The following adverse reactions are discussed in more detail in other sections of the labeling:
- Increased Mortality in Elderly Patients with Dementia - Related Psychosis Use [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
- Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
- Metabolic Changes [see WARNINGS AND PRECAUTIONS]
- Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
- Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
- Body Temperature Regulation [see WARNINGS AND PRECAUTIONS]
- Dysphagia [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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.
Safety Database of ABILIFY MAINTENA and Oral Aripiprazole
Aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.
ABILIFY MAINTENA 300-400 mg every 4 weeks has been evaluated for safety in 1,287 adult patients in clinical trials in schizophrenia, with approximately 1,281 patient-years of exposure to ABILIFY MAINTENA. A total of 832 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 630 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections).
The conditions and duration of treatment with ABILIFY MAINTENA included doubleblind and open-label studies. The safety profile of ABILIFY MAINTENA is expected to be similar to that of oral aripiprazole. Therefore, most of the safety data presented below are derived from trials with the oral formulation. In patients who tolerated and responded to treatment with oral aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to receive ABILIFY MAINTENA or placebo injections under double-blind conditions, the incidence of adverse reactions was similar between the two treatment groups.
Adverse Reactions of ABILIFY MAINTENA and Oral Aripiprazole
Adverse Reactions Associated with Discontinuation of Oral Aripiprazole
Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the incidence of discontinuation due to adverse reactions was 7% in oral aripiprazole-treated and 9% in placebo-treated patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients.
Commonly Observed Adverse Reactions of Oral Aripiprazole
Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the only commonly observed adverse reaction associated with the use of oral 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 Treated with Oral Aripiprazole
Table 7 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 bipolar mania), including only those reactions that occurred in 2% or more of patients treated with oral 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 7: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole
|System Organ Class Preferred Term||Percentage of Patients Reporting Reactiona|
|General Disorders and Administration Site Conditions|
|Musculoskeletal and Connective Tissue Disorders|
|Pain in Extremity||4||2|
|Nervous System Disorders|
|Respiratory, Thoracic, and Mediastinal Disorders|
|a 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.|
An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.
Dose-Related Adverse Reactions of Oral Aripiprazole
Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed oral doses of aripiprazole (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) 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%).
Injection Site Reactions of ABILIFY MAINTENA
In the open-label, stabilization phase of a study with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for ABILIFY MAINTENA-treated patients. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) was minimal and improved in subjects receiving ABILIFY MAINTENA from the first to the last injection in the open-label, stabilization phase (6.1 to 4.9).
Investigator evaluation of the injection site for pain, swelling, redness and induration following injections of ABILIFY MAINTENA in the open-label, stabilization phase were rated as absent for 74%-96% of subjects following the first injection and 77%-96% of subjects following the last injection.
Extrapyramidal Symptoms of Oral Aripiprazole
In short-term, placebo-controlled trials in schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for oral 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.
Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias). In the 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).
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 Abnormal Involuntary Movement Scale (for dyskinesias) did not show a difference between aripiprazole and placebo.
Class Effect: 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.
Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials of Oral Aripiprazole
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 oral 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 oral aripiprazole. In addition, in a long-term, active-controlled study, the incidence of tremor was 5% (40/859) for oral aripiprazole.
Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Aripiprazole
Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses ≥ 2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of Adverse Reactions (6), or those considered in WARNINGS AND PRECAUTIONS (5) or Overdosage (10) have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.
Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.
Blood and Lymphatic System Disorders: ≥ 1/1000 patients and < 1/100 patients - thrombocytopenia
Cardiac Disorders: ≥ 1/1000 patients and < 1/100 patients - palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia; < 1/1000 patients – atrial flutter, supraventricular tachycardia, ventricular tachycardia
Eye Disorders: ≥ 1/1000 patients and < 1/100 patients - photophobia, diplopia, eyelid edema, photopsia
Gastrointestinal Disorders: ≥ 1/1000 patients and < 1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; < 1/1000 patients - pancreatitis
General Disorders and Administration Site Conditions: ≥ 1/100 patients - asthenia, peripheral edema, chest pain; ≥ 1/1000 patients and < 1/100 patients - face edema, angioedema; < 1/1000 patients – hypothermia
Hepatobiliary Disorders: < 1/1000 patients - hepatitis, jaundice
Immune System Disorders: ≥ 1/1000 patients and < 1/100 patients - hypersensitivity
Injury, Poisoning, and Procedural Complications: ≥ 1/100 patients - fall; < 1/1000 patients - heat stroke
Investigations: ≥ 1/1000 patients and < 1/100 patients - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased; < 1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased
Metabolism and Nutrition Disorders: ≥ 1/1000 patients and < 1/100 patients - anorexia, hyponatremia, hypoglycemia, polydipsia; < 1/1000 patients - diabetic ketoacidosis
Musculoskeletal and Connective Tissue Disorders: ≥ 1/1000 patients and < 1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; < 1/1000 patients - rhabdomyolysis
Nervous System Disorders: ≥ 1/100 patients - coordination abnormal; ≥ 1/1000 patients and < 1/100 patients - speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia; < 1/1000 patients - choreoathetosis
Psychiatric Disorders: ≥ 1/100 patients - suicidal ideation; ≥ 1/1000 patients and < 1/100 patients – loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; < 1/1000 patients - catatonia, sleep walking
Renal and Urinary Disorders: ≥ 1/1000 patients and < 1/100 patients - urinary retention, polyuria, nocturia
Reproductive System and Breast Disorders: ≥ 1/1000 patients and < 1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; < 1/1000 patients - gynecomastia, priapism
Respiratory, Thoracic, and Mediastinal Disorders: ≥ 1/100 patients - nasal congestion, dyspnea
Skin and Subcutaneous Tissue Disorders: ≥ 1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥ 1/1000 patients and < 1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria
The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm).