Methylphenidate Hydrochloride

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 tablets and 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 [see Warnings and Precautions ( 5.7 )] The following adverse reactions associated with the use of methylphenidate hydrochloride tablets, 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 Tablets and 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 choreoatheetoid 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 tablets and 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: 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 Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride tablets or 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 tablets or 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 )

11 DESCRIPTION Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, a CNS stimulant. They are available as tablets of 5 mg, 10 mg, and 20 mg strength for oral administration. Methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a CNS stimulant. They are 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 tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc. Methylphenidate hydrochloride extended-release tablets contain the following inactive ingredients: hydroxypropyl methylcellulose 2208, magnesium stearate, microcrystalline cellulose, and talc. Note : Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are color-additive free. Chemical Structure

2 DOSAGE AND ADMINISTRATION Methylphenidate Hydrochloride Tablets ( 2.2 ): Pediatric Patients 6 Years and Older: Start with 5 mg twice daily (before breakfast and lunch), titrating the dose weekly in 5- to 10-mg increments. Dosages above 60 mg/day are not recommended. Adults: Average daily dosage is 20 mg to 30 mg, administered 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. 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 tablets or 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 tablets or 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 Tablets Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5 to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults: Average dosage is 20 to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. Methylphenidate Hydrochloride Extended-Release Tablets 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 tablets and 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 tablets or methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

1 INDICATIONS AND USAGE Methylphenidate hydrochloride tablets and 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 Methylphenidate hydrochloride is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy. ( 1 )

9.2 Abuse CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving. Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage ( 10 )] . To reduce the abuse of CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling ( 16 )] , monitor for signs of abuse while on therapy, and reevaluate the need for methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets use.

9.1 Controlled Substance Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a Schedule II controlled substance.

9.3 Dependence Tolerance Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Dependence Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving. Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage ( 10 )] . To reduce the abuse of CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling ( 16 )] , monitor for signs of abuse while on therapy, and reevaluate the need for methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets use. 9.3 Dependence Tolerance Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Dependence Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

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.

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7.1 ) Halogenated Anesthetics: Avoid use of methylphenidate hydrochloride tablets or 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 Tablets and Methylphenidate Hydrochloride Extended-Release Tablets Table 1 presents clinically important drug interactions with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Tablets and Methylphenidate Hydrochloride Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride tablets and 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 tablets or 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 tablets and 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 tablets or 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 tablets or 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 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate’s major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. Effect of Food After a high-fat meal, both area under the curve (AUC) (by 25%) and C max (by 27%) are higher. Time to C max (T max ) is faster after a high-fat meal (median T max : 2.5 hours) as compared to without food (median T max : 3 hours). Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended-release tablets. Studies in Specific Populations Male and Female Patients In a clinical study involving adult subjects who received methylphenidate hydrochloride extended-release tablets, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride’s plasma concentration in the same subjects. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochoride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochoride has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.

12.1 Mechanism of Action Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known.

12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.

12.3 Pharmacokinetics Absorption Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate’s major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. Effect of Food After a high-fat meal, both area under the curve (AUC) (by 25%) and C max (by 27%) are higher. Time to C max (T max ) is faster after a high-fat meal (median T max : 2.5 hours) as compared to without food (median T max : 3 hours). Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended-release tablets. Studies in Specific Populations Male and Female Patients In a clinical study involving adult subjects who received methylphenidate hydrochloride extended-release tablets, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride’s plasma concentration in the same subjects. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochoride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochoride has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.

20220923

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3 DOSAGE FORMS AND STRENGTHS Tablets 5 mg, round, white unscored tablet debossed with 5 on one side and a on the other side 10 mg, round, white scored tablet debossed with 10 on one side of the tablet and a M on the other side 20 mg, round, white scored tablet debossed with 20 on one side of the tablet and a on the other side Extended-Release Tablets 10 mg extended-release tablets, round, white to off-white tablet, debossed with 1423 on one side and a on the other side 20 mg extended-release tablets, round, white to off-white tablet, debossed with 1451 on one side and a on the other side Tablets: 5 mg, 10 mg, and 20 mg ( 3 ) Extended-Release Tablets: 10 mg and 20 mg ( 3 ) Boxed M Boxed M Boxed M Boxed M

Methylphenidate Hydrochloride Methylphenidate Hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE TALC 5;M Methylphenidate Hydrochloride Methylphenidate Hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE TALC 10;M Methylphenidate Hydrochloride Methylphenidate Hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE TALC 20;M Methylphenidate Hydrochloride Methylphenidate Hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE HYPROMELLOSE 2208 (15000 MPA.S) MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE TALC to off-white 1423;M Methylphenidate Hydrochloride Methylphenidate Hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE HYPROMELLOSE 2208 (15000 MPA.S) MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE TALC to off-white 1451;M

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.

ANDA075629

Methylphenidate Hydrochloride

Methylphenidate Hydrochloride

0406-1445

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - Methylphenidate Hydrochloride Tablet USP (5 mg bottle of 100) NDC 0406- 1142 -01 100 TABLETS Methylphenidate Hydrochloride Tablets USP CII Rx only 5 mg Each tablet contains: Methylphenidate Hydrochloride USP......5 mg PHARMACIST: Dispense the Medication Guide provided separately to each patient. Mallinckrodt™ L0M125 Rev 09/2022 Methylphenidate Hydrochloride Tablet USP (5 mg bottle of 100)

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Controlled Substance Status/High Potential for Abuse and Dependence Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets to anyone else. Advise patients to store methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence ( 9.1 , 9.2 , 9.3 ), How Supplied/Storage and Handling ( 16 )] . Serious Cardiovascular Risks Advise patients that there is a potential serious cardiovascular risk, including sudden death, myocardial infarction, stroke, and hypertension with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions ( 5.2 )] . Blood Pressure and Heart Rate Increases Instruct patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions ( 5.3 )] . Psychiatric Risks Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )] . Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.5 )] . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions ( 5.6 )] . Suppression of Growth Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss [see Warnings and Precautions ( 5.7 )] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, during pregnancy [see Use in Specific Populations ( 8.1 )] . Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and are trademarks of a Mallinckrodt company. © 2022 Mallinckrodt. Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Rev 09/2022 Mallinckrodt™ Pharmaceuticals An electronic copy of the medication guide for Methylphenidate Hydrochloride Tablets USP can be obtained from www.mallinckrodt.com/Medguide/L20M46.pdf or by calling 1-800-778-7898 for alternate delivery options. An electronic copy of the medication guide for Methylphenidate Hydrochloride Extended-Release Tablets USP can be obtained from www.mallinckrodt.com/Medguide/L20M47.pdf or by calling 1-800-778-7898 for alternate delivery options. Boxed M

MEDICATION GUIDE This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 09/2022 Methylphenidate Hydrochloride Tablets USP Methylphenidate Hydrochloride Extended-Release Tablets USP (METH il FEN i date) CII What is the most important information I should know about methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are federal controlled substances (CII) because they can be abused or lead to dependence. Keep methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in a safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may harm others, and is against the law. Tell your doctor if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines: 1. Heart-related problems: sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Call your doctor right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. 2. Mental (psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are a central nervous system (CNS) stimulant prescription medicine. They are used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are also used in the treatment of a sleep disorder called narcolepsy. It is not known if methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are safe and effective in children under 6 years of age. Who should not take methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI). Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, tell your or your child’s doctor about all health conditions (or a family history of), including: heart problems, heart defects, high blood pressure mental problems, including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Tell your doctor about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Your doctor will decide whether methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets can be taken with other medicines. Especially tell your doctor if you or your child takes: anti-depression medicines, including MAOIs blood pressure medicines (antihypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets without talking to your doctor first. How should methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets be taken? Take methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride tablets are usually taken 2 to 3 times a day. Take methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal. The effect of a dose of methylphenidate hydrochloride extended-release tablets usually lasts about 8 hours. Do not chew or crush methylphenidate hydrochloride extended-release tablets. Swallow methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow methylphenidate hydrochloride extended-release tablets whole. A different medicine may need to be prescribed. From time-to-time, your doctor may stop methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets treatment for a while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets treatment may be stopped if a problem is found during these check-ups. In case of poisoning, call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. What are the possible side effects of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: See “What is the most important information I should know about methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets?” for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your doctor if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Slowing of growth (height and weight) in children Common side effects include: • fast heartbeat • sweating a lot • abnormal heartbeat (palpitations) • decreased appetite • headache • dry mouth • trouble sleeping • nausea • nervousness • stomach pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Store methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). Protect methylphenidate hydrochloride tablets from light. Protect methylphenidate hydrochloride extended-release tablets from moisture. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets by a medicine take-back program at authorized collection sites, such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away (discard) methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in the household trash. Keep methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. What are the ingredients in methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets? Active ingredient: methylphenidate hydrochloride USP Inactive ingredients: Methylphenidate hydrochloride tablets: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc. Methylphenidate hydrochloride extended-release tablets: hydroxypropyl methylcellulose 2208, magnesium stearate, microcrystalline cellulose, and talc. Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Mallinckrodt™ For more information and request for additional copies of the Medication Guide, visit www.mallinckrodt.com or call 1-800-778-7898.

8.5 Geriatric Use Methylphenidate hydrochloride has not been studied in the geriatric population.

8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

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 tablets and 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/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 postnatal 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 tablets and 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 (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 (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 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 tablets and 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/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 postnatal 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 tablets and 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 (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 (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 the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride has not been studied in the geriatric population.

16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate Hydrochloride Tablets USP 5 mg tablets available as a round, white unscored tablet debossed with 5 on one side and a on the other side Bottles of 100........................NDC 0406-1142-01 10 mg tablets available as a round, white scored tablet debossed with 10 on one side of the tablet and a M on the other side Bottles of 100........................NDC 0406-1144-01 20 mg tablets available as a round, white scored tablet debossed with 20 on one side of the tablet and a on the other side Bottles of 100........................NDC 0406-1146-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container with child-resistant closure. Methylphenidate Hydrochloride Extended-Release Tablets USP 10 mg extended-release tablets available as a round, white to off-white tablet, debossed with 1423 on one side and a on the other side Bottles of 100........................NDC 0406-1445-01 20 mg extended-release tablets available as a round, white to off-white tablet, debossed with 1451 on one side and a on the other side Bottles of 100........................NDC 0406-1473-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container with child-resistant closure. Note : Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are color-additive free. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets by a medicine take-back 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 tablets or methylphenidate hydrochloride extended-release tablets 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 tablets or methylphenidate hydrochloride extended-release tablets in the household trash. Boxed M Boxed M Boxed M Boxed M

WARNING: ABUSE AND DEPENDENCE CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] . WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. ( 5.1 , 9.2 , 9.3 ) Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. ( 5.1 , 9.2 )