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The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials as follows].
The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Discontinuation Due to Adverse Reactions as follows].
The development program for CONCERTA included exposures in a total of 3906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 4). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.
Click on icon to see table/diagram/imageAdverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
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.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of CONCERTA based on the comprehensive assessment of the available adverse event information. A causal association for CONCERTA often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, 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.
The majority of adverse reactions were mild to moderate in severity.
Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
Children and Adolescents: Table 5 lists the adverse reactions reported in 1% or more of CONCERTA-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials. (See Table 5.)
Click on icon to see table/diagram/imageThe majority of adverse reactions were mild to moderate in severity.
Adults: Table 6 lists the adverse reactions reported in 1% or more of CONCERTA-treated adults in 2 placebo-controlled, double-blind clinical trials. (See Table 6.)
Click on icon to see table/diagram/imageThe majority of ADRs were mild to moderate in severity.
Other Adverse Reactions Observed in CONCERTA Clinical Trials: This section includes adverse reactions reported by CONCERTA-treated subjects in double-blind trials that do not meet the criteria specified for Table 5 or Table 6 and all adverse reactions reported by CONCERTA-treated subjects who participated in open-label and postmarketing clinical trials.
Blood and Lymphatic System Disorders: Leukopenia.
Eye Disorders: Accommodation disorder, Dry eye.
Vascular Disorders: Hot flush.
Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea.
General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst.
Infections and Infestations: Sinusitis.
Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased.
Musculoskeletal and Connective Tissue Disorders: Muscle spasms.
Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence.
Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic.
Reproductive System and Breast Disorders: Erectile dysfunction.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea.
Skin and Subcutaneous Tissue Disorders: Rash, Rash macular.
Vascular Disorders: Hypertension.
Discontinuation Due to Adverse Reactions: Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 CONCERTA patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).
In the 2 placebo-controlled studies of adults, 25 CONCERTA patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the CONCERTA patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).
In the 11 open-label studies of children, adolescents, and adults, 266 CONCERTA patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).
Blood Pressure and Heart Rate Increases: In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 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. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with CONCERTA at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for CONCERTA and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for CONCERTA and placebo at the end of the double-blind treatment (3.6 and -1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double-blind treatment for CONCERTA and placebo-treated patients were -1.2 and -0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Increased Blood Pressure and Heart Rate under Precautions].
Postmarketing Experience: The following additional adverse reactions have been identified during postapproval use of CONCERTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura.
Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles.
Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment.
General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased.
Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure.
Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC.
Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis.
Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics.
Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes.
Reproductive System and Breast Disorders: Priapism.
Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema.
Vascular Disorders: Raynaud's phenomenon.
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