CONCERTA

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Drug Dependence [see Box Warning ] Hypersensitivity to Methylphenidate [see Contraindications (4.1) ] Agitation [see Contraindications (4.2) ] Glaucoma [see Contraindications (4.3) ] Tics [see Contraindications (4.4) ] Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1) ] Serious Cardiovascular Events [see Warnings and Precautions (5.1) ] Psychiatric Adverse Events [see Warnings and Precautions (5.2) ] Seizures [see Warnings and Precautions (5.3) ] Priapism [see Warnings and Precautions (5.4) ] Long-Term Suppression of Growth [see Warnings and Precautions (5.6) ] Visual Disturbance [see Warnings and Precautions (5.7) ] Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8) ] Hematologic Monitoring [see Warnings and Precautions (5.9) ] The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Adverse Reactions (6.1) ]. The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3) ]. The development program for CONCERTA ® included exposures in a total of 3906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3 ). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses. Table 3. CONCERTA ® Exposure in Double-Blind and Open-Label Clinical Studies Patient Population N Dose Range Children 2216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults 1188 18 to 108 mg once daily Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of CONCERTA ® based on the comprehensive assessment of the available adverse event information. A causal association for CONCERTA ® often cannot be reliably established in individual cases. Further, 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of adverse reactions were mild to moderate in severity. The most common adverse reaction in double-blind clinical trials (>5%) in children and adolescents was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis. ( 6.1 and 6.2 ) The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased. ( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Children and Adolescents Table 4 lists the adverse reactions reported in 1% or more of CONCERTA ® -treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials. Table 4. Adverse Reactions Reported by ≥1% of CONCERTA ® -Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of CONCERTA ® System/Organ Class Adverse Reaction CONCERTA ® (n=321) % Placebo (n=318) % Gastrointestinal Disorders Abdominal pain upper 6.2 3.8 Vomiting 2.8 1.6 General Disorders and Administration Site Conditions Pyrexia 2.2 0.9 Infections and Infestations Nasopharyngitis 2.8 2.2 Nervous System Disorders Dizziness 1.9 0 Psychiatric Disorders Insomnia Terms of Initial insomnia (CONCERTA ®=0.6%) and Insomnia (CONCERTA ®=2.2%) are combined into Insomnia. 2.8 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 0.9 Oropharyngeal pain 1.2 0.9 The majority of adverse reactions were mild to moderate in severity. Adults Table 5 lists the adverse reactions reported in 1% or more of CONCERTA ® -treated adults in 2 placebo-controlled, double-blind clinical trials. Table 5. Adverse Reactions Reported by ≥1% of CONCERTA ® -Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials Included doses up to 108 mg. System/Organ Class Adverse Reaction CONCERTA ® (n=415) % Placebo (n=212) % Cardiac Disorders Tachycardia 4.8 0 Palpitations 3.1 0.9 Ear and Labyrinth Disorders Vertigo 1.7 0 Eye Disorders Vision blurred 1.7 0.5 Gastrointestinal Disorders Dry mouth 14.0 3.8 Nausea 12.8 3.3 Dyspepsia 2.2 0.9 Vomiting 1.7 0.5 Constipation 1.4 0.9 General Disorders and Administration Site Conditions Irritability 5.8 1.4 Infections and Infestations Upper respiratory tract infection 2.2 0.9 Investigations Weight decreased 6.5 3.3 Metabolism and Nutrition Disorders Decreased appetite 25.3 6.6 Anorexia 1.7 0 Musculoskeletal and Connective Tissue Disorders Muscle tightness 1.9 0 Nervous System Disorders Headache 22.2 15.6 Dizziness 6.7 5.2 Tremor 2.7 0.5 Paresthesia 1.2 0 Sedation 1.2 0 Tension headache 1.2 0.5 Psychiatric Disorders Insomnia 12.3 6.1 Anxiety 8.2 2.4 Initial insomnia 4.3 2.8 Depressed mood 3.9 1.4 Nervousness 3.1 0.5 Restlessness 3.1 0 Agitation 2.2 0.5 Aggression 1.7 0.5 Bruxism 1.7 0.5 Depression 1.7 0.9 Libido decreased 1.7 0.5 Affect lability 1.4 0.9 Confusional state 1.2 0.5 Tension 1.2 0.5 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 1.7 1.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 5.1 0.9 The majority of ADRs were mild to moderate in severity. 6.2 Other Adverse Reactions Observed in CONCERTA ® Clinical Trials This section includes adverse reactions reported by CONCERTA ® -treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by CONCERTA ® -treated subjects who participated in open-label and postmarketing clinical trials. Blood and Lymphatic System Disorders: Leukopenia Eye Disorders: Accommodation disorder, Dry eye Vascular Disorders: Hot flush Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst Infections and Infestations: Sinusitis Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased Musculoskeletal and Connective Tissue Disorders: Muscle spasms Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Rash, Rash macular Vascular Disorders: Hypertension 6.3 Discontinuation Due to Adverse Reactions Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 CONCERTA ® patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%). In the 2 placebo-controlled studies of adults, 25 CONCERTA ® patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the CONCERTA ® patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). In the 11 open-label studies of children, adolescents, and adults, 266 CONCERTA ® patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). 6.4 Tics In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with CONCERTA ® . In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months. 6.5 Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA ® once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with CONCERTA ® and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for CONCERTA ® and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with CONCERTA ® at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for CONCERTA ® and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for CONCERTA ® and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for CONCERTA ® and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.1)] . 6.6 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of CONCERTA ® . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Mydriasis, Visual impairment General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes Reproductive System and Breast Disorders: Priapism Respiratory, Thoracic and Mediastinal Disorders: Epistaxis Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud's phenomenon

4 CONTRAINDICATIONS Known hypersensitivity to the product ( 4.1 ) Marked anxiety, tension, or agitation ( 4.2 ) Glaucoma ( 4.3 ) Tics or a family history or diagnosis of Tourette's syndrome ( 4.4 ) Do not use CONCERTA ® in patients currently using or within 2 weeks of using an MAO inhibitor ( 4.5 ) 4.1 Hypersensitivity to Methylphenidate Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with CONCERTA ® . Therefore, CONCERTA ® is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.6) ] . 4.2 Agitation CONCERTA ® is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. 4.3 Glaucoma CONCERTA ® is contraindicated in patients with glaucoma. 4.4 Tics CONCERTA ® is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions (6.4) ] . 4.5 Monoamine Oxidase Inhibitors CONCERTA ® is contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions (7.1) ] .

11 DESCRIPTION CONCERTA ® is a central nervous system (CNS) stimulant. CONCERTA ® is available in four tablet strengths. Each extended-release tablet for once-a-day oral administration contains 18, 27, 36, or 54 mg of methylphenidate HCl USP and is designed to have a 12-hour duration of effect. Chemically, methylphenidate HCl is d,l (racemic) 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. CONCERTA ® also contains the following inert ingredients: butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose, phosphoric acid, poloxamer, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin. Chemical Structure 11.1 System Components and Performance CONCERTA ® uses osmotic pressure to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice on the drug-layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug release rate from the system increases with time over a period of 6 to 7 hours due to the drug-concentration gradient incorporated into the two drug layers of CONCERTA ® . The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components. It is possible that CONCERTA ® extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

2 DOSAGE AND ADMINISTRATION CONCERTA ® should be taken once daily in the morning and swallowed whole with the aid of liquids. CONCERTA ® should not be chewed or crushed. CONCERTA ® may be taken with or without food. ( 2.1 ) For children and adolescents new to methylphenidate, the recommended starting dosage is 18 mg once daily. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 54 mg/day in children and 72 mg/day in adolescents. ( 2.2 ) For adult patients new to methylphenidate, the recommended starting dose is 18 or 36 mg/day. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 72 mg/day for adults. ( 2.2 ) For patients currently using methylphenidate, dosing is based on current dose regimen and clinical judgment. ( 2.3 ) 2.1 General Dosing Information CONCERTA ® should be administered orally once daily in the morning with or without food. CONCERTA ® must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17) ] . 2.2 Patients New to Methylphenidate The recommended starting dose of CONCERTA ® for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1 ). Table 1. CONCERTA ® Recommended Starting Doses and Dose Ranges Patient Age Recommended Starting Dose Dose Range Children 6–12 years of age 18 mg/day 18 mg – 54 mg/day Adolescents 13–17 years of age 18 mg/day 18 mg – 72 mg/day not to exceed 2 mg/kg/day Adults 18–65 years of age 18 or 36 mg/day 18 mg – 72 mg/day 2.3 Patients Currently Using Methylphenidate The recommended dose of CONCERTA ® for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily. Table 2. Recommended Dose Conversion from Methylphenidate Regimens to CONCERTA ® Previous Methylphenidate Daily Dose Recommended CONCERTA ® Starting Dose 5 mg Methylphenidate twice daily or three times daily 18 mg every morning 10 mg Methylphenidate twice daily or three times daily 36 mg every morning 15 mg Methylphenidate twice daily or three times daily 54 mg every morning 20 mg Methylphenidate twice daily or three times daily 72 mg every morning Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose. 2.4 Dose Titration Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended. A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages. 2.5 Maintenance/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with CONCERTA ® . It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. The effectiveness of CONCERTA ® for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use CONCERTA ® for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient's functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. 2.6 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

1 INDICATIONS AND USAGE CONCERTA ® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see Clinical Studies (14) ] . A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. CONCERTA ® is a CNS stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65. ( 1 ) 1.1 Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics. 1.2 Need for Comprehensive Treatment Program CONCERTA ® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social). Drug treatment may not be indicated for all patients with ADHD. Stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.

9.2 Abuse As noted in the Box Warning , CONCERTA ® should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. In two placebo-controlled human abuse potential studies, single oral doses of CONCERTA ® were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration. In one study (n=40), both CONCERTA ® (108 mg) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, CONCERTA ® (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH. In another study (n=49), both doses of CONCERTA ® (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of CONCERTA ® (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, CONCERTA ® produced statistically significantly lower subjective responses on these two scales than IR MPH. CONCERTA ® (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in CONCERTA ® tablets is available for immediate release from the drug overcoat [see System Components and Performance (11.1) ] . Although these findings reveal a relatively lower response to CONCERTA ® on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of CONCERTA ® in the community is unknown.

9.1 Controlled Substance Methylphenidate is a Schedule II controlled substance under the Controlled Substances Act.

9.3 Dependence As noted in the Box Warning , careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate is a Schedule II controlled substance under the Controlled Substances Act. 9.2 Abuse As noted in the Box Warning , CONCERTA ® should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. In two placebo-controlled human abuse potential studies, single oral doses of CONCERTA ® were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration. In one study (n=40), both CONCERTA ® (108 mg) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, CONCERTA ® (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH. In another study (n=49), both doses of CONCERTA ® (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of CONCERTA ® (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, CONCERTA ® produced statistically significantly lower subjective responses on these two scales than IR MPH. CONCERTA ® (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in CONCERTA ® tablets is available for immediate release from the drug overcoat [see System Components and Performance (11.1) ] . Although these findings reveal a relatively lower response to CONCERTA ® on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of CONCERTA ® in the community is unknown. 9.3 Dependence As noted in the Box Warning , careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

10 OVERDOSAGE 10.1 Signs and Symptoms Signs and symptoms of CONCERTA ® overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, muscle twitching, convulsion, grand mal convulsion, confusional state, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension, rhabdomyolysis, mydriasis, and dry mouth. 10.2 Recommended Treatment Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for pyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for CONCERTA ® overdosage has not been established. The prolonged release of methylphenidate from CONCERTA ® should be considered when treating patients with overdose. 10.3 Poison Control Center As with the management of all overdosage, the possibility of multiple-drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.

7 DRUG INTERACTIONS Do not use CONCERTA ® in patients currently using or within 2 weeks of using an MAO inhibitor ( 7.1 ) CONCERTA ® may increase blood pressure; use cautiously with vasopressors ( 7.2 ) Inhibition of metabolism of coumarin anticoagulants, anticonvulsants, and some antidepressants ( 7.3 ) 7.1 MAO Inhibitors CONCERTA ® should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.5) ] . 7.2 Vasopressor Agents Because of possible increases in blood pressure, CONCERTA ® should be used cautiously with vasopressor agents [see Warnings and Precautions (5.1) ] . 7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. 7.4 Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. 12.3 Pharmacokinetics Absorption Methylphenidate is readily absorbed. Following oral administration of CONCERTA ® , plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of CONCERTA ® occurred between 6 and 10 hours. CONCERTA ® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1 ). The relative bioavailability of CONCERTA ® once daily and methylphenidate three times daily in adults is comparable. Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA ® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours. The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTA ® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6. Table 6. Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults Parameters CONCERTA ® (18 mg once daily) (n=36) Methylphenidate (5 mg three times daily) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng∙h/mL) 41.8 ± 13.9 38.0 ± 11.0 t ½ (h) 3.5 ± 0.4 3.0 ± 0.5 The pharmacokinetics of CONCERTA ® were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA ® were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following the first dose of CONCERTA ® in a dose range of 18 to 144 mg. Figure 1 Dose Proportionality Following administration of CONCERTA ® in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate C max and AUC (0–inf) increased disproportionately with respect to dose. Following administration of CONCERTA ® , plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple dosing of once-daily CONCERTA ® doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA ® , mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTA ® was approximately 3.5 hours. Metabolism and Excretion In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of CONCERTA ® once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of CONCERTA ® is similar. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Food Effects In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA ® when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food. Alcohol Effect An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA ® 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strengths. Special Populations Gender In healthy adults, the mean dose-adjusted AUC (0–inf) values for CONCERTA ® were 36.7 ng∙h/mL in men and 37.1 ng∙h/mL in women, with no differences noted between the two groups. Race In adults receiving CONCERTA ® , dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. Age Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. The pharmacokinetics of CONCERTA ® have not been studied in children less than 6 years of age. Renal Insufficiency There is no experience with the use of CONCERTA ® in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA ® . Hepatic Insufficiency There is no experience with the use of CONCERTA ® in patients with hepatic insufficiency.

12.1 Mechanism of Action Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

12.3 Pharmacokinetics Absorption Methylphenidate is readily absorbed. Following oral administration of CONCERTA ® , plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of CONCERTA ® occurred between 6 and 10 hours. CONCERTA ® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1 ). The relative bioavailability of CONCERTA ® once daily and methylphenidate three times daily in adults is comparable. Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA ® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours. The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTA ® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6. Table 6. Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults Parameters CONCERTA ® (18 mg once daily) (n=36) Methylphenidate (5 mg three times daily) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng∙h/mL) 41.8 ± 13.9 38.0 ± 11.0 t ½ (h) 3.5 ± 0.4 3.0 ± 0.5 The pharmacokinetics of CONCERTA ® were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA ® were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following the first dose of CONCERTA ® in a dose range of 18 to 144 mg. Figure 1 Dose Proportionality Following administration of CONCERTA ® in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate C max and AUC (0–inf) increased disproportionately with respect to dose. Following administration of CONCERTA ® , plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple dosing of once-daily CONCERTA ® doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA ® , mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTA ® was approximately 3.5 hours. Metabolism and Excretion In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of CONCERTA ® once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of CONCERTA ® is similar. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Food Effects In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA ® when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food. Alcohol Effect An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA ® 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strengths. Special Populations Gender In healthy adults, the mean dose-adjusted AUC (0–inf) values for CONCERTA ® were 36.7 ng∙h/mL in men and 37.1 ng∙h/mL in women, with no differences noted between the two groups. Race In adults receiving CONCERTA ® , dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. Age Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. The pharmacokinetics of CONCERTA ® have not been studied in children less than 6 years of age. Renal Insufficiency There is no experience with the use of CONCERTA ® in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA ® . Hepatic Insufficiency There is no experience with the use of CONCERTA ® in patients with hepatic insufficiency.

20230213

24

3 DOSAGE FORMS AND STRENGTHS CONCERTA ® (methylphenidate HCl) Extended-Release Tablets are available in the following dosage strengths: 18 mg tablets are yellow and imprinted with "alza 18," 27 mg tablets are gray and imprinted with "alza 27," 36 mg tablets are white and imprinted with "alza 36," and 54 mg tablets are brownish-red and imprinted with "alza 54." Tablets: 18, 27, 36, and 54 mg ( 3 )

CONCERTA Methylphenidate hydrochloride BUTYLATED HYDROXYTOLUENE CARNAUBA WAX HYPROMELLOSE, UNSPECIFIED LACTOSE, UNSPECIFIED FORM PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM CHLORIDE STEARIC ACID SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE TRIACETIN CELLULOSE ACETATE METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE Yellow capsule-shaped alza;18 CONCERTA Methylphenidate hydrochloride BUTYLATED HYDROXYTOLUENE CARNAUBA WAX HYPROMELLOSE, UNSPECIFIED LACTOSE, UNSPECIFIED FORM PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM CHLORIDE STEARIC ACID SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE TRIACETIN CELLULOSE ACETATE METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE Gray capsule-shaped alza;27 CONCERTA Methylphenidate hydrochloride BUTYLATED HYDROXYTOLUENE CARNAUBA WAX HYPROMELLOSE, UNSPECIFIED LACTOSE, UNSPECIFIED FORM PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM CHLORIDE STEARIC ACID SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE TRIACETIN CELLULOSE ACETATE METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE White capsule-shaped alza;36 CONCERTA Methylphenidate hydrochloride BUTYLATED HYDROXYTOLUENE CARNAUBA WAX HYPROMELLOSE, UNSPECIFIED LACTOSE, UNSPECIFIED FORM PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM CHLORIDE STEARIC ACID SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE TRIACETIN CELLULOSE ACETATE METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE Red capsule-shaped alza;54

13.1 Carcinogenesis, Mutagenesis, and 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 30 times and 4 times the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. 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 22 times and 5 times the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. 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 or the in vitro mouse lymphoma cell forward mutation assay. 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/day, approximately 80-fold and 8-fold the highest recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and 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 30 times and 4 times the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. 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 22 times and 5 times the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. 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 or the in vitro mouse lymphoma cell forward mutation assay. 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/day, approximately 80-fold and 8-fold the highest recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively.

NDA021121

CONCERTA

Methylphenidate hydrochloride

50458-585

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 18 mg Tablet Bottle Label NDC 50458-585-01 CONCERTA ® (methylphenidate HCl) CII Extended-release tablets 18 mg Each tablet contains 18 mg methylphenidate hydrochloride in a controlled-release formulation. Please see the Medication Guide provided by your pharmacist. Rx only 100 Tablets janssen PRINCIPAL DISPLAY PANEL - 18 mg Tablet Bottle Label

For more information call 1-800-526-7736. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA © 2008 Janssen Pharmaceuticals, Inc.

17 PATIENT COUNSELING INFORMATION See Medication Guide Priapism Advise patients, caregivers, and family members 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 (5.4) ] . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud's Phenomenon] Instruct patients beginning treatment with CONCERTA ® 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 CONCERTA ® . Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. General Considerations Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for CONCERTA ® . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Administration Instructions Patients should be informed that CONCERTA ® should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. Driving or Operating Heavy Machinery Stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that CONCERTA ® does not adversely affect their ability to engage in such activities.

MEDICATION GUIDE CONCERTA ® (kon SER-ta) (methylphenidate HCl) Extended-release Tablets CII Read the Medication Guide that comes with CONCERTA ® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child's treatment with CONCERTA ® . What is the most important information I should know about CONCERTA ® ? The following have been reported with use of methylphenidate HCl 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 has 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 CONCERTA ® . Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with CONCERTA ® . 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 CONCERTA ® . 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 Children and Teenagers 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 has any new or worsening mental symptoms or problems while taking CONCERTA ® , especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Painful and prolonged erections (priapism) Painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. 4. 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 have or your child has numbness, pain, skin color change, or sensitivity to temperature in your 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 CONCERTA ® . What is CONCERTA ® ? CONCERTA ® is a central nervous system stimulant prescription medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). CONCERTA ® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. CONCERTA ® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. CONCERTA ® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep CONCERTA ® in a safe place to prevent misuse and abuse. Selling or giving away CONCERTA ® may harm others, and is against the law. Tell your doctor if you or your child has (or has a family history of) ever abused or been dependent on alcohol, prescription medicines, or street drugs. Who should not take CONCERTA ® ? CONCERTA ® should not be taken if you or your child: is very anxious, tense, or agitated has an eye problem called glaucoma has tics or Tourette's syndrome, or a family history of Tourette's syndrome. Tics are hard-to-control repeated movements or sounds. is taking or has taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. is allergic to anything in CONCERTA ® . See the end of this Medication Guide for a complete list of ingredients . CONCERTA ® should not be used in children less than 6 years old because it has not been studied in this age group. CONCERTA ® may not be right for you or your child. Before starting CONCERTA ® , tell your or your child's doctor about all health conditions (or a family history of) including: heart problems, heart defects, or high blood pressure mental problems including psychosis, mania, bipolar illness, or depression tics or Tourette's syndrome seizures or have had an abnormal brain wave test (EEG) circulation problems in fingers and toes esophagus, stomach, or small or large intestine problems Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can CONCERTA ® be taken with other medicines? Tell your doctor about all of the medicines that you or your child takes including prescription and nonprescription medicines, vitamins, and herbal supplements. CONCERTA ® 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 CONCERTA ® . Your doctor will decide whether CONCERTA ® can be taken with other medicines. Especially tell your doctor if you or your child takes: antidepression medicines including MAOIs seizure medicines blood thinner medicines blood pressure medicines cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking CONCERTA ® without talking to your doctor first. How should CONCERTA ® be taken? Take CONCERTA ® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Do not chew, crush, or divide the tablets. Swallow CONCERTA ® tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow CONCERTA ® whole. A different medicine may need to be prescribed. CONCERTA ® can be taken with or without food. Take CONCERTA ® once each day in the morning. CONCERTA ® is an extended-release tablet. It releases medication into your or your child's body throughout the day. The CONCERTA ® tablet does not dissolve completely in the body after all the medicine has been released. You or your child may sometimes notice the empty tablet in a bowel movement. This is normal. From time to time, your doctor may stop CONCERTA ® treatment for a while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking CONCERTA ® . Children should have their height and weight checked often while taking CONCERTA ® . CONCERTA ® treatment may be stopped if a problem is found during these check-ups. If you or your child takes too much CONCERTA ® or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of CONCERTA ® ? See " What is the most important information I should know about CONCERTA ® ?" for information on reported heart and mental problems. Other serious side effects include: slowing of growth (height and weight) in children seizures, mainly in patients with a history of seizures eyesight changes or blurred vision blockage of the esophagus, stomach, small or large intestine in patients who already have a narrowing in any of these organs Common side effects include: decreased appetite dry mouth trouble sleeping dizziness stomach ache increased sweating headache nausea anxiety weight loss irritability Stimulants may impair the ability of you or your child to operate potentially hazardous machinery or vehicles. You or your child should exercise caution until you or your child is reasonably certain that CONCERTA ® does not adversely affect your or your child's ability to engage in such activities. Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN or (1-800-526-7736). How should I store CONCERTA ® ? Store CONCERTA ® in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture. Keep CONCERTA ® and all medicines out of the reach of children. General information about CONCERTA ® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CONCERTA ® for a condition for which it was not prescribed. Do not give CONCERTA ® to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about CONCERTA ® . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CONCERTA ® that was written for healthcare professionals. For more information about CONCERTA ® call 1-800-526-7736. What are the ingredients in CONCERTA ® ? Active Ingredient: methylphenidate HCl Inactive Ingredients: butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose, phosphoric acid, poloxamer, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA Revised: April 2022

14 CLINICAL STUDIES CONCERTA ® was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4 th edition (DSM-IV) criteria for ADHD. 14.1 Children Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared CONCERTA ® given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was CONCERTA ® versus placebo. Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTA ® . The scores for CONCERTA ® and placebo for the three studies are presented in Figure 2. Figure 2. Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with CONCERTA ® once daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean. In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP Swanson, Kotkin, Agler, M-Fynn, and Pelham laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with CONCERTA ® versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for CONCERTA ® and placebo. Figure 3. Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2) Figure 2 Figure 3 14.2 Adolescents In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, CONCERTA ® was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of CONCERTA ® (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that CONCERTA ® was statistically significantly superior to placebo. 14.3 Adults Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared CONCERTA ® administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day). Study 5 demonstrated the effectiveness of CONCERTA ® in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to CONCERTA ® and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that CONCERTA ® was statistically significantly superior to placebo. Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive CONCERTA ® administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTA ® were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.

15 REFERENCES American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

8.5 Geriatric Use CONCERTA ® has not been studied in patients greater than 65 years of age.

8.2 Labor and Delivery The effect of CONCERTA ® on labor and delivery in humans is unknown.

8.3 Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if CONCERTA ® is administered to a nursing woman. In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.

8.4 Pediatric Use CONCERTA ® should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.

8.1 Pregnancy Pregnancy Category C Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1–2 times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA ® based on the AUC. The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. CONCERTA ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category C Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1–2 times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA ® based on the AUC. The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. CONCERTA ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8 USE IN SPECIFIC POPULATIONS Caution should be exercised if administered to nursing mothers ( 8.3 ) Safety and efficacy has not been established in children less than six years old or elderly patients greater than 65 years of age ( 8.4 and 8.5 ) 8.1 Pregnancy Pregnancy Category C Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of CONCERTA ® on a mg/kg and mg/m 2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1–2 times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA ® based on the AUC. The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. CONCERTA ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.2 Labor and Delivery The effect of CONCERTA ® on labor and delivery in humans is unknown. 8.3 Nursing Mothers It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if CONCERTA ® is administered to a nursing woman. In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma. 8.4 Pediatric Use CONCERTA ® should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established. 8.5 Geriatric Use CONCERTA ® has not been studied in patients greater than 65 years of age.

16 HOW SUPPLIED/STORAGE AND HANDLING CONCERTA ® (methylphenidate HCl) Extended-release Tablets are available in 18 mg, 27 mg, 36 mg, and 54 mg dosage strengths. The 18 mg tablets are yellow and imprinted with "alza 18". The 27 mg tablets are gray and imprinted with "alza 27". The 36 mg tablets are white and imprinted with "alza 36". The 54 mg tablets are brownish-red and imprinted with "alza 54". All four dosage strengths are supplied in bottles containing 100 tablets. 18 mg 100-count bottle NDC 50458-585-01 27 mg 100-count bottle NDC 50458-588-01 36 mg 100-count bottle NDC 50458-586-01 54 mg 100-count bottle NDC 50458-587-01 Storage and Handling Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from humidity.

Storage and Handling Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from humidity.

WARNING: DRUG DEPENDENCE CONCERTA ® should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. WARNING: DRUG DEPENDENCE See full prescribing information for complete boxed warning. CONCERTA ® should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence, with varying degrees of abnormal behavior.