Aripiprazole

ABILIFY MAINTENA (aripiprazole) is indicated: for the treatment of schizophrenia in adults for maintenance monotherapy treatment of bipolar I disorder in adults ABILIFY MAINTENA is an atypical antipsychotic indicated: for treatment of schizophrenia in adults ( 1 ) for maintenance monotherapy treatment of bipolar I disorder in adults ( 1 )

For extended-release injectable suspension : 300 mg and 400 mg of lyophilized powder for reconstitution in: single-dose, pre-filled, dual chamber syringe single-dose vial The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color. For extended-release injectable suspension: 300 mg and 400 mg strength lyophilized powder for reconstitution in ( 3 ): single-dose, pre-filled, dual chamber syringe single-dose vial

ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1 and 6.2) ] . Known hypersensitivity to aripiprazole ( 4 )

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.3 ) Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.4 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) – Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with and at risk for diabetes ( 5.5 ) – Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics ( 5.5 ) – Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended ( 5.5 ) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation ( 5.6 ) Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC). Consider discontinuation if clinically significant decline in WBC/ANC in the absence of other causative factors ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.11 )

5.1 Increased Mortality in Elderly Patients with Dementia- Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

5.2 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled clinical studies (two flexible-dose and one fixed-dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis .

5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, ABILIFY MAINTENA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with ABILIFY MAINTENA drug discontinuation should be considered. However, some patients may require treatment with ABILIFY MAINTENA despite the presence of the syndrome.

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. […]

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 (5.1) ] Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3) ] Tardive Dyskinesia [see Warnings and Precautions (5.4) ] Metabolic Changes [see Warnings and Precautions (5.5) ] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.6) ] Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11) ] Body Temperature Regulation [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation ( 6.1 ). 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. Safety Database of ABILIFY MAINTENA 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 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). 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. Adverse Reactions with ABILIFY MAINTENA Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia 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 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 8 lists the adverse reactions reported in 2% or more of ABILIFY MAINTENA-treated subjects and at a greater proportion than in the placebo group. Table 8: Adverse Reactions in ≥2% of ABILIFY MAINTENA-Treated Adult Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial This table does not include adverse reactions which had an incidence equal to or less than placebo. Percentage of Patients Reporting Reaction ABILIFY MAINTENA Placebo Preferred Term (n=167) (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 Other Adverse Reactions Observed 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. […]

CYP2D6 inhibitors and CYP3A4 Inhibitors : See full prescribing information for ABILIFY MAINTENA dosage modifications when used concomitantly with CYP2D6 inhibitors and/or CYP3A4 inhibitors for greater than 14 days ( 7.1 ) CYP3A4 Inducers : Avoid concomitant use for greater than 14 days ( 7.1 ) See full prescribing information for additional clinically significant drug interactions ( 7.1 )

7.1 Drugs Having Clinically Important Interactions with ABILIFY MAINTENA Table 9: Clinically Important Drug Interactions with ABILIFY MAINTENA: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ]. With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage [see Dosage and Administration (2.4) ]. Strong CYP3A4 Inducers (e.g., carbamazepine) The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ]. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see Dosage and Administration (2.4) ] . Antihypertensive Drugs Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.7) ]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.7) ]. Monitor sedation and blood pressure. Adjust dose accordingly.

7.2 Drugs Having No Clinically Important Interactions with ABILIFY MAINTENA Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see Clinical Pharmacology (12.3) ] . In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin), or CYP3A4 (e.g., dextromethorphan) when coadministered with ABILIFY MAINTENA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY MAINTENA. [See Clinical Pharmacology (12.3) ] .

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ) Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain ( 8.2 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY MAINTENA during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including ABILIFY MAINTENA, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ABILIFY MAINTENA, during pregnancy (see Clinical Considerations ) . Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period [see Use in Specific Populations (8.2) ] . In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 11 times, respectively, the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data ) . The background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including oral aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the MRHD of 30 mg/day on a mg/m 2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m 2 basis. At 3 and 10 times the oral MRHD on a mg/m 2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on a mg/m 2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rats treated with aripiprazole intravenously at doses of 3, 9, and 27 mg/kg/day, which are 1 to 9 times the oral MRHD on mg/m 2 basis, during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose which also caused maternal toxicity. In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD of aripiprazole on mg/m 2 basis during the period of organogenesis, decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the MRHD based on AUC. In pregnant rabbits receiving aripiprazole injection intravenously at doses of 3, 10, and 30 mg/kg/day, which are 2 to 19 times the oral MRHD on mg/m 2 basis during the period of organogenesis, the highest dose caused pronounced maternal toxicity that resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD on mg/m 2 basis. In rats treated with oral doses of 3, 10, and 30 mg/kg/day, which are 1 to 10 times the oral MRHD of aripiprazole on a mg/m 2 basis, peri- and post-natally (from Day 17 of gestation through Day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. In rats treated with aripiprazole intravenously at doses of 3, 8, and 20 mg/kg/day which are 1 to 6 times the oral MRHD on mg/m 2 basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the MRHD on mg/m 2 basis, and decreases in early postnatal pup weight and survival were seen at the highest dose; these doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

8.2 Lactation Risk Summary Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period may lead to clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply may be mediated through decreases in prolactin levels, which have been observed [see Adverse Reactions (6.1) ] . Monitor the breastfed infant for dehydration and lack of appropriate weight gain. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABILIFY MAINTENA and any potential adverse effects on the breastfed infant from ABILIFY MAINTENA or from the underlying maternal condition.

8.4 Pediatric Use ABILIFY MAINTENA has not been studied in children 18 years of age or younger. However, juvenile animal studies have been conducted in rats and dogs. […]

The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown. The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D 2 and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.