Paliperidone

1 INDICATIONS AND USAGE Paliperidone Extended-Release Tablets are an atypical antipsychotic agent indicated for Treatment of schizophrenia ( 1.1 ) Adults: Efficacy was established in three 6-week trials and one maintenance trial. ( 14.1 ) Adolescents (ages 12–17): Efficacy was established in one 6-week trial. ( 14.1 ) Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants. ( 1.2 ) Efficacy was established in two 6-week trials in adult patients. ( 14.2 ) 1.1 Schizophrenia Paliperidone Extended-Release Tablets are indicated for the treatment of schizophrenia [See Clinical Studies (14.1) ]. The efficacy of Paliperidone Extended-Release Tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults. 1.2 Schizoaffective Disorder Paliperidone Extended-Release Tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2) ]. The efficacy of Paliperidone Extended-Release Tablets in schizoaffective disorder was established in two 6-week trials in adults.

2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia - adults ( 2.1 ) 6 mg/day 3 – 12 mg/day 12 mg/day Schizophrenia-adolescents ( 2.1 ) Weight < 51 kg 3 mg/day 3 – 6 mg/day 6 mg/day Weight ≥ 51 kg 3 mg/day 3 – 12 mg/day 12 mg/day Schizoaffective disorder - adults ( 2.2 ) 6 mg/day 3 – 12 mg/day 12 mg/day Tablet should be swallowed whole and should not be chewed, divided, or crushed. ( 2.3 ) 2.1 Schizophrenia Adults The recommended dose of Paliperidone Extended-Release Tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. Initial dose titration is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day. In a longer-term study, Paliperidone Extended-Release Tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on Paliperidone Extended-Release Tablets for 6 weeks [see Clinical Studies (14) ] . Paliperidone Extended-Release Tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients. Adolescents (12-17 years of age) The recommended starting dose of Paliperidone Extended-Release Tablets for the treatment of schizophrenia in adolescents 12–17 years of age is 3 mg administered once daily. Initial dose titration is not required. Dose increases, if considered necessary, should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related. 2.2 Schizoaffective Disorder The recommended dose of Paliperidone Extended-Release Tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses. This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day. 2.3 Administration Instructions Paliperidone Extended-Release Tablets can be taken with or without food. Paliperidone Extended-Release Tablets must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. 2.4 Use with Risperidone Concomitant use of Paliperidone Extended-Release Tablets with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone e…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotics. ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. ( 5.3 ) QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. ( 5.4 ) Tardive Dyskinesia: Discontinue drug if clinically appropriate. ( 5.5 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.6 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.6 ) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.6 ) Weight Gain: Significant weight gain has been reported. Monitor weight gain. ( 5.6 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.7 ) Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease. ( 5.8 ) Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. ( 5.9 ) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including Paliperidone Extended-Release Tablets. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Paliperidone Extended-Release Tablets should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. ( 5.11 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.12 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 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. Paliperidone Extended-Release Tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning ]. 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…

4 CONTRAINDICATIONS Paliperidone Extended-Release Tablets are contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the Paliperidone Extended-Release Tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone. Known hypersensitivity to paliperidone, risperidone, or to any excipients in Paliperidone Extended-Release Tablets. ( 4 )

7 DRUG INTERACTIONS Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. ( 7.1 ) Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with Paliperidone Extended-Release Tablets. ( 7.1 ) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of Paliperidone Extended-Release Tablets when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of Paliperidone Extended-Release Tablets. ( 7.2 ) Co-administration of divalproex sodium increased C max and AUC of paliperidone by approximately 50%. Adjust dose of Paliperidone Extended-Release Tablets if necessary based on clinical assessment. ( 7.2 ) 7.1 Potential for Paliperidone Extended-Release Tablets to Affect Other Drugs Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1 , 6.2) ], Paliperidone Extended-Release Tablets should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when Paliperidone Extended-Release Tablets is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9) ]. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Pharmacokinetic interaction between lithium and Paliperidone Extended-Release Tablets is unlikely. In a drug interaction study, co-administration of Paliperidone Extended-Release Tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC 24h and C max,ss ) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when Paliperidone Extended-Release Tablets 3–15 mg/day were added to their existing valproate treatment. 7.2 Potential for Other Drugs to Affect Paliperidone Extended-Release Tablets Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. Co-administration of Paliperidone Extended-Release Tablets 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C max and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation o…

8.1 Pregnancy 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 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 Paliperidone Extended-Release Tablets, during pregnancy (see Clinical Considerations ). 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 2–4% and 15–20%, respectively. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m 2 body surface area. 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 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 Paliperidone Extended-Release Tablets, 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, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the …

6 ADVERSE REACTIONS The following adverse reactions 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) ] Hyperprolactinemia [see Warnings and Precautions (5.7) ] Potential for gastrointestinal obstruction [see Warnings and Precautions (5.8) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.9) ] Falls [see Warnings and Precautions (5.10) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.11) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Dysphagia [see Warnings and Precautions (5.14) ] Priapism [see Warnings and Precautions (5.15) ] Disruption of body temperature regulation [see Warnings and Precautions (5.16) ] Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were ( 6 ) Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia. Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia. Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with Paliperidone Extended-Release Tablets and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with Paliperidone Extended-Release Tablets and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of Paliperidone Extended-Release-Tablets treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of Paliperidone Extended-Release Tablets-treated subjects. [See Adverse Reactions (6) ]. The safety of Paliperidone Extended-Release Tablets was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received Paliperidone Extended-Release Tablets at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received Paliperidone Extended-Release Tablets at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of Paliperidone Extended-Release Tablets was evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received Paliperidone Extended-Release Tablets in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-co…