SIDE EFFECTS

The pre-marketing clinical development program for Daytrana™ (methylphenidate transdermal) included exposures in a total of 1,158 participants in clinical trials (758 pediatric patients and 400 healthy adult subjects). These participants received Daytrana™ (methylphenidate transdermal) in patch sizes ranging from 6.25 cm² to 50 cm². The 758 pediatric patients (age 6 to 16 years) were evaluated in 9 controlled clinical studies, 2 open-label clinical studies, and 4 clinical pharmacology studies. Adverse reactions were assessed by collecting adverse events data, the results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse events during exposure were obtained primarily by general inquiry at each visit, and were recorded by the 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. 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 Daytrana™ (methylphenidate transdermal)

Adverse Events Associated With Discontinuation of Treatment

In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Daytrana™ (methylphenidate transdermal) discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The reasons for discontinuation among the patients treated with Daytrana™ (methylphenidate transdermal) were application site erythema, application site reaction, confusional state, crying, tics, headaches, irritability, infectious mononucleosis, and viral infection.

Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated With Daytrana™ (methylphenidate transdermal)

Table 1 enumerates the incidence of treatment-emergent adverse events reported in a 7 week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting.

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 those 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 1 : Most Commonly Reported Treatment-Emergent Adverse Events ( ≥ 5% and 2x Placebo) in a 7-week Placebo-controlled Study

Skin Irritation

Daytrana™ (methylphenidate transdermal) is a dermal irritant. The majority of subjects in the pivotal phase III clinical efficacy study had minimal to definite erythema. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself an indication of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site.

In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with Daytrana™ (methylphenidate transdermal) using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at Daytrana™ (methylphenidate transdermal) application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. The subject was not transitioned to oral methylphenidate. Confirmation of a diagnosis of allergic contact dermatitis may require further diagnostic testing (see WARNINGS - Contact Sensitization).

Adverse Events With the Long-Term Use of Daytrana™ (methylphenidate transdermal)

In a long-term open-label study of up to 40-month duration in 191 children with ADHD, the most frequently reported treatment-emergent adverse events in pediatric patients treated with Daytrana™ (methylphenidate transdermal) for 12 hours daily were anorexia (87 subjects, 46%), insomnia (57 subjects, 30%), viral infection (54 subjects, 28%), and headache (53 subjects, 28%). A total of 45 (24%) subjects were withdrawn from the study because of treatment-emergent adverse events. The most common events leading to withdrawal were application site reaction (12 subjects, 6%), anorexia (7 subjects, 4%), and insomnia (7 subjects, 4%).

Adverse Events With Oral Methylphenidate Products

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, 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 hepatic coma

Psychiatric: transient depressed mood

Skin/Subcutaneous: scalp hair loss

Neuroleptic Malignant Syndrome:

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.

Postmarketing Reports

Postmarketing reports of the following events have been reported. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to Daytrana™ (methylphenidate transdermal) exposure.

Cardiac Disorders: palpitation

Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder

Gastrointestinal Disorders: abdominal pain

General Disorders and Administration Site Disorders: application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth.

Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis

Investigations: heart rate increased, blood pressure increased

Nervous System Disorders: convulsion, dizziness

Psychiatric Disorders: transient depressed mood, hallucination, nervousness

Skin and Subcutaneous Tissue Disorders: alopecia

Drug Abuse And Dependence

Controlled Substance Class

Daytrana™ (methylphenidate transdermal system), like other methylphenidate products, is classified as a Schedule II controlled substance by federal regulation.

Abuse, Dependence, and Tolerance

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

Read the entire FDA prescribing information for Daytrana (Methylphenidate Transdermal) »