PERSERIS

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

2 DOSAGE AND ADMINISTRATION Establish tolerability with oral risperidone prior to initiating PERSERIS. ( 2.1 ) Administer monthly by subcutaneous injection in the abdomen or back of the upper arm by a healthcare provider. Do not administer by any other route. ( 2.1 ) PERSERIS may be initiated at a dose of 90 mg or 120 mg once monthly. Do not administer more than one dose per month. ( 2.1 ) Supplementation with oral risperidone is not recommended. ( 2.1 ) See Full Prescribing Information for important preparation and administration information. Failure to fully mix the medication could result in incorrect dosage. ( 2.4 ) 2.1 Recommended Dosage Administer PERSERIS by a healthcare provider as a subcutaneous injection in the abdomen or back of the upper arm. Do not administer PERSERIS by any other route. For detailed preparation and administration instructions, see Dosage and Administration ( 2.4 ) . For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating PERSERIS. Initiate PERSERIS at a dose of 90 mg or 120 mg once monthly by subcutaneous injection. Do not administer more than one dose (90 mg or 120 mg total) per month. For patients switching from oral risperidone: 3 mg of oral risperidone per day, administer a 90 mg PERSERIS dose one day after the last oral risperidone dose. 4 mg of oral risperidone per day, administer a 120 mg PERSERIS dose one day after the last oral risperidone dose. Patients who are on stable oral risperidone doses lower than 3 mg per day or higher than 4 mg per day may not be candidates for PERSERIS [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Neither a loading dose nor any supplemental oral risperidone is recommended. When a dose of PERSERIS is missed, administer the next PERSERIS injection as soon as possible. 2.2 Dosage Recommendations for Patients with Renal or Hepatic Impairment Prior to initiating treatment with PERSERIS in patients with renal or hepatic impairment, titrate with oral risperidone up to at least 3 mg daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of PERSERIS is 90 mg once monthly [see Use in Specific Populations ( 8.6 , 8.7 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Co-administration with Strong CYP2D6 Inhibitors Between 2 to 4 weeks prior to initiating a strong CYP2D6 inhibitor (such as fluoxetine or paroxetine), switch patients (if applicable) to the lowest PERSERIS dosage (90 mg once monthly) to adjust for the expected increase in plasma concentrations of risperidone [see Drug Interactions ( 7.1 )] . Co-administration with Strong CYP3A4 Inducers With concomitant use of PERSERIS 90 mg and strong CYP3A4 inducers (such as carbamazepine), increase the PERSERIS dosage to 120 mg once monthly and consider starting additional oral risperidone therapy. In patients already receiving PERSERIS 120 mg once monthly, additional oral risperidone therapy may need to be considered. Upon discontinuation of a strong CYP3A4 inducer in a patients receiving PERSERIS 120 mg once monthly, re-evaluate the dosage of PERSERIS or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone. Upon discontinuation of a strong CYP3A4 inducer in a patient receiving PERSERIS 90 mg once monthly, continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment [see Drug Interactions ( 7.1 )] . 2.4 Preparation and Administration Instructions Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider “Instructions for Use” for additional preparation and administration considerations. For subcutaneous injection only. Do not inject by any other route. Allow package to come to room temperature for at leas…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). ( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. ( 5.3 ) Tardive Dyskinesia: Discontinue treatment if clinically appropriate. ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a history of a clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing PERSERIS if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 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 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. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.2 )] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85-years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Neuroleptic Malignant Syndrome (NMS) NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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. If NMS is suspected, immediately discontinue PERSERIS and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may dev…

4 CONTRAINDICATIONS PERSERIS is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Known hypersensitivity to risperidone, paliperidone, or other components of PERSERIS. ( 4 )

7 DRUG INTERACTIONS The interactions of PERSERIS with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on studies with oral risperidone. Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone. ( 2.3 , 7.1 ) Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration. ( 2.3 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with PERSERIS Table 5 includes clinically significant drug interactions with PERSERIS. Table 5 Clinically Important Drug Interactions with PERSERIS Strong CYP2D6 Inhibitors Clinical Impact: Concomitant use of PERSERIS with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology ( 12.3 )] . Intervention: When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on the lowest dose (90 mg) of PERSERIS between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors is initiated in patients receiving PERSERIS 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of PERSERIS treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A4 Inducers Clinical Impact: Concomitant use of PERSERIS and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone which could lead to decreased efficacy of PERSERIS [see Clinical Pharmacology ( 12.3 )] . Intervention: Changes in efficacy and safety should be carefully monitored with any dose adjustment of PERSERIS. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving PERSERIS 90 mg, consider increasing the dose to 120 mg. In patients receiving PERSERIS 120 mg, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of PERSERIS or any additional oral risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with PERSERIS 90 mg and discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment [see Dosage and Administration ( 2.3 )] . Centrally-Acting Drugs and Alcohol Clinical Impact: Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders. Intervention: Caution should be used when PERSERIS is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact: Because of its potential for inducing hypotension, PERSERIS may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention: Caution should be used when PERSERIS is administered in combination with other therapeutic agents with hypotensive effects. Dopamine Agonists Clinical Impact: Agents with central antidopaminergic activity such as PERSERIS may antagonize the pharmacologic effects of dopamine agonists. Intervention: Caution should be used when PERSERIS is administered in combination with levodopa and dopamine agonists. Methylphenidate Clinical Impact: Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions ( 6.2 )] . Intervention: Monitor for symptoms of EPS with concomitant …

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including PERSERIS, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs 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 risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including PERSERIS, during pregnancy (see Clinical Considerations ) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the oral MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the oral MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6 times the oral MRHD and offspring mortality increased at doses 0.1 to 3 times the oral MRHD based on mg/m 2 body surface area. Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity that included post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be attributed to N -methyl-2-pyrrolidone (NMP) an excipient in the delivery system based on information in the published literature (see Data ) . Subcutaneous administration of the delivery system to pregnant and lactating rats had no effect on embryofetal and postnatal development at doses up to 17 times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The estimated background risks of major birth defects and miscarriage for the indicated population is 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, 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, including risperidone, 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 recovered within hours or days without spe…

6 ADVERSE REACTIONS The following are discussed in more detail in previous sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [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 (NMS) [see Warnings and Precautions ( 5.3 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic Changes [see Warnings and Precautions ( 5.5 )] Hyperprolactinemia [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 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Priapism [see Warnings and Precautions ( 5.13 )] Body Temperature Regulation [see Warnings and Precautions ( 5.14 )] The most common adverse reactions in clinical trials (≥ 5% and greater than twice placebo) were increased weight, sedation/somnolence, and musculoskeletal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 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 PERSERIS was evaluated in a total of 837 adult patients with schizophrenia who received at least 1 dose of PERSERIS during the clinical development program. A total of 322 patients were exposed to PERSERIS for at least 6 months, of which 234 patients were exposed to PERSERIS for at least 12 months; 281 and 176 of these, respectively, received the 120 mg dose. Adverse drug reactions in adult patients with schizophrenia (≥ 5% in any PERSERIS-treated group and greater than placebo) during the 8-week double-blind, placebo-controlled study) were weight increased, constipation, sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and musculoskeletal pain. In addition, the frequency of reported injection site reactions was similar across treatment groups with both PERSERIS and placebo; the most common (≥ 5%) of which were injection site pain, and erythema. The systemic safety profile for PERSERIS was consistent with the known safety profile of oral risperidone. Commonly-Observed Adverse Drug Reactions in Double-Blind, Placebo-Controlled Clinical Studies – Schizophrenia Adverse Reactions with an incidence of 2% or more and greater than placebo are shown in Table 4 . Table 4 Adverse Drug Reactions in 2% or More of PERSERIS-Treated Patients (and Greater than Placebo) in an 8-Week Double-Blind, Placebo-Controlled Study * Sedation includes sedation and somnolence System Organ Class Preferred Term PERSERIS 90 mg (n = 115) PERSERIS 120 mg (n = 117) Placebo (n = 118) Percentage of Patients Reporting ADR Gastrointestinal disorders Constipation 7.0 7.7 5.1 Abdominal discomfort 2.6 2.6 1.7 Dry mouth 1.7 2.6 1.7 Investigations Weight increased 13.0 12.8 3.4 Metabolism and nutrition disorders Increased appetite 1.7 3.4 1.7 Musculoskeletal and connective tissue disorders Back pain 3.5 6.8 4.2 Pain in extremity 0.9 7.7 5.1 Musculoskeletal pain 5.2 5.1 2.5 Musculoskeletal stiffness 2.6 0.9 1.7 Muscle spasms 0 2.6 0 Nervous system disorders Sedation* 7.0 7.7 0 Akathisia 2.6 6.8 4.2 Extrapyramidal disorder 4.3 1.7 0.8 Psychiatric disorders Anxiety 2.6 6.8 5.1 Other Adverse Drug Reactions Observed During the Clinical Trial Evaluation of PERSERIS The following list does not include reactions: 1) already listed in previous tables or elsew…