The development program for CONCERTA® included exposures in a total of 2121 participants in clinical trials (1797 patients, 324 healthy adult subjects). These participants received CONCERTA® 18, 36, 54 and/or 72 mg/day. Children, adolescents, and adults with ADHD were evaluated in four controlled clinical studies, three open-label clinical studies and two clinical pharmacology studies. 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 in children (Study 3) 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 the 2-week placebo-controlled phase of a trial in adolescents (Study 4), no CONCERTA®-treated patients (0%; 0/87) and 1 placebo-treated patient (1.1%; 1/90) discontinued due to an adverse event (increased mood irritability).

In the two open-label, long-term safety trials (Studies 5 and 6: one 24-month study in children aged 6 to 13 and one 9-month study in child, adolescent and adult patients treated with CONCERTA®) 6.7% (101/1514) of patients discontinued due to adverse events. These events with an incidence of >0.5% included: insomnia (1.5%), twitching (1.0%), nervousness (0.7%), emotional lability (0.7%), abdominal pain (0.7%), and anorexia (0.7%).

Treatment-Emergent Adverse Events Among CONCERTA®-Treated Patients Table 2 enumerates, for a 4-week placebo-controlled, parallel-group trial (Study 3) 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® In Children

Table 3 lists the incidence of treatment-emergent adverse events for a 2-week placebo-controlled trial (Study 4) in adolescents with ADHD at CONCERTA® doses of 18, 36, 54 or 72 mg/day.

TABLE 3: Incidence of Treatment-Emergent Events¹ in a 2-Week Placebo-Controlled Clinical Trial of CONCERTA® in Adolescents

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.

Hypertension

In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA® qd 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.

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 (see WARNINGS).

Post-Marketing Experience With CONCERTA®:

Post-marketing experiences with CONCERTA® have revealed spontaneous reports of the following adverse events: difficulties in visual accommodation, blurred vision, abnormal liver function test (e.g., transaminase elevation), palpitations, arrhythmia, leucopenia, and thrombocytopenia.

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; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; 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: hepatic coma; isolated cases of cerebral arteritis and/or occlusion; 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.

CONCERTA® should not be used in patients being treated (currently or within the proceeding 2 weeks) with MAO inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).

Because of possible increases in blood pressure, CONCERTA® should be used cautiously with vasopressor agents.

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.

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.

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