ARISTADA INITIO

1 INDICATIONS AND USAGE ARISTADA INITIO, in combination with oral aripiprazole, is indicated for the initiation of ARISTADA when used for the treatment of schizophrenia in adults. ARISTADA INITIO, in combination with oral aripiprazole, is indicated for the initiation of ARISTADA ® when used for the treatment of schizophrenia in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION Administer one 675 mg injection of ARISTADA INITIO and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection ( 2.1 ). ARISTADA INITIO is only to be used as a single dose and is not for repeated dosing ( 2.1 ). Administer ARISTADA INITIO by intramuscular injection in either the deltoid or gluteal muscle by a healthcare professional ( 2.1 ). For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA INITIO ( 2.1 ). See Dosage and Administration for detailed preparation and administration instructions ( 2.4 ). Avoid use in known CYP2D6 poor metabolizers ( 2.3 , 7.1 ). Avoid use with strong CYP2D6 or CYP 3A4 inhibitors and strong CYP3A4 inducers ( 2.3 , 7.1 ). ARISTADA INITIO is not interchangeable with ARISTADA ( 2.1 , 5.3 ). 2.1 Recommended Dosage ARISTADA INITIO is only to be used as a single dose to initiate ARISTADA treatment or as a single dose to re-initiate ARISTADA treatment following a missed dose of ARISTADA. ARISTADA INITIO is not for repeated dosing. ARISTADA INITIO is not interchangeable with ARISTADA due to differing pharmacokinetic profiles [see Warnings and Precautions ( 5.3 )] . ARISTADA INITIO is to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA INITIO. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation. After establishing tolerability with oral aripiprazole, administer the first ARISTADA intramuscular injection (441 mg, 662 mg, 882 mg, or 1064 mg) in conjunction with both: One 675 mg injection of ARISTADA INITIO in the deltoid or gluteal muscle (which corresponds to 459 mg of aripiprazole) [see Clinical Pharmacology ( 12.3 )]; and One 30 mg dose of oral aripiprazole. The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA prescribing information for additional information regarding dosage and administration of ARISTADA. Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. 2.2 Missed Doses of ARISTADA ARISTADA INITIO may be used to re-initiate treatment with ARISTADA following a missed dose of ARISTADA. When a dose of ARISTADA is missed, administer the next injection of ARISTADA as soon as possible. Depending on the time elapsed since the last ARISTADA injection, supplement the next ARISTADA injection as recommended in Table 1 below. Table 1: Recommendation for Concomitant Supplementation Following Missed Doses of ARISTADA Dose of Patient's Last ARISTADA Injection Length of Time Since Last Injection 441 mg ≤ 6 weeks > 6 and ≤ 7 weeks > 7 weeks 662 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 882 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 1064 mg ≤ 10 weeks > 10 and ≤ 12 weeks > 12 weeks Dosage and Administration for Re-initiation of ARISTADA No Supplementation Required Supplement with a Single Dose of ARISTADA INITIO Re-initiate with a Single Dose of ARISTADA INITIO and a Single Dose of Oral Aripiprazole 30 mg 2.3 Dose Adjustments for CYP450 Considerations ARISTADA INITIO is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Therefore, avoid use in patients who are known CYP2D6 poor metabolizers or taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers. 2.4 Important Administration Instructions The kit contains a syringe containing ARISTADA INITIO sterile aqueous extended-release injectable suspension and 3 safety needles (a 2-inch 20 gauge needle with yellow needle hub, a 1 ½-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gau…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemia attack, including fatalities) ( 5.2 ). Potential for Dosing and Medication Errors : Substitution and dispensing errors between ARISTADA INITIO and ARISTADA could occur. Do not substitute ARISTADA INITIO for ARISTADA ( 5.3 ). Neuroleptic Malignant Syndrome : Manage with immediate discontinuation and close monitoring ( 5.4 ). Tardive Dyskinesia : Discontinue if clinically appropriate ( 5.5 ). Metabolic Changes : Monitor for hyperglycemia, dyslipidemia, and weight gain ( 5.6 ). Pathological Gambling and Other Compulsive Behaviors : Consider discontinuation ( 5.7 ). Orthostatic Hypotension : Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.8 ). Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors ( 5.10 ). Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.11 ). Potential for Cognitive and Motor Impairment : Use caution when operating machinery ( 5.12 ). 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. ARISTADA INITIO is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.2 )]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. ARISTADA INITIO is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )]. 5.3 Potential for Dosing and Medication Errors Medication errors, including substitution and dispensing errors, between ARISTADA INITIO and ARISTADA could occur. ARISTADA INITIO is intended for single administration only. Do not substitute ARISTADA INITIO for ARISTADA because of differing pharmacokinetic profiles [see Dosage and Administration ( 2.1 )]. 5.4 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with antipsychotic drugs, including ARISTADA INITIO. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, a…

4 CONTRAINDICATIONS ARISTADA INITIO is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions ( 6 )]. Known hypersensitivity to aripiprazole ( 4 ).

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with ARISTADA INITIO Table 4: Clinically Important Drug Interactions with ARISTADA INITIO Strong CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: Concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with strong CYP3A4 or strong CYP2D6 inhibitors because the dosage of ARISTADA INITIO cannot be modified [see Dosage and Administration ( 2.3 )]. Examples: itraconazole, clarithromycin, quinidine, fluoxetine, paroxetine Strong CYP3A4 Inducers Clinical Impact: Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with strong CYP3A4 inducers because the dosage of ARISTADA INITIO cannot be modified [see Dosage and Administration ( 2.3 )]. Examples: carbamazepine, rifampin Antihypertensive Drugs Clinical Impact: Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Intervention: Avoid concomitant use of ARISTADA INITIO with antihypertensive drugs because the dosage of ARISTADA INITIO cannot be modified [see Warnings and Precautions ( 5.8 )]. Examples: carvedilol, lisinopril, prazosin Benzodiazepines Clinical Impact: 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 ( 5.8 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with benzodiazepines because the dosage of ARISTADA INITIO cannot be modified [see Warnings and Precautions ( 5.8 )]. Example: lorazepam 7.2 Drugs Having No Clinically Important Interactions with ARISTADA INITIO Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ARISTADA INITIO is required when administered concomitantly with famotidine, valproate, or lithium [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, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ARISTADA INITIO. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with ARISTADA INITIO [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 ARISTADA INITIO 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 ARISTADA INITIO, 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 and with exposure to antipsychotics, including ARISTADA INITIO, 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 )] . No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 8 and 23 times, respectively, the maximum recommended human dose (MRHD) of 675 mg based on body surface area (mg/m 2 ). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data ]. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is 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 during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data for ARISTADA (Aripiprazole Lauroxil) Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 1 to 8 times the MRHD of 675 mg based on mg/m 2 , and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 2 to 23 times the MRHD based on mg/m 2 . However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below] . Animal Data for Aripiprazole 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 based on mg/m 2 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 based on mg/m 2 . At 3 and 10 times the oral MRHD based on mg/m 2 , delivered offspring had decreased body weights…

6 ADVERSE REACTIONS The following are discussed in more details in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke [see Boxed Warning , Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Metabolic Changes [see Warnings and Precautions ( 5.6 )] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions ( 5.7 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.8 )] Falls [see Warnings and Precautions ( 5.9 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Regulation [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Most commonly observed adverse reaction (incidence ≥5% and at least twice that for placebo) was akathisia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 1-866-274-7823 or FDA at 1-800-FDA-1088 or WWW.FDA.GOV/MEDWATCH. 6.1 Clinical Studies 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 ARISTADA INITIO, in combination with oral aripiprazole, for the initiation of ARISTADA when used for the treatment of schizophrenia in adults has been established and is based on clinical trials of ARISTADA (aripiprazole lauroxil) including 1019 adult patients with schizophrenia. Patient Exposure ARISTADA INITIO has been evaluated for safety in 170 adult patients in clinical trials in schizophrenia. In pharmacokinetic studies, the safety profile of ARISTADA INITIO was generally consistent with that observed for ARISTADA. ARISTADA (Aripiprazole Lauroxil) Trials in Adults with Schizophrenia Commonly Observed Adverse Reactions with Aripiprazole Lauroxil The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with aripiprazole lauroxil) was akathisia. Adverse Reactions Occurring at an Incidence of 2% or More in Aripiprazole Lauroxil-Treated Patients Adverse reactions associated with the use of aripiprazole lauroxil (incidence of 2% or greater, rounded to the nearest percent and aripiprazole lauroxil incidence greater than placebo) that occurred were: injection site pain, increased weight, increased blood creatinine phosphokinase, akathisia, headache, insomnia, and restlessness. Injection Site Reactions ARISTADA INITIO In pharmacokinetic studies evaluating ARISTADA INITIO, the incidences of injection site reactions with ARISTADA INITIO were similar to the incidence observed with aripiprazole lauroxil. ARISTADA (Aripiprazole Lauroxil) Injection site reactions were reported by 4% of patients treated with 441 mg aripiprazole lauroxil and 5% of patients treated with 882 mg aripiprazole lauroxil compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg aripiprazole lauroxil, 882 mg aripiprazole lauroxil and placebo groups, respectively). Other injection site reactions (induration, swelling and redness) occurred at less than 1%. Extrapyramidal Symptoms In a schizophrenia efficacy study in aripiprazole lauroxil-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patients. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days o…