DEXMETHYLPHENIDATE HYDROCHLORIDE

Dexmethylphenidate hydrochloride extended-release capsules are an extended-release formulation of dexmethylphenidate with a bi-modal release profile. Each bead-filled dexmethylphenidate hydrochloride 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 second delayed release of dexmethylphenidate. Dexmethylphenidate hydrochloride extended-release is available as 5 mg, 10 mg, 15 mg, 20 mg and 30 mg extended-release capsules. Dexmethylphenidate hydrochloride extended-release 5 mg, 10 mg, 15 mg, 20 mg and 30 mg extended-release capsules provide in a single dose the same amount of dexmethylphenidate as dosages of 2.5 mg, 5 mg, 7.5 mg, 10 mg or 15 mg of dexmethylphenidate hydrochloride given twice a day as tablets. Dexmethylphenidate hydrochloride, the d-threo enantiomer of racemic methylphenidate hydrochloride, is a central nervous system (CNS) stimulant. Dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R’)-(+)-. Its molecular formula is C 14 H 19 NO 2 •HCl. Its molecular weight is 269.77 and 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. Inactive ingredients: acetyltributyl citrate, ethylcellulose, gelatin, hypromellose, hypromellose acetate succinate, sugar spheres (which contain sucrose and starch [maize]), talc, and titanium dioxide. The 5 mg capsule also contains FD&C Red #3 and FD&C Blue #1. The 10 mg capsule also contains acid red 27 and FD&C Blue #1. The 15 mg capsule also contains D&C Red #28 and FD&C Blue #1. The 20 mg capsule also contains D&C Red #28, D&C Red #33, and FD&C Blue #1. Black printing ink SW-9008/SW-9009 contains black iron oxide, potassium hydroxide, propylene glycol, and shellac. 32f71710-figure-01

Dexmethylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older. The effectiveness of dexmethylphenidate hydrochloride extended-release in the treatment of ADHD in patients aged 6 years and older was established in 2 placebo-controlled studies in patients meeting DSM-IV criteria for ADHD [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 2 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 6 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 6 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 Types requires both inattentive and hyperactive-impulsive criteria to be met. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of 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 child and not solely on the presence of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Dexmethylphenidate hydrochloride extended-release capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits 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 child’s symptoms. Long-Term Use The effectiveness of dexmethylphenidate hydrochloride extended-release for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use dexmethylphenidate hydrochloride extended-release for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3 ) ]. Dexmethylphenidate hydrochloride extended-release is a CNS stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older. ( 1 )

Dexmethylphenidate hydrochloride extended-release is for oral administration once daily in the morning. Dexmethylphenidate hydrochloride extended-release may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Dexmethylphenidate hydrochloride extended-release capsules and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosage should be individualized according to the needs and responses of the patient. Dexmethylphenidate hydrochloride extended-release is intended for oral administration once daily in the morning. Dexmethylphenidate hydrochloride extended-release capsules may be swallowed whole, or capsule contents can be sprinkled on applesauce. Dexmethylphenidate hydrochloride extended-release capsules and/or their contents should not be crushed, chewed, or divided. ( 2 ) For patients new to methylphenidate: Begin treatment with dexmethylphenidate hydrochloride extended-release at 5 mg/day for pediatrics and 10 mg/day for adults, titrating the dose weekly in 5 mg increments for pediatrics and in 10 mg increments for adults. Doses above 30 mg/day in children and 40 mg/day in adults have not been studied. ( 2.1 ) For patients already using methylphenidate: Initiate dexmethylphenidate hydrochloride extended-release therapy with half (1/2) the current total daily dose of methylphenidate. ( 2.2 ) Patients already using dexmethylphenidate hydrochloride immediate release: switch to the same daily dose of dexmethylphenidate hydrochloride extended-release. ( 2.2 ) 2.1 Patients New to Methylphenidate The recommended starting dose of dexmethylphenidate hydrochloride extended-release for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg/day for pediatric patients and 10 mg/day for adult patients. Dosage may be adjusted in 5 mg increments for pediatric patients and in 10 mg increments for adult patients. In general, dosage adjustments may proceed at approximately weekly intervals. The patient should be observed for a sufficient duration at a given dose to ensure that a maximal benefit has been achieved before a dose increase is considered. In dose-response (fixed-dose) studies (pediatric from 10 to 30 mg/day and adult from 20 to 40 mg/day), all doses were effective vs. placebo. There was no clear finding, however, of greater average benefits for the higher doses compared to the lower doses. Adverse events and discontinuations, however, were dose-related. Doses above 30 mg/day in pediatrics and 40 mg/day in adults have not been studied and are not recommended. 2.2 Patients Currently Using Methylphenidate For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate hydrochloride extended-release is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate hydrochloride may be switched to the same daily dose of dexmethylphenidate hydrochloride extended-release. 2.3 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 dexmethylphenidate hydrochloride extended-release. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate hydrochloride extended-release for extended periods in patients with ADHD should periodically reevaluate the long-term usefulness of the drug for the individual patient with periods off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. 2.4 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 1-month period, the drug should be discontinued.

Agitation, marked anxiety, and tension ( 4.1 ) Known hypersensitivity to methylphenidate or product components ( 4.2 ) Glaucoma ( 4.3 ) History of motor tics or a family history or diagnosis of Tourette’s syndrome ( 4.4 ) During, or within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI) ( 4.5 ) 4.1 Agitation Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. 4.2 Hypersensitivity to Methylphenidate Dexmethylphenidate hydrochloride extended-release is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of the product. Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been observed in patients treated with methylphenidate [see Adverse Reactions (6.5 , 6.6 )]. 4.3 Glaucoma Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with glaucoma. 4.4 Tics Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome [see Adverse Reactions (6.1) ]. 4.5 Monoamine Oxidase Inhibitors Dexmethylphenidate hydrochloride extended-release is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).

Dexmethylphenidate hydrochloride extended-release was administered to 46 children and 7 adolescents with ADHD for up to 7 weeks and 206 adults with ADHD in clinical studies. During the clinical studies, 101 adult patients were treated for at least 6 months. Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MedDRA terminology has been used to classify reported adverse events. 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. Most common adverse reactions (at least 5% and twice the incidence among placebo-treated patients) are dyspepsia, decreased appetite, headache, and anxiety for pediatric patients and dry mouth, dyspepsia, headache, and anxiety for adult patients. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Events Associated with Discontinuation of Treatment in Acute Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release-Children Overall, 50 of 684 children treated with dexmethylphenidate hydrochloride immediate-release formulation (7.3%) experienced an adverse event 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). None of the 53 dexmethylphenidate hydrochloride extended-release-treated pediatric patients discontinued treatment due to adverse events in the 7-week, placebo-controlled study. 6.2 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-Treated Patients-Children Table 1 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release doses of 5 to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release was at least twice the incidence in placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence rate in the population studied. Table 1. Treatment-Emergent Adverse Events Events, regardless of causality, for which the incidence for patients treated with dexmethylphenidate hydrochloride extended-release was at least 5% and twice the incidence among placebo-treated patients. Incidence has been rounded to the nearest whole number. Occurring During Double-Blind Treatment–Pediatric Patients Dexmethylphenidate Hydrochloride Extended-Release Placebo N=53 N=47 No. of Patients with AEs Total 76% 57% Primary System Organ Class / Adverse Event Preferred Term Gastrointestinal Disorders 38% 19% Dyspepsia 8% 4% Metabolism and Nutrition Disorders 34% 11% Decreased Appetite 30% 9% Nervous System Disorders 30% 13% Headache 25% 11% Psychiatric Disorders 26% 15% Anxiety 6% 0% Table 2 below enumerates the incidence of dose-related adverse events that occurred during a fixed-dose, double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride extended-release up to 30mg/day versus placebo in children and adolescents with ADHD. Table 2: Dose-related Adverse Events from a Fixed-dose Study of Double-Blind Treatment in Pediatric Patients by Organ-System and Preferred Term ADVERSE Dexmethylphenidate Dexmethylphenidate Dexmethylphenidate EVENT Hydrochloride Hydrochloride Hydrochloride Extended-Release Extended-Release Extended-Release 10 mg/d 20 mg/d 30 mg/d Placebo N=64 N=60 N=58 N=63 Gastrointestinal Disorders 22% 23% 29% 24% Vomiting 2% 8% 9% 0 Metabolism and Nutritional Disorders 16% 17% 22% 5% Anorexia 5% 5% 7% 0 Psychiatric Disorders 19% 20% 38% 8% Insomnia 5% 8% 17% 3% Depression 0 0 3% 0 Mood Swings 0 0 3% 2% Other Adverse Events Irritability 0 2% 5% 0 Nasal Congestion 0 0 5% 0 Pruritus 0 0 3% 0 6.3 Adverse Events Associated with Discontinuation of Treatment in Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release-Adults In the adult placebo-controlled study, 10.7% of the dexmethylphenidate hydrochloride extended-release-treated patients and 7.5% of the placebo-treated patients discontinued for adverse events. Among dexmethylphenidate hydrochloride extended-release-treated patients, insomnia (1.8%, n=3), feeling jittery (1.8%, n=3), anorexia (1.2%, n=2), and anxiety (1.2%, n=2) were the reasons for discontinuation reported by more than 1 patient. 6.4 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-Treated Patients-Adults Table 3 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate hydrochloride extended-release doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release appeared to increase with dose. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Table 3. Treatment-Emergent Adverse Events Events, regardless of causality, for which the incidence was at least 5% in a dexmethylphenidate hydrochloride extended-release group and which appeared to increase with randomized dose. Incidence has been rounded to the nearest whole number. Occurring During Double-Blind Treatment–Adults Dexmethylphenidate Dexmethylphenidate Dexmethylphenidate Hydrochloride Hydrochloride Hydrochloride Extended-Release Extended-Release Extended-Release Placebo 20 mg 30 mg 40 mg N=57 N=54 N=54 N=53 No. of Patients with AEs Total 84% 94% 85% 68% Primary System Organ Class / Adverse Event Preferred Term Gastrointestinal Disorders 28% 32% 44% 19% Dry Mouth 7% 20% 20% 4% Dyspepsia 5% 9% 9% 2% Nervous System Disorders 37% 39% 50% 28% Headache 26% 30% 39% 19% Psychiatric Disorders 40% 43% 46% 30% Anxiety 5% 11% 11% 2% Respiratory, Thoracic and Mediastinal Disorders 16% 9% 15% 8% Pharyngolaryngeal Pain 4% 4% 7% 2% Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride extended-release 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 hydrochloride extended-release in the treatment of ADHD. Table 4. Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment – Adults Dexmethylphenidate Hydrochloride Extended-Release Dexmethylphenidate Hydrochloride Extended-Release Dexmethylphenidate Hydrochloride Extended-Release Placebo 20 mg 30 mg 40 mg (N=57) (N=54) (N=54) (N=53) Pulse (bpm) 3.1 ± 11.1 4.3 ± 11.7 6.0 ± 10.1 -1.4 ± 9.3 Diastolic BP (mmHg) -0.2 ± 8.2 1.2 ± 8.9 2.1 ± 8.0 0.3 ± 7.8 Weight (kg) -1.4 ± 2.0 -1.2 ± 1.9 -1.7 ± 2.3 -0.1 ± 3.9 6.5 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate hydrochloride extended-release. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Musculoskeletal : rhabdomyolysis Immune System Disorders : hypersensitivity reactions, including angioedema and anaphylaxis 6.6 Adverse Events with Other Methylphenidate HCl Dosage Forms Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, serotonin syndrome in combination with serotonergic drugs, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/Lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Psychiatric: transient depressed mood, aggressive behavior, libido changes Skin/Subcutaneous: scalp hair loss Urogenital: priapism Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a 10-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Dexmethylphenidate hydrochloride extended-release should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO Inhibitors [see Contraindications (4.5) ]. Because of possible effects on blood pressure, dexmethylphenidate hydrochloride extended-release should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Dexmethylphenidate is metabolized primarily to d -ritalinic acid by de-esterification and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of dexmethylphenidate from dexmethylphenidate hydrochloride extended-release have not been studied. Since the modified release characteristics of dexmethylphenidate hydrochloride extended-release are pH dependent, the coadministration of antacids or acid suppressants could alter the release of dexmethylphenidate. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. Dexmethylphenidate hydrochloride extended-release should not be used in patients being treated (currently or within the preceding two weeks) with MAO Inhibitors ( 4.5 ) Dexmethylphenidate hydrochloride extended-release should be used cautiously with pressor agents ( 7 ) Antacids or acid suppressants could alter the release of dexmethylphenidate hydrochloride extended-release ( 7 ) Racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants, and tricyclic drugs ( 7 )