ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
- Drug Dependence [see Box Warning ]
- Hypersensitivity to Methylphenidate [see Contraindications]
- Agitation [see Contraindications]
- Glaucoma [see Contraindications]
- Tics [see Contraindications]
- Monoamine Oxidase Inhibitors [see Contraindications and Drug Interactions]
- Serious Cardiovascular Events [see Warnings and Precautions]
- Psychiatric Adverse Events [see Warnings and Precautions]
- Seizures [see Warnings and Precautions]
- Long-Term Suppression of Growth [see Warnings and Precautions]
- Visual Disturbance [see Warnings and Precautions]
- Potential for Gastrointestinal Obstruction [see Warnings and Precautions]
- Hematologic Monitoring [see Warnings and Precautions]
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 Adverse Reactions].
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 Adverse Reactions].
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 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.
Table 3. CONCERTA® Exposure in Double-Blind and Open-Label Clinical Studies
Patient Population |
N |
Dose Range |
Children |
2216 |
18 to 54 mg once daily |
Adolescents |
502 |
18 to 72 mg once daily |
Adults |
1188 |
18 to 108 mg once daily |
Adverse 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 4 lists the adverse reactions reported in 1% or more of CONCERTA®-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.
Table 4. Adverse Reactions Reported by ≥1% of CONCERTA®-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of CONCERTA®
System/Organ Class Adverse Reaction |
CONCERTA®
(n=321) % |
Placebo (n=318) % |
Gastrointestinal Disorders
|
|
|
Abdominal pain upper |
6.2 |
3.8 |
Vomiting |
2.8 |
1.6 |
General Disorders and Administration Site Conditions
|
|
|
Pyrexia |
2.2 |
0.9 |
Infections and Infestations
|
|
|
Nasopharyngitis |
2.8 |
2.2 |
Nervous System Disorders
|
|
|
Dizziness |
1.9 |
0 |
Psychiatric Disorders
|
|
|
InsomniaTerms of Initial insomnia (CONCERTA®=0.6%) and Insomnia (CONCERTA®=2.2%) are combined into Insomnia.
|
2.8 |
0.3 |
Respiratory, Thoracic and Mediastinal Disorders
|
|
|
Cough |
1.9 |
0.9 |
Oropharyngeal pain |
1.2 |
0.9 |
The majority of adverse reactions were mild to moderate in severity.
Adults
Table 5 lists the adverse reactions reported in 1% or more of CONCERTA®-treated adults in 2 placebo-controlled, double-blind clinical trials.
Table 5. Adverse Reactions Reported by ≥1% of CONCERTA®-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical TrialsIncluded doses up to 108 mg.
System/Organ Class Adverse Reaction |
CONCERTA®
(n=415) % |
Placebo (n=212) % |
Cardiac Disorders
|
|
|
Tachycardia |
4.8 |
0 |
Palpitations |
3.1 |
0.9 |
Ear and Labyrinth Disorders
|
|
|
Vertigo |
1.7 |
0 |
Eye Disorders
|
|
|
Vision blurred |
1.7 |
0.5 |
Gastrointestinal Disorders
|
|
|
Dry mouth |
14.0 |
3.8 |
Nausea |
12.8 |
3.3 |
Dyspepsia |
2.2 |
0.9 |
Vomiting |
1.7 |
0.5 |
Constipation |
1.4 |
0.9 |
General Disorders and Administration Site Conditions
|
|
|
Irritability |
5.8 |
1.4 |
Infections and Infestations
|
|
|
Upper respiratory tract infection |
2.2 |
0.9 |
Investigations
|
|
|
Weight decreased |
6.5 |
3.3 |
Metabolism and Nutrition Disorders
|
Decreased appetite |
25.3 |
6.6 |
Anorexia |
1.7 |
0 |
Musculoskeletal and Connective Tissue Disorders
|
Muscle tightness |
1.9 |
0 |
Nervous System Disorders
|
|
|
Headache |
22.2 |
15.6 |
Dizziness |
6.7 |
5.2 |
Tremor |
2.7 |
0.5 |
Paresthesia |
1.2 |
0 |
Sedation |
1.2 |
0 |
Tension headache |
1.2 |
0.5 |
Psychiatric Disorders
|
|
|
Insomnia |
12.3 |
6.1 |
Anxiety |
8.2 |
2.4 |
Initial insomnia |
4.3 |
2.8 |
Depressed mood |
3.9 |
1.4 |
Nervousness |
3.1 |
0.5 |
Restlessness |
3.1 |
0 |
Agitation |
2.2 |
0.5 |
Aggression |
1.7 |
0.5 |
Bruxism |
1.7 |
0.5 |
Depression |
1.7 |
0.9 |
Libido decreased |
1.7 |
0.5 |
Affect lability |
1.4 |
0.9 |
Confusional state |
1.2 |
0.5 |
Tension |
1.2 |
0.5 |
Respiratory, Thoracic and Mediastinal Disorders
|
Oropharyngeal pain |
1.7 |
1.4 |
Skin and Subcutaneous Tissue Disorders
|
Hyperhidrosis |
5.1 |
0.9 |
The 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 4 or Table 5 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%).
Tics
In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with CONCERTA®.
In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months.
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 Warnings and Precautions (5.1])
.
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, Mydriasis, Visual impairment
General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased
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
Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia
Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania
Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema
Vascular Disorders: Raynaud's phenomenon
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