UZEDY

1 INDICATIONS AND USAGE UZEDY is an atypical antipsychotic indicated: for the treatment of schizophrenia in adults. ( 1.1 ) as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults. ( 1.2 ) 1.1 Schizophrenia UZEDY is indicated for the treatment of schizophrenia in adults . 1.2 Bipolar Disorder UZEDY is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder in adults.

2 DOSAGE AND ADMINISTRATION Establish tolerability with oral risperidone prior to initiating UZEDY. ( 2.1 ) Administer UZEDY by subcutaneous injection in the abdomen or upper arm by a healthcare professional. Do not administer by any other route. ( 2.1 ) See Full Prescribing Information for important preparation and administration information. ( 2.7 ) Schizophrenia Initiate UZEDY at the clinically appropriate dose using the following table. ( 2.2 ) Comparable Daily Oral Risperidone Therapy UZEDY Dosage Once Monthly UZEDY Dosage Once Every 2 Months 2 mg 50 mg 100 mg 3 mg 75 mg 150 mg 4 mg 100 mg 200 mg 5 mg 125 mg 250 mg Bipolar I disorder Following establishment of tolerability with oral risperidone, initiate UZEDY at the clinically appropriate dose using the following table. ( 2.3 ) Comparable Daily Oral Risperidone Therapy UZEDY Dosage Once Monthly 2 mg 50 mg 3 mg 75 mg 4 mg 100 mg For patients currently receiving risperidone long acting intramuscular injectable given once every 2 weeks, switch to UZEDY as a once monthly injection, starting at least 5 weeks after the last dose of risperidone long acting injectable given once every 2 weeks. ( 2.3 ) Switch to UZEDY at the clinically appropriate dose using the following table. ( 2.3 ). Another Risperidone Long-Acting Intramuscular Injection Given Once Every 2 Weeks UZEDY Dosage Once Monthly 25 mg 50 mg 37.5 mg 75 mg 50 mg 100 mg 2.1 General Administration Information For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating UZEDY. UZEDY must be administered by a healthcare professional as an abdominal or upper arm subcutaneous injection. Do not administer UZEDY by any other route. For detailed preparation and administration instructions, see Dosage and Administration ( 2.7 ) . 2.2 Dosage Recommendations for the Treatment of Schizophrenia To start UZEDY for the treatment of schizophrenia, switch from oral daily risperidone. Initiate UZEDY, as either a once monthly injection or a once every 2 month injection, the day after the last dose of oral therapy. See Table 1 to determine how to switch from oral risperidone to UZEDY once monthly (50 mg, 75 mg, 100 mg, or 125 mg) or once every 2 months (100 mg, 150 mg, 200 mg, or 250 mg) given via abdominal or upper arm subcutaneous injection. Neither a loading dose nor supplemental oral risperidone doses are recommended when switching. Table 1: Dosage Recommendations for Switching from Daily Oral Risperidone to UZEDY Given Once Monthly or Once Every 2 Months Comparable Daily Oral Risperidone Therapy UZEDY Dosage Once Monthly UZEDY Dosage Once Every 2 Months 2 mg 50 mg 100 mg 3 mg 75 mg 150 mg 4 mg 100 mg 200 mg 5 mg 125 mg 250 mg Patients can switch between doses of UZEDY once monthly and once every 2 months by administering the first dose of the new dosing regimen on the next scheduled date of administration in the original dosing regimen. Revise the dose administration schedule to reflect the change. 2.3 Dosage Recommendations for Maintenance Treatment of Bipolar I Disorder Following establishment of tolerability with oral risperidone, start UZEDY as a once monthly injection for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder, according to the dosage recommendations in Table 2 . UZEDY once every 2 months injection is not recommended for the maintenance treatment of bipolar I disorder. Table 2: Dosage Recommendations for Switching from Daily Oral Risperidone to UZEDY Given Once Monthly Comparable Daily Oral Risperidone Therapy UZEDY Dosage Once Monthly 2 mg 50 mg 3 mg 75 mg 4 mg 100 mg For patients currently receiving risperidone long acting intramuscular injectable given once every 2 weeks, switch to UZEDY as a once monthly subcutaneous injection, starting at least 5 weeks after the last dose of risperidone long acting intramuscular injectable given once every 2 weeks. Refer to Table 3 to determine how to switch from risperi…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular reactions (e.g., stroke, transient ischemia 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/diabetes mellitus, dyslipidemia, and weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. Long-standing hyperprolactinemia, when associated with hypogonadism, can lead to decreased bone density in females and males. ( 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 clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing UZEDY if a clinically significant decline in WBC occurs in the 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 ) Priapism: Priapism has been reported. Severe priapism may require surgical intervention. ( 5.13 ) 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. In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. UZEDY 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 Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97 years) 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. UZEDY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )]. 5.3 Neuroleptic Malignant Syndrome Neurolep…

4 CONTRAINDICATIONS UZEDY 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 to any of the components in UZEDY. ( 4 )

7 DRUG INTERACTIONS The interactions of UZEDY 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. Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Increase risperidone plasma concentration. ( 2.6 , 7.1 ) Strong CYP3A4 inducers (e.g., carbamazepine): Decrease plasma concentrations of risperidone. ( 2.6 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with UZEDY Table 13 includes clinically significant drug interactions with UZEDY. Table 13: Clinically Important Drug Interactions with UZEDY Strong CYP2D6 Inhibitors Clinical Impact: Concomitant use of UZEDY 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 (50 mg once monthly or 100 mg once every 2 months) of UZEDY prior to the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving UZEDY 50 mg once monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY 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 UZEDY 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 UZEDY [see Clinical Pharmacology ( 12.3 )] . Intervention: Changes in efficacy and safety should be carefully monitored with any dose adjustment of UZEDY. 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 UZEDY at a specific dose, consider increasing the dose to the next highest dose. In patients receiving UZEDY 125 mg once monthly or 250 mg once every 2 months, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of UZEDY or any additional oral risperidone therapy should be reevaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with UZEDY 50 mg once monthly or UZEDY 100 mg once every 2 months discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of UZEDY treatment [see Dosage and Administration ( 2.6 )] . 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 UZEDY is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact: Because of its potential for inducing hypotension, UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention: Caution should be used when UZEDY is administered with other therapeutic effects of other therapeutic agents with this potential. Dopamine Agonists Clinical Impact: Agents with central antidopaminergic activity such as UZEDY may antagonize the pharmacologic effects of dopamine agonists. Intervention: Caution should be used when UZEDY 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…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, 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 or bipolar I disorder and with exposure to antipsychotics, including UZEDY, 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 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. The 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 or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia or 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 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 specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI = 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI = 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of a…

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Cerebrovascular adverse events, 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 )] 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 with risperidone in patients with schizophrenia (≥5% and greater than placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6.1 ) The most common adverse reactions with risperidone in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and parkinsonism (≥10% in adjunctive therapy trial). ( 6.1 ) The most common injection site reactions with UZEDY in patients with schizophrenia (≥5% and greater than placebo) were pruritus and nodule. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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 clinical practice. Treatment of Schizophrenia in Adults UZEDY is to be administered subcutaneously [see Dosage and Administration ( 2.1 )]. The safety of UZEDY for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of oral risperidone in studies of patients with schizophrenia and other indications. The results of those adequate and well-controlled studies are presented below. The data described in this section are derived from a clinical trial database consisting of 9,803 patients exposed to one or more doses of oral risperidone for the treatment of schizophrenia and other psychiatric disorders. Of these 9,803 patients, 2,687 were patients who received oral risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with oral risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse reactions and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. Injection site reactions for UZEDY presented in this section (see “Injection Site Reactions with UZEDY” below) are based on a randomized withdrawal study in patients with schizophrenia consisting of a 12-week open-label oral risperidone (2 mg to 5 mg) stabilization phase, followed by a placebo-controlled phase in which patients were randomized to U…