Methylphenidate Hydrochloride Extended-Release

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse and Dependence [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Hypersensitivity to Methylphenidate and Other Component of Methylphenidate HCl Extended-Release Capsules [see Contraindications ( 4 )] Hypertensive Crisis when Used Concomitantly with MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] 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 most common adverse reactions (≥ 5% and twice the rate of placebo) were anorexia and insomnia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 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 HCl extended-release capsules included 188 pediatric patients 6 to 15 years old with ADHD exposed to methylphenidate HCl extended-release capsules. Patients received methylphenidate HCl extended-release capsules 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 HCl extended-release capsules 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 HCl extended-release capsules-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 HCl extended-release capsules in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate HCl extended-release capsules 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 HCl extended-release capsules 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 HCl Extended-Release Capsules in Pooled Three to Four Week Trials Body System Preferred Term Methylphenidate HCl Extended-Release Capsules (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 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of methylphenidate HCl extended-release capsules and other methylphenidate HCl products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions with Methylphenidate HCl Extended-Release Capsules Blood and the lymphatic system disorders: thrombocytopenia Cardiac disorders: cardiac arrest, sudden death Immune system disorders: angioedema Musculoskeletal and connective tissue disorders: rhabdomyolysis Psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs Nervous system disorders : migraine, reversible ischemic neurological deficit, bruxism Skin and subcutaneous tissue disorders: fixed drug eruption Vascular disorders: peripheral coldness, Raynaud’s phenomenon Adverse Reactions with Other Methylphenidate HCl Products Blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia Cardiac disorders: palpitations, increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis Gastrointestinal disorders: nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation General disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Immune system disorders : hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Infections and infestations: nasopharyngitis Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching Nervous system disorders : nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough Skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash Urogenital disorders: priapism Vascular disorders: isolated cases of cerebral arteritis and/or occlusion

4 CONTRAINDICATIONS Methylphenidate HCl extended-release capsules are contraindicated in patients with: Known hypersensitivity to methylphenidate or other component of methylphenidate HCl extended-release capsules. Angioedema has been reported in patients treated with methylphenidate HCl 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 HCl 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 HCl 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 )

11 DESCRIPTION Methylphenidate HCl extended-release capsules contain methylphenidate hydrochloride, a CNS stimulant. The extended-release capsules comprise both immediate-release (IR) and extended-release (ER) beads such that 30% of the dose is provided by the IR component and 70% of the dose is provided by the ER component. Methylphenidate HCl extended-release capsules are available in six capsule strengths containing 10 mg (3 mg IR; 7 mg ER), 20 mg (6 mg IR; 14 mg ER), 30 mg (9 mg IR; 21 mg ER), 40 mg (12 mg IR; 28 mg ER), 50 mg (15 mg IR; 35 mg ER), or 60 mg (18 mg IR; 42 mg ER) of methylphenidate hydrochloride for oral administration. Chemically, methylphenidate HCl is d , l (racemic)- threo -methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Methylphenidate HCl USP is a white, odorless, 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. Methylphenidate HCl extended-release capsules also contain the following inactive ingredients: Sugar Spheres, Ethylcellulose, Oleic Acid, Medium-Chain Triglycerides, Titanium Dioxide, Gelatin, Shellac, Propylene Glycol, Hypromellose, Polyethylene Glycol, and Black Iron Oxide. The individual capsules contain the following color agents: 10 mg capsules: FD&C Blue No. 2, Yellow Iron Oxide, Sodium Hydroxide, Povidone 20 mg capsules: FD&C Blue No. 2, Sodium Hydroxide, Povidone 30 mg capsules: FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, Sodium Hydroxide, Povidone 40 mg capsules: Yellow Iron Oxide 50 mg capsules: FD&C Blue No. 2, Red Iron Oxide, Sodium Hydroxide, Povidone Chemical Structure

2 DOSAGE AND ADMINISTRATION Take orally once daily in the morning, before breakfast ( 2.3 ) Swallow whole with the aid of liquids, or sprinkle contents onto a small amount of applesauce and give immediately ( 2.3 ) Do not crush or chew the capsule or capsule contents ( 2.3 ) Recommended starting dose is 20 mg once daily. Dosage may be increased 10-20 mg at weekly intervals; do not exceed 60 mg per day ( 2.2 ) 2.1 Pretreatment Screening Prior to initiating treatment with methylphenidate HCl extended-release capsules, 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 re-evaluate the need for methylphenidate HCl extended-release capsules use [see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9 )] . 2.2 Dosage Recommendations The recommended starting dose of methylphenidate HCl 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. Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of methylphenidate HCl extended-release capsules, and adjust the dosage as needed. 2.3 Administration Instructions Administer methylphenidate HCl 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 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue methylphenidate HCl extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate HCl extended-release capsules.

1 INDICATIONS AND USAGE Methylphenidate HCl extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 15 years of age. Methylphenidate HCl 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 )

9.2 Abuse CNS stimulants, including methylphenidate HCl extended-release capsules, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physicological effect. Drug addiction is a cluster of behavioral, cognitive, and psychological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking methylphenidate HCl extended-release capsules as prescribed. 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. Individual who abuser CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage ( 10 )] . To reduce the abuse of methylphenidate HCl extended-release capsules, 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 re-evaluate the need for methylphenidate HCl extended-release capsules use.

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

9.3 Dependence Physical Dependence Methylphenidate HCl extended-release capsules may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by a withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of a drug. 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. Tolerance Methylphenidate HCl extended-release capsules may produce tolerance from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate HCl extended-release capsules contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse CNS stimulants, including methylphenidate HCl extended-release capsules, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physicological effect. Drug addiction is a cluster of behavioral, cognitive, and psychological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking methylphenidate HCl extended-release capsules as prescribed. 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. Individual who abuser CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage ( 10 )] . To reduce the abuse of methylphenidate HCl extended-release capsules, 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 re-evaluate the need for methylphenidate HCl extended-release capsules use. 9.3 Dependence Physical Dependence Methylphenidate HCl extended-release capsules may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by a withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of a drug. 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. Tolerance Methylphenidate HCl extended-release capsules may produce tolerance from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

10 OVERDOSAGE Human Experience Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (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 guidance and advice on the management of overdosage with methylphenidate. Provide supportive care, including close medication supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage.

7 DRUG INTERACTIONS Table 3 presents clinically important drug interactions with methylphenidate HCl extended-release capsules. Table 3: Clinically Important Drug Interactions with Methylphenidate HCl Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate HCl extended-release capsules, 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 HCl extended-release capsules with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate HCl extended-release capsules 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. 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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD 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 increases the release of these monoamines into the extraneuronal space. 12.3 Pharmacokinetics Following one week of once-daily doses of 20 mg or 40 mg methylphenidate HCl extended-release capsules to children aged 7 to 12 years old with ADHD, C max and AUC of methylphenidate were approximately proportional to the administered doses. Absorption Following administration of methylphenidate HCl extended-release capsules in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median T max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median T max2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for C max and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours. *25-30% of the subjects had only one observed peak (C max ) concentration of methylphenidate. Figure 1: Comparison of Immediate Release (IR) and Methylphenidate HCl Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate HCl in Pediatric Patients 7 to 12 Years of Age with ADHD Effect of Food Ingestion of a high-fat meal with methylphenidate HCl extended-release capsules increased the mean C max and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration ( 2.1 )] . The bioavailability (C max and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate HCl extended-release capsule contents on applesauce as compared to the intact capsule. Effect of Alcohol At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions ( 7 )] . Distribution Plasma protein binding is 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 mean terminal half-life (t½) of methylphenidate following administration of methylphenidate HCl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. Metabolism In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women. Racial or Ethnic Groups The influence of race on the pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied. Pediatric Patients The pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied in children less than 6 years of age. Patients with Renal Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate HCl extended-release capsules. Patients with Hepatic Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with hepatic insufficiency. 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. Drug Interaction Studies In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations. Figure 1

12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD 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 increases the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics Following one week of once-daily doses of 20 mg or 40 mg methylphenidate HCl extended-release capsules to children aged 7 to 12 years old with ADHD, C max and AUC of methylphenidate were approximately proportional to the administered doses. Absorption Following administration of methylphenidate HCl extended-release capsules in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median T max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median T max2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for C max and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours. *25-30% of the subjects had only one observed peak (C max ) concentration of methylphenidate. Figure 1: Comparison of Immediate Release (IR) and Methylphenidate HCl Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate HCl in Pediatric Patients 7 to 12 Years of Age with ADHD Effect of Food Ingestion of a high-fat meal with methylphenidate HCl extended-release capsules increased the mean C max and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration ( 2.1 )] . The bioavailability (C max and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate HCl extended-release capsule contents on applesauce as compared to the intact capsule. Effect of Alcohol At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions ( 7 )] . Distribution Plasma protein binding is 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 mean terminal half-life (t½) of methylphenidate following administration of methylphenidate HCl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. Metabolism In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women. Racial or Ethnic Groups The influence of race on the pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied. Pediatric Patients The pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied in children less than 6 years of age. Patients with Renal Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate HCl extended-release capsules. Patients with Hepatic Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with hepatic insufficiency. 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. Drug Interaction Studies In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations. Figure 1

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3 DOSAGE FORMS AND STRENGTHS Methylphenidate HCl extended-release capsules are available in the following dosage strengths (see Table 1): Table 1: Strengths and Identifying Characteristics of Methylphenidate HCl Extended-Release Capsules Strength Capsule Color (cap/body) Imprinting on Capsule Cap Imprinting on Capsule Body 10 mg dark green/white “M” in a box over “1810” in white letters “10 mg” in black letters 20 mg medium blue/white “M” in a box over “1820” in white letters “20 mg” in black letters 30 mg maroon/white “M” in a box over “1830” in white letters “30 mg” in black letters 40 mg yellow ivory/white “M” in a box over “1840” in black letters “40 mg” in black letters 50 mg purple/white “M” in a box over “1850” in white letters “50 mg” in black letters 60 mg white/white “M” in a box over “1860” in black letters “60 mg” in black letters Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg ( 3 )

Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE FD&C BLUE NO. 2 FERRIC OXIDE YELLOW SODIUM HYDROXIDE POVIDONE, UNSPECIFIED dark green 10;MG;M;1810 Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE FD&C BLUE NO. 2 SODIUM HYDROXIDE POVIDONE, UNSPECIFIED medium blue 20;MG;M;1820 Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE SODIUM HYDROXIDE POVIDONE, UNSPECIFIED FD&C BLUE NO. 1 FD&C RED NO. 40 FD&C YELLOW NO. 6 maroon 30;MG;M;1830 Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW yellow ivory 40;MG;M;1840 Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE FD&C BLUE NO. 2 FERRIC OXIDE RED SODIUM HYDROXIDE POVIDONE, UNSPECIFIED 50;MG;M;1850 Methylphenidate Hydrochloride Extended-Release methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE SUCROSE STARCH, CORN ETHYLCELLULOSE, UNSPECIFIED OLEIC ACID MEDIUM-CHAIN TRIGLYCERIDES TITANIUM DIOXIDE GELATIN, UNSPECIFIED SHELLAC PROPYLENE GLYCOL HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED FERROSOFERRIC OXIDE 60;MG;M;1860

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 per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a 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 increases 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 per 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 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 per day, approximately 10 times the maximum recommended human dose 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 per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a 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 increases 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 per 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 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 per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.

ANDA203583

Methylphenidate Hydrochloride Extended-Release

methylphenidate hydrochloride

0406-1820

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL 10 mg Label NDC 0406-1810-01 100 CAPSULES Once Daily Methylphenidate HCl Extended-Release Capsules 10 mg CII Rx only PHARMACIST: Dispense the Medication Guide provided separately to each patient. Mallinckrodt ™ L0M135 Rev 09/2017 PRINCIPAL DISPLAY PANEL 10 mg Label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Controlled Substance Status/Potential for Abuse and Dependence Advise patients and their caregivers that methylphenidate HCl extended-release capsules are a federally controlled substance, and it can be abused and lead to dependence [see Drug Abuse and Dependence ( 9.1 , 9.2 , and 9.3 )] . Instruct patients that they should not give methylphenidate HCl extended-release capsules to anyone else. Advise patients to store methylphenidate HCl extended-release capsules 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 HCl extended-release capsules by a medicine take-back program if available [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9 ), How Supplied/Storage and Handling ( 16 )] . Administration Instructions Instruct patients and their caregivers that the methylphenidate HCl extended-release capsules and the capsule contents must not be crushed or chewed. Instruct patients that the capsule may be swallowed whole, or alternatively, the capsule may be opened and the capsule contents sprinkled onto a small amount (tablespoon) of applesauce and given immediately, and not stored for future use [see Dosage and Administration ( 2.3 )] . Serious Cardiovascular Risks Advise patients and their caregivers that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, stroke, and hypertension with methylphenidate HCl extended-release capsules 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 and their caregivers that methylphenidate HCl extended-release capsules can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions ( 5.3 )] . Psychiatric Risks Advise patients and their caregivers that methylphenidate HCl extended-release capsules, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )] . Priapism Advise patients and their caregivers of the possibility of painful or prolonged penile erections (priapism). Instruct the patient 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. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions ( 5.6 )] . Suppression of Growth Advise patients and their caregivers that methylphenidate HCl extended-release capsules can cause slowing of growth and weight loss [see Warnings and Precautions ( 5.7 )] . Pregnancy Registry Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate HCl extended-release capsules during pregnancy [see Use in Specific Populations ( 8.1 )] . Alcohol Use Advise patients to avoid alcohol while taking methylphenidate HCl extended-release capsules. Consumption of alcohol while taking methylphenidate HCl extended-release capsules may result in a more rapid release of the dose of methylphenidate [see Drug Interactions ( 7 )] . Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2022 Mallinckrodt. Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Mallinckrodt™ Pharmaceuticals An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/L20M54.pdf or by calling 1-800-778-7898 for alternate delivery options.

MEDICATION GUIDE Methylphenidate HCl Extended-Release Capsules, CII (METH il FEN i date) What is the most important information I should know about methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules can cause serious side effects, including: Abuse and dependence. Methylphenidate HCl extended-release capsules, other methylphenidate containing medicines, and amphetamines have a high chance for abuse and can cause physical and psychological dependence. Your healthcare provider should check your child for signs of abuse and dependence before and during treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider if your child has ever abused or been dependent on alcohol, prescription medicines, or street drugs. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. Heart-related problems, including: sudden death in children who have heart problems or heart defects increased blood pressure and heart rate Your healthcare provider should check your child carefully for heart problems before starting treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider if your child has any heart problems, heart defects, high blood pressure, or has a family history of these problems. Your healthcare provider should check your child’s blood pressure and heart rate regularly during treatment with methylphenidate HCl extended-release capsules. Call your healthcare provider or go to the nearest hospital emergency room right away if your child has any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate HCl extended-release capsules. Mental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems your child has, or about a family history of, suicide, bipolar illness, or depression. Call your healthcare provider right away if your child has any new or worsening mental symptoms or problems during treatment with methylphenidate HCl extended-release capsules, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What are methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules are a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 to 15 years of age. Methylphenidate HCl extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if methylphenidate HCl extended-release capsules are safe and effective for use in children younger than 6 years of age or older than 15 years of age. Methylphenidate HCl extended-release capsules are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate HCl extended-release capsules in a safe place to protect it from theft. Never give your methylphenidate HCl extended-release capsules to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate HCl extended-release capsules may harm others and is against the law. Who should not take methylphenidate HCl extended-release capsules? Your child should not take methylphenidate HCl extended-release capsules if your child: is allergic to methylphenidate hydrochloride or any of the ingredients in methylphenidate HCl extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in methylphenidate HCl extended-release capsules. has a rare inherited problem with the breaking down, absorbing, and processing of certain types of sugar in the body. Methylphenidate HCl extended-release capsules contain a type of sugar called sucrose. is taking, or has stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). Before starting methylphenidate HCl extended-release capsules tell your healthcare provider about all your child’s medical conditions, including: if your child: has heart problems, heart defects, or high blood pressure has mental problems including psychosis, mania, bipolar illness, or depression or has a family history of suicide, bipolar illness, or depression has circulation problems in fingers and toes is pregnant or plan to become pregnant. It is not known if methylphenidate HCl extended-release capsules will harm the unborn baby. There is a pregnancy registry for females who are exposed to methylphenidate HCl extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate HCl extended-release capsules and their baby. If you or your child becomes pregnant during treatment with methylphenidate HCl extended-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. is breastfeeding or plan to breastfeed. Methylphenidate HCl passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider about all the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate HCl extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate HCl extended-release capsules. Your healthcare provider will decide whether methylphenidate HCl extended-release capsules can be taken with other medicines. Especially tell your healthcare provider if your child takes a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Know the medicines that your child takes. Keep a list of the medicines with you to show your healthcare provider and pharmacist. Your child should not start taking any new medicines during treatment with methylphenidate HCl extended-release capsules without talking to your healthcare provider first. How should methylphenidate HCl extended-release capsules be taken? Take methylphenidate HCl extended-release capsules exactly as prescribed by your healthcare provider. Your healthcare provider may change the dose if needed. Take methylphenidate HCl extended-release capsules 1 time each day in the morning before breakfast. Swallow methylphenidate HCl extended-release capsules whole with water or other liquids. If methylphenidate HCl extended-release capsules cannot be swallowed whole, the capsule may be opened and the contents sprinkled onto a tablespoonful of applesauce. Follow with a drink of water or other liquid. Do not chew the applesauce and medicine mixture. Swallow all the applesauce and medicine mixture right away. Do not store the applesauce and medicine mixture. Your healthcare provider may sometimes stop methylphenidate HCl extended-release capsules treatment for a while to check ADHD symptoms. If your child takes too much methylphenidate HCl extended-release capsules, call your poison control center at 1-800-222-1222 or go to your nearest hospital emergency room right away. What should be avoided during treatment with methylphenidate HCl extended-release capsules? Avoid drinking alcohol during treatment with methylphenidate HCl extended-release capsules. This may cause a faster release of the methylphenidate HCl extended-release capsules medicine. What are the possible side effects of methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules can cause serious side effects, including: See “ What is the most important information I should know about methylphenidate HCl extended-release capsules? ” Painful and prolonged erections (priapism). Priapism has happened in males who take products that contain methylphenidate. If your child develops priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if your child has any signs of unexplained wounds appearing on the fingers or toes during treatment with methylphenidate HCl extended-release capsules. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate HCl extended-release capsules. Methylphenidate HCl extended-release capsules treatment may be stopped if your child is not growing or gaining weight. The most common side effects of methylphenidate HCl extended-release capsules include anorexia and trouble sleeping. These are not all the possible side effects of methylphenidate HCl extended-release capsules. 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 HCl extended-release capsules? Store methylphenidate HCl extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). Store methylphenidate HCl extended-release capsules in a safe place, like a locked cabinet. Protect from light and moisture. Dispose of remaining, unused, or expired methylphenidate HCl extended-release capsules by a medication 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 HCl extended-release capsules 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 methylphenidate HCl extended-release capsules in the household trash. Keep methylphenidate HCl extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate HCl extended-release capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate HCl extended-release capsules for a condition for which it was not prescribed. Do not give methylphenidate HCl extended-release capsules to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate HCl extended-release capsules that was written for healthcare professionals. What are the ingredients in methylphenidate HCl extended-release capsules? Active Ingredient: methylphenidate hydrochloride Inactive Ingredients: Sugar Spheres, Ethylcellulose, Oleic Acid, Medium-Chain Triglycerides, Titanium Dioxide, Gelatin, Shellac, Propylene Glycol, Hypromellose, Polyethylene Glycol, and Black Iron Oxide. The individual capsules contain the following coloring agents: 10 mg capsules: FD&C Blue No. 2, Yellow Iron Oxide, Sodium Hydroxide, Povidone 20 mg capsules: FD&C Blue No. 2, Sodium Hydroxide, Povidone 30 mg capsules: FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, Sodium Hydroxide, Povidone 40 mg capsules: Yellow Iron Oxide 50 mg capsules: FD&C Blue No. 2, Red Iron Oxide, Sodium Hydroxide, Povidone Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Mallinckrodt™ For more information about methylphenidate HCl extended-release capsules call 1-800-778-7898. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2022 L20M54

14 CLINICAL STUDIES Methylphenidate HCl extended-release capsules were evaluated in a double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), 6 to 15 years of age, received a single morning dose for up to 3 weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the methylphenidate HCl extended-release capsules group received 20 mg daily for the first week. Their dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment. The patient’s regular school teacher completed the teachers’ version of the Conners’ Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The primary efficacy endpoint was determined by the average of the total scores for the 10-item TCGIS completed by the classroom teacher in the morning and again in the afternoon on the three observation days during the last week of double-blind therapy. Patients treated with methylphenidate HCl extended-release capsules showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (See Figure 2). Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with methylphenidate HCl extended-release capsules over placebo during both time periods (See Figure 3). Figure 2: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD Figure 3: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD: Morning (AM) and Afternoon (PM) * FIGURES 2 & 3 : Last observation carried forward analysis at week 3. Error bars represent the standard error of the mean. Figure 2 Figure 3

8.5 Geriatric Use Methylphenidate HCl extended-release capsules have not been studied in patients over the age of 65 years.

8.4 Pediatric Use The safety and effectiveness of methylphenidate HCl extended-release capsules for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age. The safety and effectiveness of methylphenidate HCl extended-release capsules in pediatric patients younger than 6 years of age have not been established. Long-term efficacy of methylphenidate HCl extended-release capsules in pediatric patients have not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate HCl extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data 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 6 times the MRHD 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 (12 times the MRHD on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.1 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate HCl extended-release capsules, 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 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 53 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 HCl extended-release capsules, 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).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate HCl extended-release capsules, 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 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 53 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 HCl extended-release capsules, 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). 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 HCl extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate HCl extended-release capsules 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 HCl extended-release capsules for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age. The safety and effectiveness of methylphenidate HCl extended-release capsules in pediatric patients younger than 6 years of age have not been established. Long-term efficacy of methylphenidate HCl extended-release capsules in pediatric patients have not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate HCl extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data 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 6 times the MRHD 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 (12 times the MRHD on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD 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 HCl extended-release capsules have not been studied in patients over the age of 65 years.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methylphenidate HCl extended-release capsules are available in six strengths (see Table 4): Table 4: Strengths, Identifying Characteristics, and Packaging Configurations of Methylphenidate HCl Extended-Release Capsules Strength Capsule Color (cap/body) Imprinting on Capsule Cap Imprinting on Capsule Body Capsules per Bottle NDC Number 10 mg dark green/white “M” in a box over “1810” in white letters “10 mg” in black letters 100 NDC 0406-1810-01 20 mg medium blue/white “M” in a box over “1820” in white letters “20 mg” in black letters 100 NDC 0406-1820-01 30 mg maroon/white “M” in a box over “1830” in white letters “30 mg” in black letters 100 NDC 0406-1830-01 40 mg yellow ivory/white “M” in a box over “1840” in black letters “40 mg” in black letters 100 NDC 0406-1840-01 50 mg purple/white “M” in a box over “1850” in white letters “50 mg” in black letters 100 NDC 0406-1850-01 60 mg white/white “M” in a box over “1860” in black letters “60 mg” in black letters 100 NDC 0406-1860-01 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired methylphenidate HCl extended-release capsules 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 HCl extended-release capsules 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 HCl extended-release capsules in the household trash.

WARNING: ABUSE AND DEPENDENCE CNS stimulants, including methylphenidate HCl extended-release capsules, 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 HCl extended-release capsules, 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 )