Paliperidone (Page 5 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of paliperidone extended-release tablets; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, catatonia, ileus, priapism, somnambulism, swollen tongue, tardive dyskinesia, thromobotic thrombocytopenic purpura, urinary incontinence, urinary retention.

6.3 Adverse Reactions Reported with Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

7 DRUG INTERACTIONS

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 2,000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,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 mg/day to 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 Cmax 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 of carbamazepine, the dose of paliperidone extended-release tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone extended-release tablets should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone extended-release tablets was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of paliperidone extended-release tablets 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for paliperidone extended-release tablets should be considered when paliperidone extended-release tablets are co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and paliperidone extended-release tablets is unlikely.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone, 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, 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/m2 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, 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 9,258 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 1,566 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/m2 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/m2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams (see RISPERDAL® package insert).

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