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate [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 crises [see Drug Interactions (7.1)] . • Known hypersensitivity to methylphenidate or other product components of Methylphenidate hydrochloride extended-release tablets (4). • Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days (4).

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Abuse and Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)] • Known hypersensitivity to methylphenidate or other ingredients of Methylphenidate hydrochloride extended-release tablets [see Contraindications (4)] • Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)] • Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)] • Blood Pressure and Heart Rate Increases [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)] The following adverse reactions associated with the use of Methylphenidate hydrochloride extended-release tablets and other methylphenidate products 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 not listed for Methylphenidate hydrochloride extended-release tablets that have been 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: mya …

7 DRUG INTERACTIONS • Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed (7.1). • Halogenated anesthetics: Avoid use of Methylphenidate hydrochloride extended-release tablets on the day of surgery if halogenated anesthetics will be used (7.1). 7.1 Clinically Important Drug Interactions with Methylphenidate hydrochloride extended-release tablets Table 1 presents clinically important drug interactions with Methylphenidate hydrochloride extended-release tablets. Table 1: Clinically Important Drug Interactions with Methylphenidate hydrochloride extended-release tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Methylphenidate hydrochloride extended-release tablets 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 tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Examples Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and Methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane Risperidone Clinical Impact Combined use of methylphenidate with risperidone when there is 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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ Risk Summary Published studies and postmarketing 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/m2 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 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 tablets, 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 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 (15times 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 (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 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 (~2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on …

11 DESCRIPTION Methylphenidate hydrochloride extended-release tablet contains methylphenidate hydrochloride, a CNS stimulant. It is available as extended-release tablets of 10 mg and 20 mg strength for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Methylphenidate hydrochloride extended-release tablet contains the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, and talc. chemical structure

10 OVERDOSAGE Human Experience Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (which may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis. Overdose Management Consult with a Certified Poison Control Center (1-800-222-1222) for the latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate hydrochloride extended-release tablets, USP are available as follows: Tablets 10 mg – White to off-white, round, biconvex tablets debossed “K75” on one side and plain on the other side. Bottles of 60 NDC 10702-075-06 Bottles of 100 NDC 10702-075-01 Tablets 20 mg – White to off-white, round, biconvex tablets debossed “K76” on one side and plain on the other side. Bottles of 60 NDC 10702-076-06 Bottles of 100 NDC 10702-076-01 Note: Methylphenidate hydrochloride extended-release tablets are color additive free. Store at 20°C to 25°C (68°F to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F). [see USP controlled room temperature]. Protect from moisture. Dispense in tight, light-resistant container, as defined in the USP, with a child-resistant closure. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets, USP by a medicine takeback program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride extended-release tablets, USP with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard Methylphenidate hydrochloride extended-release tablets, USP in the household trash.