1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are 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.

Methylphenidate hydrochloride extended-release Tablets 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 Methylphenidate hydrochloride extended-release tablets are 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.

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 methylphenidate hydrochloride extended-release tablets included exposures in a total of 3,906 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.

Methylphenidate Hydrochloride Extended-Release Tablets 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 methylphenidate hydrochloride extended-release tablets based on the comprehensive assessment of the available adverse event information.

A causal association for methylphenidate hydrochloride extended-release tablets 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 Dr. Reddy’s Laboratories, Inc.

at 1-888-375-3784 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 methylphenidate hydrochloride extended-release tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table 4.

Adverse Reactions Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets System/Organ Class Adverse Reaction Methylphenidate Hydrochloride (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* 2.8 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 0.9 Oropharyngeal pain 1.2 0.9 *Terms of Initial insomnia (methylphenidate hydrochloride=0.6%) and Insomnia (methylphenidate hydrochloride=2.2%) are combined into Insomnia.

The majority of adverse reactions were mild to moderate in severity.

Adults Table 5 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated adults in 2 placebo-controlled, double-blind clinical trials.

Table 5.

Adverse Reactions Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials* System/Organ Class Adverse Reaction Methylphenidate Hydrochloride (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 * Included doses up to 108 mg.

The majority of ADRs were mild to moderate in severity .

6.2 Other Adverse Reactions Observed in Methylphenidate Hydrochloride Extended-Release Tablets Clinical Trials This section includes adverse reactions reported by methylphenidate hydrochloride extended-release tablets-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 methylphenidate hydrochloride extended-release tablets-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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets.

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 methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride 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 methylphenidate hydrochloride 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 methylphenidate hydrochloride Extended-Release Tablets 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 methylphenidate hydrochloride 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 methylphenidate hydrochloride Extended-Release Tablets 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 methylphenidate hydrochloride Extended-Release Tablets 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 methylphenidate hydrochloride extended-release tablets.

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 Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud’s phenomenon