DEXMETHYLPHENIDATE HYDROCHLORIDE EXTENDED-RELEASE

Dexmethylphenidate HCl extended-release capsules contain dexmethylphenidate hydrochloride, a CNS stimulant. Dexmethylphenidate hydrochloride is the d-threo enantiomer of racemic methylphenidate hydrochloride. Dexmethylphenidate HCl extended-release capsules are an extended-release formulation of dexmethylphenidate with a bi-modal release profile. Each bead-filled dexmethylphenidate HCl extended-release capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate and a delayed release of dexmethylphenidate. Dexmethylphenidate HCl extended-release capsules are intended for oral administration and are available as 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg extended-release capsules. Chemically, dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R’)-(+)-. Its molecular formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Note*=asymmetric carbon center Dexmethylphenidate hydrochloride is a white to off-white powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Inactive ingredients : ammonio methacrylate copolymer, D&C Red #28 (5 mg, 10 mg, 25 mg and 35 mg strengths), edible printing ink Red SB-1010N containing Shellac NF and Carmine Powder Red, FD&C Blue #1 (5 mg, 15 mg, 25 mg, 35 mg and 40 mg strengths), FDA/E172 Yellow Iron Oxide (15 mg and 40 mg strengths), gelatin, methacrylic acid copolymer, Opadry Clear containing hypromellose and polyethylene glycol, povidone, sugar spheres containing corn starch as well as sugar syrup and sucrose derived from sugar cane, talc, titanium dioxide, and triethyl citrate. Structure

Dexmethylphenidate HCl extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies ( 14 )] . Dexmethylphenidate HCl extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) ( 1 ).

Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2 ). Patients currently on methylphenidate: Dexmethylphenidate HCl extended-release capsules dosage is half (1/2) the current total daily dosage of methylphenidate ( 2.2 ). Patients currently on dexmethylphenidate immediate release tablets: Give the same daily dose of dexmethylphenidate HCl extended-release capsules ( 2.2 ). Titrate weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients ( 2.2 ). Maximum recommended daily dose: 30 mg in pediatric patients and 40 mg in adults ( 2.2 ). Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce ( 2.3 ). 2.1 Pretreatment Screening Prior to treating patients with dexmethylphenidate HCl extended-release capsules, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [ see Warnings and Precautions ( 5.2 )] . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating dexmethylphenidate HCl extended-release capsules [ see Warnings and Precautions ( 5.10 )]. 2.2 Recommended Dosage Patients New to Methylphenidate The recommended starting dosage of dexmethylphenidate HCl extended-release capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are: • Pediatric patients: Start with 5 mg orally once daily in the morning with or without food. • Adult patients: Start with 10 mg orally once daily in the morning with or without food. Patients Currently on Methylphenidate The recommended starting dose of dexmethylphenidate HCl extended-release capsules for patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate immediate-release tablets may be given the same daily dose of dexmethylphenidate HCl extended-release capsules. Titration Schedule The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended. 2.3 Administration Instructions Dexmethylphenidate HCl extended-release capsules are administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue dexmethylphenidate HCl extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Hypersensitivity to methylphenidate or other components of dexmethylphenidate HCl extended-release capsules. Hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions ( 6.1 )] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions ( 7.1 )] . Known hypersensitivity to methylphenidate or other components of dexmethylphenidate HCl extended-release capsules ( 4 ). Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 ).

The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [ see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients of dexmethylphenidate HCl extended-release capsules [ see Contraindications ( 4 )] Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [ see Contraindications ( 4 ), Drug Interactions ( 7.1 )] Risks to Patients with Serious Cardiac Disease [ see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [ see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [ see Warnings and Precautions ( 5.4 )] Priapism [ see Warnings and Precautions ( 5.5 )] Peripheral Vasculopathy, Including Raynaud’s Phenomenon [ see Warnings and Precautions ( 5.6 )] Long-Term Suppression of Growth in Pediatric Patients [ see Warnings and Precautions ( 5.7 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.8 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.9 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo): • Pediatric patients 6 to 17 years: dyspepsia, decreased appetite, headache, and anxiety ( 6.1 ). • Adults: dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc at 1-844-834-0530, 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 clinical practice. Adverse Reactions in Studies with Dexmethylphenidate HCl Extended-Release Capsules in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate HCl extended-release capsules in 100 (103 randomized) pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17). This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of dexmethylphenidate HCl extended-release capsules 5 mg to 30 mg/day who met The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD [ see Clinical Studies (14.1)] . Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache, and anxiety. Adverse Reactions Leading to Discontinuation : 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate immediate-release tablets experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). Table 1 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate HCl extended-release capsules doses of 5–30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate HCl extended-release capsules and for which the incidence in patients treated with dexmethylphenidate HCl extended-release capsules was at least twice the incidence in placebo-treated patients. Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD System organ class Adverse reaction Dexmethylphenidate HCl Extended-Release Capsules N = 53 Placebo N = 47 Gastrointestinal disorders Dyspepsia 38% 8% 19% 4% Metabolism and nutrition disorders Decreased appetite 34% 30% 11% 9% Nervous system disorders Headache 30% 25% 13% 11% Psychiatric disorders Anxiety 26% 6% 15% 0% Abbreviation: ADHD, attention deficit hyperactivity disorder. Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking dexmethylphenidate HCl extended-release capsules up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate HCl extended-release capsules for which the incidence was at least 5% and greater than the incidence among placebo-treated patients. Table 2: Dose-Related Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD System organ class Adverse reaction Dexmethylphenidate HCl ER Capsules 10 mg/day N = 64 Dexmethylphenidate HCl ER Capsules 20 mg/day N = 60 Dexmethylphenidate HCl ER Capsules 30 mg/day N = 58 Placebo N = 63 Gastrointestinal disorders Vomiting 22% 2% 23% 8% 29% 9% 24% 0% Metabolism and n utritional disorders Anorexia 16% 5% 19% 17% 5% 20% 22% 7% 38% 5% 0 8% Psychiatric disorders Insomnia Depression Mood swings 5% 0 0% 8% 0 0% 17% 3% 3% 3% 0 2% Other adverse reactions Irritability Nasal congestion Pruritus 0% 0% 0% 2% 0% 0% 5% 5% 3% 0% 0% 0% Abbreviation: ADHD, attention deficit hyperactivity disorder. Adverse Reactions in Studies with Dexmethylphenidate HCl Extended-Release Capsules in Adult Patients with ADHD The safety data in this section is based on data from a 5-week controlled clinical study of dexmethylphenidate HCl extended-release capsules in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least 6 months. This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of dexmethylphenidate HCl extended-release capsules 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [ see Clinical Studies (14.2)] . Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dry mouth, dyspepsia, headache, anxiety, and pharyngolaryngeal pain. Adverse Reactions Leading to Discontinuation : During the double-blind phase of the study, 10.7% of the dexmethylphenidate HCl extended-release capsules-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the dexmethylphenidate HCl extended-release capsules discontinued due to insomnia and jittery respectively; and two patients (1.2%) in the dexmethylphenidate HCl extended-release capsules discontinued due to anorexia and anxiety, respectively. Table 3 enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate HCl extended-release capsules doses of 20, 30, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate HCl extended-release capsules dose group and for which the incidences in patients treated with dexmethylphenidate HCl extended-release capsules appeared to increase with dose. Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHD System organ class A dverse reaction Dexmethylphenidate HCl ER Capsules 20 mg N = 57 Dexmethylphenidate HCl ER Capsules 30 mg N = 54 Dexmethylphenidate HCl ER Capsules 40 mg N = 54 Placebo N = 53 Gastrointestinal disorders Dry mouth Dyspepsia 28% 7% 5% 32% 20% 9% 44% 20% 9% 19% 4% 2% Nervous system disorders Headache 37% 26% 39% 30% 50% 39% 28% 19% Psychiatric disorders Anxiety 40% 5% 43% 11% 46% 11% 30% 2% Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain 16% 4% 9% 4% 15% 7% 8% 2% Two other adverse reactions occurring in clinical trials with dexmethylphenidate HCl extended-release capsules at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively). Table 4 summarizes changes in vital signs and weight that were recorded in the adult study (N = 218) of dexmethylphenidate HCl extended-release capsules in the treatment of ADHD. Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment-Adults Dexmethylphenidate HCl ER Capsules 20 mg (N = 57) Dexmethylphenidate HCl ER Capsules 30 mg (N = 54) Dexmethylphenidate HCl ER Capsules 40 mg (N = 54) Placebo (N = 53) Pulse (bpm) Diastolic BP (mmHg) Weight (kg) 3.1 ± 11.1 -0.2 ± 8.2 -1.4 ± 2.0 4.3 ± 11.7 1.2 ± 8.9 -1.2 ± 1.9 6.0 ± 10.1 2.1 ± 8.0 -1.7 ± 2.3 -1.4 ± 9.3 0.3 ± 7.8 -0.1 ± 3.9 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal : rhabdomyolysis Immune System Disorders : hypersensitivity reactions, including angioedema and anaphylaxis Adverse Reactions Reported With All Ritalin and Focalin Formulations The following adverse reactions associated with the use of all Ritalin and Focalin formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Infections and Infestations : nasopharyngitis Blood and the Lymphatic System Disorders : leukopenia, thrombocytopenia, anemia Immune System Disorders : hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders : decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders : insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders : headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders : blurred vision, difficulties in visual accommodation Cardiac Disorders : tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders : cough Gastrointestinal Disorders : dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders : abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders : hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders : arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations : weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate Products The list below shows adverse reactions not listed with Ritalin and Focalin formulations that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports. Blood and Lymphatic Disorders : pancytopenia Immune System Disorders : hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders : affect lability, mania, disorientation, libido changes Nervous System Disorders : migraine, motor and verbal tics Eye Disorders : diplopia, increased intraocular pressure, mydriasis Cardiac Disorders : sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole Vascular Disorders : peripheral coldness, Raynaud’s phenomenon Respiratory, Thoracic, and Mediastinal Disorders : pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders : diarrhea, constipation Skin and Subcutaneous Tissue Disorders : angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders : myalgia, muscle twitching Renal and Urinary Disorders : hematuria Reproductive System and Breast Disorders : gynecomastia General Disorders : fatigue, hyperpyrexia Urogenital Disorders : priapism

Antihypertensive Drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions With Dexmethylphenidate HCl Extended-Release Capsules Table 5 presents clinically important drug interactions with dexmethylphenidate HCl extended-release capsules. Table 5: Clinically Important Drug Interactions With Dexmethylphenidate HCl Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOIs) Clinical impact Concomitant use of MAOIs and CNS stimulants, including dexmethylphenidate 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 dexmethylphenidate HCl extended-release capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical impact Dexmethylphenidate HCl extended-release capsules may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical impact Concomitant use of halogenated anesthetics and dexmethylphenidate HCl extended- release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of dexmethylphenidate HCl extended-release capsules in patients being treated with anesthetics on the day of surgery. Risperidone Clinical impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention Monitor for signs of EPS