Aripiprazoleside effects

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 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis Neuroleptic Malignant Syndrome Tardive Dyskinesia Metabolic Changes Pathological Gambling and Other Compulsive Behaviors Orthostatic Hypotension and Syncope Falls Leukopenia, Neutropenia, and Agranulocytosis Seizures Potential for Cognitive and Motor Impairment Body Temperature Regulation Dysphagia Most commonly observed adverse reactions (incidence ≥5% and at least twice the rate of placebo) were increased weight, akathisia, injection site pain, and sedation To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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. The safety of ABILIFY ASIMTUFII for the treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults is based on adequate and well-controlled studies of Abilify Maintena. The safety data from those studies is presented below. Safety Database of Abilify Maintena (once monthly dosing) and Oral Aripiprazole. Oral 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 (once monthly dosing) has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to Abilify Maintena. A total of 1,229 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 935 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections). Abilify Maintena has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to Abilify Maintena. A total of 419 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 287 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections). Safety Database of ABILIFY ASIMTUFII (once every 2 month dosing) In a 32 week open-label study of ABILIFY ASIMTUFII in adult patients with schizophrenia or bipolar I disorder, 266 patients were randomized to receive either ABILIFY ASIMTUFII 960 mg (132 patients) or Abilify Maintena 400 mg (134 patients). A total of the 132 patients received at least one injection of ABILIFY ASIMTUFII, a total of 114 patients received at least two consecutive injections (4 months treatment) of ABILIFY ASIMTUFII, and a total of 104 patients received at least four consecutive injections (8 months treatment) of ABILIFY ASIMTUFII. Of the total 266 patients receiving ABILIFY ASIMTUFII 960 mg or Abilify Maintena 400 mg, 185 had schizophrenia and 81 had bipolar I disorder. Injection site reactions for ABILIFY ASIMTUFII (once every 2 month dosing) presented in this section is based on this open-label study (see section titled " Injection Site Reactions with Abilify ASIMTUFII "). Adverse Reactions in Studies with Abilify Maintena (once monthly dosing) The conditions and duration of treatment with Abilify Maintena included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of Abilify Maintena in adult patients with schizophrenia. Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena Based on the placebo-controlled trial of Abilify Maintena in schizophrenia, the most commonly observed adverse reactions associated with the use of Abilify Maintena in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%). Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena The following findings are based on the double-blind, placebo-controlled trial that compared Abilify Maintena 400 mg or 300 mg to placebo in patients with schizophrenia. Table 6 lists the adverse reactions reported in 2% or more of Abilify Maintena-treated patients and at a greater proportion than in the placebo group.

Table 6: Adverse Reactions in ≥2% of Adult Patients with Schizophrenia Treated with Abilify Maintena in a 12-Week Double-Blind, Placebo-Controlled Study This table does not include adverse reactions which had an incidence equal to or less than placebo. Preferred Term Abilify Maintena (n=167) Placebo (n=172) Gastrointestinal Disorders Constipation 10 7 Dry Mouth 4 2 Diarrhea 3 2 Vomiting 3 1 Abdominal Discomfort 2 1 General Disorders and Administration Site Conditions Injection Site Pain 5 1 Infections and Infestations Upper Respiratory Tract Infection 4 2 Investigations Increased Weight 17 7 Decreased Weight 4 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 1 Back Pain 4 2 Myalgia 4 2 Musculoskeletal pain 3 1 Nervous System Disorders Akathisia 11 4 Sedation 5 1 Dizziness 4 2 Tremor 3 1 Respiratory, Thoracic and Mediastinal Nasal Congestion 2 1 Demographic Differences An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of Abilify Maintena patients at least twice the rate of placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial. This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few patients ≥65 years of age. Injection Site Reactions with ABILIFY ASIMTUFII ABILIFY ASIMTUFII was evaluated in 266 patients with schizophrenia or bipolar I disorder in an open-label, multiple-dose, randomized, parallel-arm multi-center study. The percentage of patients in the open-label study reporting any injection site-related adverse reactions (all reported as injection site pain) was 19% for patients treated with ABILIFY ASIMTUFII 960 mg and 9% for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of the injection site pain events coincided with the first injection of ABILIFY ASIMTUFII 960 mg (21/24 patients) or Abilify Maintena 400 mg (7/12 patients), was reported with decreasing frequency upon subsequent injections. The overall mean visual analog scale scores (0=no pain to 100=unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the ABILIFY ASIMTUFII 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group. Extrapyramidal Symptoms (EPS) In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify Maintena-treated patients was 9.6% vs. 5.2% for placebo. The incidence of akathisia-related events for Abilify Maintena-treated patients was 11.5% vs. 3.5% for 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. In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of dystonia was 1.8% for Abilify Maintena vs. 0.6% for placebo. Neutropenia In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for Abilify Maintena-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on Abilify Maintena and resolved spontaneously without any associated adverse reactions. Other Adverse Reactions During the Clinical Trial Evaluation of Abilify Maintena 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. Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, sinus tachycardia, tachycardia Endocrine Disorders: hypoprolactinemia Eye Disorders: vision blurred, oculogyric crisis Gastrointestinal Disorders: abdominal pain upper, dyspepsia, nausea, swollen tongue General Disorders and Administration Site Conditions: chest discomfort, fatigue, gait disturbance, injection site reaction (erythema, induration, pruritus, swelling, rash, inflammation, hemorrhage), irritability, pyrexia Hepatobiliary Disorders: drug-induced liver injury Immune System Disorders: drug hypersensitivity Infections and Infestations: nasopharyngitis Investigations: blood creatine phosphokinase increased, blood cholesterol decreased, blood pressure decreased, blood triglycerides decreased, electrocardiogram T wave abnormal, electrocardiogram QT-prolonged, hepatic enzyme increased, liver function test abnormal Metabolism and Nutrition Disorders: decreased appetite, hyperinsulinemia, obesity Musculoskeletal and Connective Tissue Disorders: joint stiffness, muscle twitching, rhabdomyolysis, trismus Nervous System Disorders: bradykinesia, convulsion, dysgeusia, extrapyramidal disorder, hypersomnia, lethargy, memory impairment, oromandibular dystonia, Psychiatric Disorders: anxiety, insomnia, restlessness, agitation, bruxism, psychotic disorder, suicidal ideation, aggression, hypersexuality, panic attack Renal and Urinary Disorders: glycosuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: ejaculation delayed Vascular Disorders: hypertension Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Abilify Maintena: Cardiac Disorders: angina pectoris, atrial flutter, atrioventricular block, cardiopulmonary failure, cardio-respiratory arrest, extrasystoles, myocardial infarction, myocardial ischemia, palpitations, supraventricular tachycardia, ventricular tachycardia Eye Disorders: diplopia, photophobia, eyelid edema, photopsia Gastrointestinal Disorders: gastroesophageal reflux disease, swollen tongue, esophagitis, pancreatitis, stomach discomfort, toothache General Disorders and Administration Site Conditions: asthenia, chest pain, face edema, hypothermia, peripheral edema, pain Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: heat stroke Investigations: blood prolactin decreased, blood bilirubin increased, blood creatinine increased, blood glucose increased, blood lactate dehydrogenase increased, blood prolactin increased, blood urea increased, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, diabetic ketoacidosis, hyponatremia, hypoglycemia, polydipsia Musculoskeletal and Connective Tissue Disorders: mobility decreased, muscle rigidity, muscle tightness, muscular weakness, musculoskeletal stiffness, pain in extremity, muscle spasms Nervous System Disorders: akinesia, choreoathetosis, coordination abnormal, hypokinesia, hypotonia, myoclonus, speech disorder Psychiatric Disorders: anger, anorgasmia, catatonia, completed suicide, delirium, loss of libido, homicidal ideation, intentional self-injury, hostility, libido increased, sleepwalking, suicide attempt, tic Renal and Urinary Disorders: nocturia, polyuria, urinary retention Reproductive System and Breast Disorders: amenorrhea, breast pain, erectile dysfunction, gynecomastia, menstruation irregular, priapism Respiratory, Thoracic, and Mediastinal Disorders: dyspnea, nasal congestion, pharyngolaryngeal pain, cough Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis, photosensitivity reaction, pruritus, rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), urticaria

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 reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), hiccups, pathological gambling, and fecal incontinence.