Paliperidone

Dosage and Administration (2.5) 01/2025 Warnings and Precautions (5.7) 01/2025

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 …

3 DOSAGE FORMS AND STRENGTHS Paliperidone Extended-Release Tablets are available in the following strengths and colors 3 mg(white), 6 mg(light biege) or 9 mg(pink) of paliperidone, USP. The 3 mg tablets are white, film-coated, round, unscored tablets imprinted with M over PD3 in black ink on one side of the tablet and blank on the other side. The 6 mg tablets are light beige, film-coated, round, unscored tablets imprinted with M over PD6 in black ink on one side of the tablet and blank on the other side. The 9 mg tablets are pink, film-coated, round, unscored tablets imprinted with M over PD9 in black ink on one side of the tablet and blank on the other side. Tablets: 3 mg, 6 mg, and 9 mg ( 3 )

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 )

6 ADVERSE REACTIONS 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 RK Pharma Inc at 1-844-757-4276 (1-844-RKPHARM) or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 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) ] 6.1 Clincal Trails 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, place …

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 are 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 initiatio …

8 USE IN SPECIFIC POPULATIONS Renal Impairment: Dosing must be individualized according to renal function status. ( 2.5 ) Elderly: Same as for younger adults (adjust dose according to renal function status). ( 2.4 ) Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Pediatric Use: Safety and effectiveness in the treatment of schizophrenia not established in patients less than 12 years of age. Safety and effectiveness in the treatment of schizoaffective disorder not established in patients less than 18 years of age. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone extended-release tablets, 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 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 du …

12.1 Mechanism of Action Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug’s therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2A ) receptor antagonism.

11 DESCRIPTION Paliperidone Extended-Release Tablets contain paliperidone, USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contain a racemic mixture of (+)- and (-)- paliperidone. The chemical name is (9 RS )-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4 H -pyrido[1,2- a ]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 3 and its molecular weight is 426.49. The structural formula is: Paliperidone is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide. Paliperidone extended-release tablets are intended for oral administration and are available in 3 mg (white), 6 mg (light beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets utilize osmotic drug-release technology [see Description (11) ] . Inactive ingredients are butylated hydroxytoluene, cellulose acetate, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polyethylene oxide, red iron oxide, sodium chloride, sodium stearyl fumarate, talc, titanium dioxide and yellow iron oxide. The 3 mg tablets also contain polyvinyl alcohol. The 6 mg tablets also contain black iron oxide, FD&C Blue No. 1 Aluminum Lake and polyvinyl alcohol. The 9 mg tablets also contain FD&C Blue No. 1 Aluminum Lake and polyvinyl alcohol. The imprinting ink contains the following: black iron oxide, hypromellose and propylene glycol. Delivery System Components and Performance Paliperidone extended-release uses osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components. description

10 OVERDOSAGE 10.1 Human Experience While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone extended-release tablets was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose. Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert. 10.2 Management of Overdosage There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered. In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

16 HOW SUPPLIED/STORAGE AND HANDLING Paliperidone extended-release tablets are available in the following strengths and packages. 1.5 mg tablets are brown, circular, biconvex, beveled edged, film-coated tablets imprinted with “744” in black ink on one side and plain on the other side. NDC Number Size 47335-744-83 Bottle of 30 Tablets with Child Resistant Cap 47335-744-88 Bottle of 100 Tablets with Child Resistant Cap 3 mg tablets are white to off-white, circular, biconvex, beveled edged, film-coated tablets imprinted with “765” in black ink on one side and plain on the other side. NDC Number Size 47335-765-83 Bottle of 30 Tablets with Child Resistant Cap 47335-765-88 Bottle of 100 Tablets with Child Resistant Cap 6 mg tablets are yellow, circular, biconvex, beveled edged, film-coated tablets imprinted with “766” in black ink on one side and plain on the other side. NDC Number Size 47335-766-83 Bottle of 30 Tablets with Child Resistant Cap 47335-766-88 Bottle of 100 Tablets with Child Resistant Cap 9 mg tablets are pink, circular, biconvex, beveled edged, film-coated tablets imprinted with “767” in black ink on one side and plain on the other side. NDC Number Size 47335-767-83 Bottle of 30 Tablets with Child Resistant Cap 47335-767-88 Bottle of 100 Tablets with Child Resistant Cap Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep out of reach of children.