Paliperidone

FDA Drug Information • Also known as: Invega, Paliperidone

Brand Names: Invega, Paliperidone
Dosage Form: POWDER
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: 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. Paliperidone extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)] WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Paliperidone extended-release tablets are not approved for use in patients with dementia-related psychosis. (5 1)

Description

11 DESCRIPTION Paliperidone extended-release tablet contains paliperidone, USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contain a racemic mixture of (+)- and (-)- Paliperidone, USP. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido [l,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, USP is sparingly soluble in 0.1 N hydrochloride and in methylene chloride, slightly soluble in N,N dimethyl formamide and in tetrahydrofuran; practically insoluble in water, in 0.1 N sodium hydroxide, and in hexane. Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. Paliperidone Extended-Release Tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use. Inactive ingredients are mannitol, microcrystalline cellulose, hypromellose, magnesium stearate, hydroxypropyl cellulose, hypromellose phthalate, ethylcellulose, dibutyl sebacate, polyethylene glycol and titanium dioxide. The 1.5 mg tablets also contain FD&C Yellow #6 Aluminum Lake, D&C Yellow #10 Aluminum Lake and FD&C Blue #2 Aluminum Lake. The 6 mg tablets also contain iron oxide yellow, iron oxide red and iron oxide black. The 9 mg tablets also contain iron oxide red. The tablets are imprinted with edible black ink. The edible ink contains shellac, isopropyl alcohol, iron oxide black, n-butyl alcohol, propylene glycol and ammonium hydroxide. Delivery System Components and Performance Paliperidone Extended-Release Tablet uses a pH-independent hydrophilic matrix and pH dependent enteric coating to deliver Paliperidone, USP at a controlled rate. The Paliperidone Extended-Release Tablet comprises of an inner core...

What Is Paliperidone Used For?

1 INDICATIONS AND USAGE Paliperidone extended-release tablet is 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 to 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia - adults (2.1) 6 mg/day 3 to 12 mg/day 12 mg/day Schizophrenia adolescents (2.1) Weight < 51kg 3 mg/day 3 to 6 mg/day 6 mg/day Weight ≥ 51kg 3 mg/day 3 to 12 mg/day 12 mg/day Schizoaffective disorder - adults (2.2) 6 mg/day 3 to 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 has 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 to 17 years of age) The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 to 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....

Side Effects (Adverse Reactions)

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 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 were 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 were evaluated in 150 adolescent subjects 12 to 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-controlled trial. The safety of paliperidone extended-release...

Drug Interactions

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 tablet 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 tablet 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 to 15 mg/day was 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...

Contraindications

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)

Pregnancy and Breastfeeding

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 to 4% and 15 to 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...

Overdosage

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 tablet 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...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Paliperidone extended-release tablets are available in the following strengths and packages. 1.5 mg tablets are orange-brown, capsule-shaped, biconvex coated tablets, imprinted with ‘T1’ on one side and plain on the other side. They are available as follows: Bottle of 30 tablets with child-resistant closure, NDC 46708-803-30 3 mg tablets are white, capsule-shaped, biconvex coated tablets, imprinted with ‘T2’ on one side and plain on the other side. They are available as follows: Bottle of 30 tablets with child-resistant closure, NDC 46708-804-30 6 mg tablets are beige, capsule-shaped, biconvex coated tablets, imprinted with ‘T3’ on one side and plain on the other side. They are available as follows: Bottle of 30 tablets with child-resistant closure, NDC 46708-805-30 9 mg tablets are pink, capsule-shaped, biconvex coated tablets, imprinted with ‘T4’ on one side and plain on the other side. They are available as follows: Bottle of 30 tablets with child-resistant closure, NDC 46708-806-30 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep out of reach of children.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.