ARISTADA

1 INDICATIONS AND USAGE ARISTADA is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14 )]. ARISTADA is an atypical antipsychotic indicated for the treatment of schizophrenia in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION Administer ARISTADA by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg, 882 mg or 1064 mg) muscle by a healthcare professional ( 2.1 ). For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA ( 2.1 ). There are two options for initiating treatment with ARISTADA: Option #1: Administer one injection of 675 mg of ARISTADA INITIO ® and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection. ( 2.1 ). Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection ( 2.1 ). ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every 6 weeks, or 1064 mg dose every 2 months ( 2.1 ). Dosing regimen adjustments may be required for missed doses ( 2.2 ). Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks ( 2.4 ). 2.1 Recommended Dosage ARISTADA is only 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. 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. There are two ways to initiate treatment with ARISTADA: Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle) and one dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection. The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO. Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection. Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively [see Clinical Pharmacology ( 12.3 )]. Table 1: ARISTADA Dosing Frequency and Site of Injection Dose Dosing Frequency Site of Intramuscular Injection 441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2 . Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole Dose Intramuscular ARISTADA Dose 10 mg per day 441 mg every month 15 mg per day 662 mg every month 882 mg every 6 weeks 1064 mg every 2 months 20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg, or continue treatment with oral aripiprazole for 21 consecutive days [see Recommended Dosage ( 2.1 )]. Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA [see Clinical Pharmacology ( 12.3 )]. 2.2 Missed Doses 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 3 below. Table 3: Reco…

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 and ARISTADA INITIO 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 dose reduction or 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 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 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 and ARISTADA INITIO could occur. ARISTADA INITIO is for single administration in contrast to ARISTADA which is administered monthly, every 6 weeks, or every 8 weeks [see Dosage and Administration ( 2.1 )] . Do not substitute ARISTADA INITIO for ARISTADA because of differing pharmacokinetic profiles [see Clinical Pharmacology ( 12.3 )]. 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. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental s…

4 CONTRAINDICATIONS ARISTADA 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 Table 10: Clinically Important Drug Interactions with ARISTADA Strong CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: The 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: With concomitant use of ARISTADA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 2 weeks, reduce the ARISTADA dose [see Dosage and Administration ( 2.4 )]. Examples: itraconazole, clarithromycin, quinidine, fluoxetine, paroxetine Strong CYP3A4 Inducers Clinical Impact: The 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: With concomitant use of ARISTADA with a strong CYP3A4 inducer for more than 2 weeks consider increasing the ARISTADA dose [see Dosage and Administration ( 2.4 )]. 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: Monitor blood pressure and adjust dose accordingly [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: Monitor sedation and blood pressure. Adjust dose accordingly. Example: lorazepam 7.2 Drugs Having No Clinically Important Interactions with ARISTADA Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ARISTADA 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. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with ARISTADA [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 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, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage (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, 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 5 and 15 times, respectively, the maximum recommended human dose (MRHD) of 1,064 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 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 0.6 to 5 times the MRHD of 1064 mg on mg/m 2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 15 times the MRHD on mg/m 2 basis. 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 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 ora…

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 with ARISTADA (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. ARISTADA Patient Exposure ARISTADA has been evaluated for safety in 1180 adult patients in clinical trials in schizophrenia. Commonly Observed Adverse Reactions The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia. Adverse Reactions Occurring at an Incidence of 2% or More in ARISTADA-Treated Patients Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater, rounded to the nearest percent and ARISTADA incidence greater than placebo) that occurred are shown in Table 8 . Table 8: Adverse Reaction in 2% or More of ARISTADA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Adverse Reaction System Organ Class Preferred Term Placebo N=207 (%) Aripiprazole Lauroxil 441 mg N=207 (%) 882 mg N=208 (%) General disorders and administration site conditions Injection site pain 2 3 4 Investigations Increased weight 1 2 2 Increased blood creatine phosphokinase 0 2 1 Nervous system disorders Akathisia 4 11 11 Headache 3 3 5 Psychiatric disorders Insomnia 2 3 4 Restlessness 1 3 1 In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months were similar across the dose groups. Injection Site Reactions Injection site reactions were reported by 4% of patients treated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADA compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg ARISTADA, 882 mg ARISTADA and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of ARISTADA and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%. In an open label pharmacokinetic study evaluating 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months, injection site reactions were similar across the dose groups. Extrapyramidal Symptoms In the 12-week schizophrenia efficacy study [see Clinical Studies ( 14 )] , for ARISTADA-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for pati…