The pre-marketing clinical development program for Daytrana™ included exposures in a total of 1,158 participants in clinical trials (758 pediatric patients and 400 healthy adult subjects). These participants received Daytrana™ 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™
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™ discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The reasons for discontinuation among the patients treated with Daytrana™ 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™
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
| System Organ Class || Number (%) of Subjects Reporting Adverse Events|
| Adverse Event || Daytrana™ (N = 98)|| Placebo (N = 85)|
| Number of Subjects With ≥ 1 Adverse Event|| 74 || (76)|| 49|| (58)|
| Gastrointestinal Disorders|
| Nausea|| 12|| (12)|| 2|| (2)|
| Vomiting|| 10|| (10)|| 4|| (5)|
| Infections and Infestations|
| Nasopharyngitis|| 5|| (5)|| 2|| (2)|
| Weight decreased|| 9|| (9)|| 0|| (0)|
| Metabolism and Nutrition Disorders|
| Anorexia|| 5|| (5)|| 1|| (1)|
| Decreased appetite|| 25|| (26)|| 4|| (5)|
| Psychiatric Disorders|
| Affect lability
|| 6|| (6)|| 0|| (0)|
| Insomnia|| 13|| (13)|| 4|| (5)|
| Tic|| 7|| (7)|| 0|| (0)|
| Nasal congestion|| 6|| (6)|| 1|| (1)|
Daytrana™ 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. If erythema, edema, and/or papules do not resolve or significantly reduce within 24 hours after patch removal, further evaluation should be sought. Erythema is not by itself an indication of contact sensitization. However, sensitization should be considered if erythema is accompanied by edema, papules, vesicles, or other evidence of more intense local reactions. Diagnosis of allergic contact dermatitis should be corroborated by appropriate diagnostic testing (see WARNINGS - Contact Sensitization)
Adverse Events With the Long-Term Use of Daytrana™
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™ 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.
REPORTS OF SUSPECTED DAYTRANA SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Daytrana. The information is not vetted and should not be considered as verified clinical evidence.
Possible Daytrana side effects / adverse reactions in 8 year old male
Reported by a physician from United States on 2011-12-08
Patient: 8 year old male weighing 34.0 kg (74.8 pounds)
Reactions: Application Site Reaction, Vitiligo
Possible Daytrana side effects / adverse reactions in 9 year old male
Reported by a health professional (non-physician/pharmacist) from France on 2012-05-21
Patient: 9 year old male weighing 30.0 kg (66.0 pounds)
Reactions: Blood Creatine Phosphokinase Increased, Hyperthermia, Dystonia, Dehydration
Adverse event resulted in: hospitalization
Dosage: 20 mg, qd
Dosage: 36 mg, qd
Other drugs received by patient: Risperidone
Possible Daytrana side effects / adverse reactions in 21 year old male
Reported by a health professional (non-physician/pharmacist) from United States on 2012-05-30
Patient: 21 year old male
Reactions: OFF Label USE, Application Site Erythema, Application Site Rash