Detailed information on serious and adverse reactions of particular importance is provided in the Boxed Warning and Warnings and Precautions (5) sections:
- Drug dependence [see BOX WARNING]
- Hypersensitivity to Methylphenidate [see CONTRAINDICATIONS]
- Marked anxiety, tension, or agitation [see CONTRAINDICATIONS]
- Glaucoma [see CONTRAINDICATIONS]
- Tics or a family history of Tourette's syndrome [see CONTRAINDICATIONS]
- Monoamine Oxidase Inhibitors [see CONTRAINDICATIONS and DRUG INTERACTIONS]
- Serious Cardiovascular Events [see WARNINGS AND PRECAUTIONS]
- Increase in Blood Pressure [see WARNINGS AND PRECAUTIONS]
- Psychiatric Adverse Events [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Priapism [see WARNINGS AND PRECAUTIONS]
- Peripheral Vasculopathy[see WARNINGS AND PRECAUTIONS]
- Long-Term Suppression of Growth [see WARNINGS AND PRECAUTIONS]
- Visual Disturbance [see WARNINGS AND PRECAUTIONS]
- Contact Sensitization [see WARNINGS AND PRECAUTIONS]
- External Heat [see WARNINGS AND PRECAUTIONS]
- Hematologic Monitoring [see WARNINGS AND PRECAUTIONS]
The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia.
The most common ( ≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions.
The overall Daytrana development program included exposure to Daytrana in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using Daytrana with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents have been exposed for ≥ 6 months. Most patients studied were exposed to Daytrana patch sizes of 12.5 cm², 18.75 cm², 25 cm² or 37.5 cm², with a wear time of 9 hours.
In the data presented below, the adverse reactions reported 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 reactions without first grouping similar types of events into a smaller number of standardized event categories.
Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trials Experience
Adverse Reactions 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 most commonly reported ( ≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%).
In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%) and decreased appetite/anorexia (1.4%).
Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials
Skin Irritation and Application Site Reactions
Daytrana is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the patch application site. 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 a manifestation 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 [see WARNINGS AND PRECAUTIONS].
Most Commonly Reported Adverse Reactions
Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% Daytrana-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event.
Table 2 : Number (%) of Subjects with Commonly Reported Adverse Reactions ( ≥ 1% in the Daytrana Group) in 7-Week Placebo-controlled Studies in Either Children or Adolescents - Safety Population
|System Organ Class Preferred term||Adolescents||Children|
N = 72
N = 145
N = 85
N = 98
|Tachycardia||0 (0)||1 (0.7)||0 (0)||1 (1.0)|
|Abdominal pain||0 (0)||7 (4.8)||5 (5.9)||7 (7.1)|
|Nausea||2 (2.8)||14 (9.7)||2 (2.4)||12 (12.2)|
|Vomiting||1 (1.4)||5 (3.4)||4 (4.7)||10 (10.2)|
|Weight decreased||1 (1.4)||8 (5.5)||0 (0)||9 (9.2)|
|Metabolism and nutrition disorders|
|Anorexia||1 (1.4)||7 (4.8)||1 (1.2)||5 (5.1)|
|Decreased appetite||1 (1.4)||37 (25.5)||4 (4.7)||25 (25.5)|
|Nervous system disorders|
|Dizziness||1 (1.4)||8 (5.5)||1 (1.2)||0 (0)|
|Headache||9 (12.5)||18 (12.4)||10 (11.8)||15 (15.3)|
|Affect lability||1 (1.4)||0 (0)||0 (0)||6 (6.1)*|
|Insomnia||2 (2.8)||9 (6.2)||4 (4.7)||13 (13.3)|
|Irritability||5 (6.9)||16 (11)||4 (4.7)||7 (7.1)|
|Tic||0 (0)||0 (0)||0 (0)||7 (7.1)|
|* Six subjects had affect lability, all judged as mild and described as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and intermittent emotional|
Adverse Reactions With the Long-Term Use of Daytrana
In a long-term open-label study of up to 12 months duration in 326 children wearing Daytrana 9 hours daily, the most common ( ≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%.
In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common ( ≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%).
In addition, the following adverse reactions have been identified during the postapproval use of Daytrana. 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 exposure.
Cardiac Disorders: palpitations
Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder
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: blood pressure increased
Nervous System Disorders: convulsion, dyskinesia
Psychiatric Disorders: transient depressed mood, hallucination, nervousness, libido changes
Skin and Subcutaneous Tissue Disorders: alopecia
Adverse Reactions 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, pulse increased or decreased
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: drowsiness, 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.