Concerta (Methylphenidate Hydrochloride) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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 näive 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.

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®.

Post-Marketing Experience with CONCERTA®:

Additional very rare undesirable effects were reported during the marketing experience: difficulties in visual accomodation, blurred vision, abnormal liver function tests (eg, transaminase elevation), palpitations, arrhythmia, leukopenia, 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 BOX WARNING containing drug abuse and dependence information.