Abilify Asimtufii

1 INDICATIONS AND USAGE ABILIFY ASIMTUFII is indicated: for the treatment of schizophrenia in adults for maintenance monotherapy treatment of bipolar I disorder in adults ABILIFY ASIMTUFII is an atypical antipsychotic indicated: for the treatment of schizophrenia in adults ( 1 ) as maintenance monotherapy treatment of bipolar I disorder in adults ( 1 )

2 DOSAGE AND ADMINISTRATION For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY ASIMTUFII ( 2.1 ) Administer by intramuscular injection in the gluteal muscle by a healthcare professional. Do not administer by any other route ( 2.1 ) Recommended dosage is 960 mg administered once every 2 months as a single injection. Dose can be reduced to 720 mg in patients with adverse reactions ( 2.2 ) For patients currently receiving an oral antipsychotic, there are two ways to initiate treatment with ABILIFY ASIMTUFII 1-day initiation: Administer one injection of ABILIFY ASIMTUFII 960 mg, one injection of Abilify Maintena 400 mg and a single oral dose of aripiprazole 20 mg ( 2.2 ) 14-day initiation: In conjunction with first ABILIFY ASIMTUFII 960 mg dose, take 14 consecutive days of concurrent oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic ( 2.2 ) For patients currently receiving Abilify Maintena Administer ABILIFY ASIMTUFII 960 mg in place of the next scheduled injection of the Abilify Maintena. Missed doses: Dosage adjustment may be required ( 2.3 ) Known CYP2D6 poor metabolizers: Recommended dosage is 720 mg administered once every 2 months as a single injection ( 2.4 ) See Full Prescribing Information for important preparation and administration information ( 2.5 ) 2.1 Important Administration Information For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY ASIMTUFII. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability. ABILIFY ASIMTUFII must be administered as an intramuscular gluteal injection by a healthcare professional. Do not administer by any other route . For detailed preparation and administration instructions, [see Dosage and Administration (2.5) ] . 2.2 Recommended Dosage for ABILIFY ASIMTUFII The recommended dosage of ABILIFY ASIMTUFII is 960 mg, administered once every 2 months (56 days after previous injection). Patients Receiving Oral Antipsychotics There are two ways to initiate treatment with ABILIFY ASIMTUFII in patients receiving oral antipsychotics: 1-day initiation: Administer one intramuscular injection of ABILIFY ASIMTUFII 960 mg in the gluteal muscle, one injection of Abilify Maintena 400 mg in a separate gluteal or deltoid muscle, and one dose of oral aripiprazole 20 mg, on the first day of treatment with ABILIFY ASIMTUFII. Do not administer both injections into the same muscle. 14-day initiation: Administer one intramuscular injection of ABILIFY ASIMTUFII 960 mg in the gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days. For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY ASIMTUFII 960 mg in the gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days. Patients Receiving Abilify Maintena For patients receiving Abilify Maintena 400 mg (once monthly dosing), administer ABILIFY ASIMTUFII 960 mg (once every 2 month dosing) in place of the next scheduled injection of the Abilify Maintena. The first ABILIFY ASIMTUFII injection may be administered in place of the second, or later injection of Abilify Maintena. If there are adverse reactions with the ABILIFY ASIMTUFII 960 mg dosage, the dosage may be reduced to 720 mg once every 2 months. Patients may be given the ABILIFY ASIMTUFII injection up to 2 weeks before or 2 weeks after the 2-month scheduled timepoint. 2.3 Missed Doses If more than 8 weeks and less than 14 weeks have elapsed since the last injection, administer the next dose of ABILIFY ASIMTUFII as soon as possible. The once every 2 month schedule should be resumed. If more than 14 weeks have elapsed since the last injection, restart …

5 WARNINGS AND PRECAUTIONS 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 : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain ( 5.5 ) Pathological Gambling and Other Compulsive Behaviors : Consider dose reduction or discontinuation ( 5.6 ) Orthostatic Hypotension and Syncope : Monitor heart rate and blood pressure and caution in patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with history of clinically significant low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing ABILIFY ASIMTUFII if clinically significant decline in WBC 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 ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] . 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 ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ]. 5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex has been reported with antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global 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…

4 CONTRAINDICATIONS ABILIFY ASIMTUFII is contraindicated in patients with a known hypersensitivity to aripiprazole, or any of the excipients. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1) ] . Known hypersensitivity to aripiprazole, or to any excipients of ABILIFY ASIMTUFII ( 4 )

7 DRUG INTERACTIONS Dosage adjustments for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 inducers for greater than 14 days ( 2.4 , 7.1 ): Factors Dosage Recommendation CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors Avoid use Patients taking strong CYP2D6 or CYP3A4 inhibitors 720 mg For the 1-day initiation regimen, administer a single 20 mg oral aripiprazole, 300 mg Abilify Maintena and 720 mg ABILIFY ASIMTUFII on Day 1. Patients taking CYP2D6 and CYP3A4 inhibitors Avoid use Patients taking CYP3A4 inducers Avoid use 7.1 Drugs Having Clinically Important Interactions with ABILIFY ASIMTUFII Table 7 presents clinically significant drug interactions with ABILIFY ASIMTUFII. Table 7: Clinically Important Drug Interactions with ABILIFY ASIMTUFII Strong CYP3A4 Inhibitors AND/OR strong CYP2D6 inhibitors Clinical Rationale Concomitant use of oral aripiprazole with strong CYP3A4 AND/OR CYP2D6 inhibitors increased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ]. Clinical Recommendation Concomitant use of a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor Reduce the dosage of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor for more than 14 days [see Dosage and Administration (2.4) ]. Concomitant Use of a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor Avoid use of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor for more than 14 days [see Dosage and Administration (2.4) ]. Strong CYP3A4 Inducers Clinical Rationale Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ]. Clinical Recommendation Avoid use of ABILIFY ASIMTUFII in combination with a strong CYP3A4 inducer (e.g., carbamazepine) for greater than 14 days [see Dosage and Administration (2.4) ] . Antihypertensive Drugs Clinical Rationale Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Clinical Recommendation Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.7) ]. Benzodiazepines Clinical Rationale 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) ]. Clinical Recommendation Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with ABILIFY ASIMTUFII Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY ASIMTUFII 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, CYP2C9, CYP2C19, or CYP3A4 when coadministered with ABILIFY ASIMTUFII. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY ASIMTUFII [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ABILIFY ASIMTUFII, during pregnancy. Healthcare providers are encouraged to register patients by contacting 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 ASIMTUFII, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (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 ASIMTUFII, 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 oral 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 oral 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 No developmental toxicity studies were conducted with intramuscular aripiprazole suspension. In animal oral or intravenous 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 oral MRHD of 30 mg/day on 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 mg/m 2 basis, delivered offspring had decreased body …

6 ADVERSE REACTIONS 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 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 (incidence ≥5% and at least twice the rate of 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. 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 t…