Methylphenidate (Ex R Tablets)

DESCRIPTION

CONCERTA™ (methylphenidate HCl) Extended-release Tablets CII

CONCERTA™ is a central nervous system (CNS) stimulant. CONCERTA™ is available in two tablet strengths. Each extended-release tablet for once-a-day oral administration contains 18 or 36 mg of methylphenidate HCl USP and is designed to have a 12-hour duration of effect. Chemically, methylphenidate HCl is d,l (racemic) methyl a-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C₁₄H₁₉NO₂•HCl.

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, hydroxypropyl methylcellulose, lactose, phosphoric acid, poloxamer, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin.

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. 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.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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

Pharmacokinetics

Absorption

Methylphenidate is readily absorbed. Following oral administration of CONCERTA™ to adults, plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 to 2 hours, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which a gradual decrease in plasma levels of methylphenidate begins. CONCERTA™ qd minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate t.i.d. The relative bioavailability of CONCERTA™ qd and methylphenidate tid in adults is comparable.

The mean pharmacokinetic parameters in 36 adults following the administration of CONCERTA™ 18 mg qd and methylphenidate 5 mg tid are summarized in Table 1.

INDICATIONS

Attention Deficit Hyperactivity Disorder (ADHD)

CONCERTA™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of CONCERTA™ in the treatment of ADHD was established in three controlled trials of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).

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 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

CONCERTA™ is indicated as an integral party 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 CONCERTA™ for long-term use, i.e., for more than 4 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use CONCERTA™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see

DOSAGE AND ADMINISTRATION

DOSAGE AND ADMINISTRATION

CONCERTA™ is administered orally once daily in the morning.

CONCERTA™ must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. See PATIENT INFORMATION.

CONCERTA™ may be administered with or without food and should be administered once daily in the morning.

Dosage should be individualized according to the needs and responses of the patient.

Patients New to Methylphenidate

The recommended starting dose of CONCERTA™ for patients who are not currently taking methylphenidate, or for patients who are on stimulants other than methylphenidate, is 18 mg once daily.

Dosage may be adjusted in 18 mg increments to a maximum of 54 mg/day taken once daily in the morning. In general, dosage adjustment may proceed at approximately weekly intervals.

Patients Currently Using Methylphenidate

The recommended dose of CONCERTA™ for patients who are currently taking methylphenidate bid, tid, or sustained-release (SR) at doses of 10 to 60 mg/day is provided in Table 3. Dosing recommendations are based on current dose regimen and clinical judgement.

Dosage may be adjusted in 18 mg increments to a maximum of 54 mg/day taken once daily in the morning. In general, dosage adjustment may proceed at approximately weekly intervals.

Table 3
Recommended Dose Conversion from
Methylphenidate Regimens to CONCERTA™

Other methylphenidate regimens: Clinical judgement should be used when selecting the starting dose.

Daily dosage above 54 mg is not recommended.

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. Nevertheless, 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.

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.

HOW SUPPLIED

CONCERTA™ (methylphenidate HCl) Extended-release Tablets are available in 18 mg and 36 mg dosage strengths. The 18 mg tablets are yellow and imprinted with "alza 18". The 36 mg tablets are white and imprinted with "alza 36". Both dosage strengths are supplied in bottles containing 100 tablets.

Storage

Store at 25EC (77EF); excursions permitted to 15-30EC (59-86EF) [see USP Controlled Room Temperature]. Protect from humidity.

REFERENCE

American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association 1994.

Rx Only.

SIDE EFFECTS

The premarketing development program for CONCERTA™ included exposures in a total of 755 participants in clinical trials (469 patients, 286 healthy adult subjects). These participants received CONCERTA™ 18, 36, and/or 54 mg/day. The 469 patients (ages 6 to 13) were evaluated in three controlled clinical studies (Studies 1, 2, and 3), two uncontrolled clinical studies (including a long-term safety study), and one clinical pharmacology study in children with ADHD. Of the 469 patients in this program, 68 CONCERTA™-treated patients in one uncontrolled dose-initiation study were naïve to any pharmacologic therapy for their ADHD. Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

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, COSTART 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.

Adverse Findings in Clinical Trials with CONCERTA™

Adverse Events Associated with Discontinuation of Treatment

In the 4-week placebo-controlled, parallel-group trial one CONCERTA™-treated patient (0.9%; 1/106) and one placebo-treated patient (1.0%; 1/99) discontinued due to an adverse event (sadness and increase in tics, respectively).

In uncontrolled studies up to 12 months with CONCERTA™, 6.6% (29/441) patients discontinued for adverse events. Those events associated with discontinuation of CONCERTA™ in more than one patient included the following: twitching (tics, 1.8%); anorexia (loss of appetite, 0.9%); aggravation reaction (0.7%); hostility (0.7%); insomnia (0.7%); and somnolence (0.5%).

Adverse Events Occurring at an Incidence of 1% or more Among CONCERTA™-Treated Patients

Table 2 enumerates, for a 4-week placebo-controlled, parallel-group trial in children with ADHD at CONCERTA™ doses of 18, 36, or 54 mg/day, the incidence of treatment-emergent adverse events. The table includes only those events that occurred in 1% or more of patients treated with CONCERTA™ where the incidence in patients treated with CONCERTA™ was greater than 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 non-drug factors to the adverse event incidence rate in the population studied.

Table 2
Incidence of Treatment-Emergent Events¹ in a 4-Week Placebo-Controlled Clinical Trial of CONCERTA™

Tics

In a long-term uncontrolled study (n=407 children), the cumulative incidence of new onset of tics was 8% after 10 months of treatment with CONCERTA™.

Adverse Events with Other Methylphenidate HCl Products

Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourette's syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss. 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 ten 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. 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 above may also occur.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

CONCERTA™, like other methylphenidate products, is classified as a Schedule II controlled substance by federal regulation.

Abuse, Dependence, and Tolerance

See WARNINGS for boxed warning containing drug abuse and dependence information.

DRUG INTERACTIONS

Because of possible effects on blood pressure, CONCERTA™ should be used cautiously with pressor agents.

Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., 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.

Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.

WARNINGS

Depression

CONCERTA™ should not be used to treat severe depression.

Fatigue

CONCERTA™ should not be used for the prevention or treatment of normal fatigue states.

Long-Term Suppression of Growth

Sufficient data on the safety of long-term use of methylphenidate in children are not yet available. Although a causal relationship has not been established, suppression of growth (i.e., weight gain, and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. Patients who are not growing or gaining weight as expected should have their treatment interrupted.

Psychosis

Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.

Seizures

There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in absence of history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

Potential for Gastrointestinal Obstruction

Because the CONCERTA™ tablet is nondeformable and does not appreciably change in shape in the GI tract, CONCERTA™ should ordinarily not be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, CONCERTA™ should only be used in patients who are able to wswallow the tablet whole (see PATIENT INFORMATION).

Hypertension and other Cardiovascular Conditions

Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate intervals in patients taking CONCERTA™, especially patients with hypertension. In the laboratory classroom clinical trials (Studies 1 and 2), both CONCERTA™ and methylphenidate tid increased resting pulse by an average of 2-6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1-4 mm Hg during the day, relative to placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or hyperthyroidism.

Visual Disturbance

Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.

Use in Children Under Six Years of Age

CONCERTA™ should not be used in children under six years, since safety and efficacy in this age group have not been established.

PRECAUTIONS

Hematologic Monitoring

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

Information for Patients

See PATIENT INFORMATION section.

Drug Interactions

See DRUG INTERACTIONS section.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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/m2 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/m2 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.

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.

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/m2 basis, respectively.

Pregnancy: Teratogenic Effects

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/m2 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/m2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPA in pregnant rats was 2 times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA™ based on the AUC.

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.

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.

Pediatric Use

The safety and efficacy of CONCERTA™ in children under 6 years old have not been established. Long-term effects of methylphenidate in children have not been well established (see

WARNINGS