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adverse reactions
6 ADVERSE REACTIONS 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 the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions are discussed in more detail in other sections of the labeling: •Increased Mortality in Elderly Patients with Dementia-Related Psychosis •Cerebrovascular Adverse Events, Including Stroke •Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults •Neuroleptic Malignant Syndrome (NMS) •Tardive Dyskinesia •Metabolic Changes •Orthostatic Hypotension •Leukopenia, Neutropenia, and Agranulocytosis •Seizures/Convulsions •Potential for Cognitive and Motor Impairment •Body Temperature Regulation •Suicide •Dysphagia The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)] [see WARNINGS AND PRECAUTIONS (5.2)] [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.3)] [see WARNINGS AND PRECAUTIONS (5.4)] [see WARNINGS AND PRECAUTIONS (5.5)] [see WARNINGS AND PRECAUTIONS (5.6)] [see WARNINGS AND PRECAUTIONS (5.7)] [see WARNINGS AND PRECAUTIONS (5.8)] [see WARNINGS AND PRECAUTIONS (5.9)] [see WARNINGS AND PRECAUTIONS (5.10)] [see WARNINGS AND PRECAUTIONS (5.11)] [see WARNINGS AND PRECAUTIONS (5.12)] [see WARNINGS AND PRECAUTIONS (5.13)] The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased. Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, another indication, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure. Aripiprazole has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia or other indications and who had approximately 1,342 patient-years of exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 pediatric patients treated with oral aripiprazole had at least 1 year of exposure. The conditions and duration of treatment with aripiprazole tablets included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. •Adult patients with schizophrenia: akathisia •Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.1): To report SUSPECTED ADVERSE REACTIONS, contact Trigen Laboratories, LLC at 888 9 TRIGEN (888-987-4436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Adult Patients with Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Commonly Observed Adverse Reactions The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%). Less Common Adverse Reactions in Adults Table 10 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. Table 10: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole System Organ Class Preferred Term Percentage of Patients Reporting Reaction a Aripiprazole (n=1843) Placebo (n=1166) Eye Disorder Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. a An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Pediatric Patients (13 to 17 years) with Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor. Table 11 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in one indication, up to 8 weeks in another indication, and up to 10 weeks in another indication), including only those reactions that occurred in 2% or more of pediatric patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo. Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia or Other Indications Table 11: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction a System Organ Class Preferred Term Aripiprazole (n=732) Placebo (n=370) Eye Disorders Blurred Vision 3 0 Gastrointestinal Disorders Abdominal Discomfort 2 1 Vomiting 8 7 Nausea 8 4 Diarrhea 4 3 Salivary Hypersecretion 4 1 Abdominal Pain Upper 3 2 Constipation 2 2 General Disorders and Administration Site Conditions Fatigue 10 2 Pyrexia 4 1 Irritability 2 1 Asthenia 2 1 Infections and Infestations Nasopharyngitis 6 3 Investigations Weight Increased 3 1 Metabolism and Nutrition Disorders Increased Appetite 7 3 Decreased Appetite 5 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 2 1 Muscle Rigidity 2 1 Nervous System Disorders Somnolence 16 4 Headache 12 10 Sedation 9 2 Tremor 9 1 Extrapyramidal Disorder 6 1 Akathisia 6 4 Drooling 3 0 Lethargy 3 0 Dizziness 3 2 Dystonia 2 1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 2 1 Skin and Subcutaneous Disorders Rash 2 1 Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. a Dose-Related Adverse Reactions Schizophrenia Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5%; 10 mg, 13%; 30 mg, 21.6%); somnolence (incidences were placebo, 6%; 10 mg, 11%; 30 mg, 21.6%); and tremor (incidences were placebo, 2%; 10 mg, 2%; 30 mg, 11.8%). Extrapyramidal Symptoms Schizophrenia In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, –0.29). Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Additional Findings Observed in Clinical Trials Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of aripiprazole. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: adverse reactions are those occurring in at least 1/100 patients; adverse reactions are those occurring in 1/100 to 1/1000 patients; reactions are those occurring in fewer than 1/1000 patients: frequent infrequent rare Adults - Oral Administration Blood and Lymphatic System Disorders: - thrombocytopenia rare Cardiac Disorders: – bradycardia, palpitations, – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure infrequent rare Eye Disorders: – photophobia; -diplopia infrequent rare Gastrointestinal Disorders: - gastroesophageal reflux disease infrequent General Disorders and Administration Site Conditions: - asthenia; peripheral edema, chest pain; – face edema frequent infrequent – rare Hepatobiliary Disorders: - hepatitis, jaundice rare Immune System Disorders: -hypersensitivity rare Injury, Poisoning, and Procedural Complications: – fall; – heat stroke infrequent rare Investigations: - weight decreased, - hepatic enzyme increased, blood glucose frequent infrequent increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; – blood prolactin increased, blood urea inceased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased rare Metabolism and Nutrition Disorders: anorexia; - hypokalemia, hyponatremia, hypoglycemia frequent – infrequent rare - Musculoskeletal and Connective Tissue Disorders: -muscular weakness, muscle tightness; – rhabdomyolysis, mobility decreased infrequent rare Nervous System Disorders: parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia; – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; < choreoathetosis infrequent - rare 1/10,000 patients - Psychiatric Disorders: aggression, loss of libido, delirium; – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking infrequent – rare Renal and Urinary Disorders: - urinary retention, nocturia rare Reproductive System and Breast Disorders: - erectile dysfunction; – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism infrequent rare Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea infrequent - Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; urticaria infrequent - rare - Vascular Disorders: – hypotension, hypertension; infrequent Pediatric Patients - Oral Administration Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below. Eye Disorders: oculogyric crisis infrequent - Gastrointestinal Disorders: tongue dry, tongue spasm infrequent - Investigations: blood insulin increased frequent - Nervous System Disorders: - sleep talking infrequent Renal and Urinary Disorders: frequent – enuresis Skin and Subcutaneous Tissue Disorders: - hirsutism infrequent Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), and blood glucose fluctuation.