INVEGA HAFYERA

1 INDICATIONS AND USAGE INVEGA HAFYERA, an every-six-month injection, is indicated for the treatment of schizophrenia in adults after they have been adequately treated with: A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA) for at least four months, or An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA) for at least one three-month cycle. INVEGA HAFYERA, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with: A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA) for at least four months or An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA) for at least one three-month cycle. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer INVEGA HAFYERA by gluteal injection once every 6 months by a healthcare professional. Do not administer by any other route. ( 2.1 ) See Full Prescribing Information for complete dosing information. ( 2.2 ) Initiate INVEGA HAFYERA when the next once-a-month or every three-month paliperidone palmitate extended-release injectable suspension dose is scheduled. Dose is based on the previous once-a-month or every-three-month product. ( 2.2 ): INVEGA HAFYERA Doses for Adults Adequately Treated with Once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) Switching from the PP1M 39 mg, 78 mg and 117 mg doses was not studied. If the Last Dose of PP1M is: Initiate INVEGA HAFYERA at the Following Dose: 156 mg 1,092 mg 234 mg 1,560 mg INVEGA HAFYERA Doses for Adults Adequately Treated with Every-three-month paliperidone palmitate injectable suspension (PP3M) Switching from the PP3M 273 mg and 410 mg doses was not studied. If the Last Dose of PP3M is: Initiate INVEGA HAFYERA at the Following Dose: 546 mg 1,092 mg 819 mg 1,560 mg Missed Doses: Refer to the Full Prescribing Information. ( 2.3 ) See Full Prescribing Information for important preparation and administration information. ( 2.5 ) Moderate to severe renal impairment (creatinine clearance <50 mL/min): INVEGA HAFYERA is not recommended. ( 2.4 ) Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust dosage and stabilize the patient using PP1M before transitioning to INVEGA HAFYERA, or from PP1M to PP3M before transitioning to INVEGA HAFYERA. See appropriate table above. ( 2.4 ) 2.1 Important Dosage and Administration Information INVEGA HAFYERA must be administered as a gluteal intramuscular injection by a healthcare professional once every 6 months. Do not administer by any other route [see Dosage and Administration (2.5) ] . Initiate INVEGA HAFYERA only after adequate treatment has been established with either: A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA), referred to as PP1M, once monthly for at least four months; or An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA), referred to as PP3M, once every three months for at least one three-month injection cycle. See Prescribing Information of the PP1M and PP3M products for the recommended dosage of these products. 2.2 Recommended Dosage for INVEGA HAFYERA Switching to INVEGA HAFYERA from a PP1M Product The recommended initial INVEGA HAFYERA dose is based on the previous PP1M dose (see Table 1 ). Initiate INVEGA HAFYERA when the next PP1M dose is scheduled. INVEGA HAFYERA may be administered up to 1 week before or 1 week after the next scheduled PP1M dose. When switching from PP1M to INVEGA HAFYERA, the two injection cycles immediately preceding the switch should be the same dosage strength before starting INVEGA HAFYERA. Table 1. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP1M PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension Product Last Dose of PP1M There are no equivalent doses of INVEGA HAFYERA for 39 mg, 78 mg, or 117 mg doses of a PP1M product, which were not studied [see Clinical Studies (14)] . Initial Dose of INVEGA HAFYERA 156 mg 1,092 mg 234 mg 1,560 mg Switching to INVEGA HAFYERA from a PP3M Product The recommended initial INVEGA HAFYERA dose is based on the previous PP3M dose (see Table 2 ). Initiate INVEGA HAFYERA when the next PP3M dose is scheduled. INVEGA HAFYERA may be administered up to 2 weeks before or 2 weeks after the next scheduled PP3M dose. Table 2. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP3M PP3M: Every-three-month paliperidone palmitate extended-release injectable suspension Product Last Dose of PP3M There are no equivalent doses of INVEGA HAFYERA for the 273 mg or 410 mg doses of a PP3M product, which were not studied [see Clinical Studi…

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 of drug and close monitoring. ( 5.3 ) QT Prolongation : Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. ( 5.4 ) Tardive Dyskinesia : Discontinue treatment if clinically appropriate ( 5.5 ) Metabolic Changes : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.6 ) Orthostatic Hypotension and Syncope : Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing INVEGA HAFYERA if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.9 ) Hyperprolactinemia : Prolactin elevations occur and persist during chronic administration. ( 5.10 ) Potential for Cognitive and Motor Impairment : Use caution when operating machinery. ( 5.11 ) Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 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. INVEGA HAFYERA 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 trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, the 3-month paliperidone extended-release injectable suspension or INVEGA HAFYERA in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] . 5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. 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). Ad…

4 CONTRAINDICATIONS INVEGA HAFYERA is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA HAFYERA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone. Known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA HAFYERA. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4/P-glycoprotein (P-gp) inducers : Avoid using strong CYP3A4 and/or P-gp inducers during a dosing interval for INVEGA HAFYERA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets. ( 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Interactions with INVEGA HAFYERA Because paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 6-month dosing interval and the half-life of INVEGA HAFYERA [see Clinical Pharmacology (12.3) ] . Table 10 presents clinically significant drug interactions with INVEGA HAFYERA. Table 10. Clinically Important Drug Interactions with INVEGA HAFYERA Centrally acting Drugs and Alcohol Clinical Rationale Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA HAFYERA. Clinical Recommendation INVEGA HAFYERA should be used with caution with other centrally acting drugs and alcohol. Drugs with Potential for Inducing Orthostatic Hypotension Clinical Rationale Because INVEGA HAFYERA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA HAFYERA is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.7) ] . Clinical Recommendation Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7) ] . Strong Inducers of CYP3A4 and P-gp Clinical Rationale The concomitant use of INVEGA HAFYERA and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) ] . Clinical Recommendation Avoid using CYP3A4 and/or P-gp inducers with INVEGA HAFYERA during the 6-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.1) ] . Examples carbamazepine, rifampin, or St. John's Wort Levodopa and Other Dopamine Agonists Clinical Rationale Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Clinical Recommendation Monitor and manage patient as clinically appropriate. 7.2 Drugs Having No Clinically Important Interactions with INVEGA HAFYERA Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA HAFYERA is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3) ] . Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA HAFYERA [see Clinical Pharmacology (12.3) ] . Pharmacokinetic interaction between lithium and INVEGA HAFYERA is unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely [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 INVEGA HAFYERA, 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 paliperidone have not established a drug-associated risk for 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 INVEGA HAFYERA during pregnancy (see Clinical Considerations ) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate extended-release injectable suspension. [See Clinical Pharmacology (12.3) ] . The clinical significance of INVEGA HAFYERA administered before pregnancy or anytime during pregnancy is not known. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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. In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate or when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal Data ) . 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 INVEGA HAFYERA, 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, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. 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 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperido…

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 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) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [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) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] The most common adverse reactions were upper respiratory tract infection, injection site reaction, weight increased, headache, and parkinsonism. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 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. Patient Exposure The data described in this section is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 (86.97) days in the INVEGA HAFYERA group and 336.4 (80.89) days in the PP3M group during the double-blind phase: Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial Commonly Observed Adverse Reactions : The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism. Discontinuation of Treatment Due to Adverse Reactions : In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate extended-release injectable suspension group discontinued due to adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients : Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial. Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia Double Blind System Organ Class PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Adverse Reaction Gastrointestinal disorders Diarrhea The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious. Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling. Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper resp…