Paliperidone

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 INVEGA. ( 7.1 ) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA 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 INVEGA. ( 7.2 ) Co-administration of divalproex sodium increased C max and AUC of paliperidone by approximately 50%. Adjust dose of INVEGA if necessary based on clinical assessment. ( 7.2 )

7.1 Potential for INVEGA to Affect Other Drugs Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1 , 6.2 )] , INVEGA 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 INVEGA 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 INVEGA is unlikely.

In a drug interaction study, co-administration of INVEGA (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 INVEGA 3–15 mg/day was added to their existing valproate treatment.

7.2 Potential for Other Drugs to Affect INVEGA 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 INVEGA 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 of carbamazepine, the dose of INVEGA should be re-evaluated and increased if necessary.

Conversely, on discontinuation of carbamazepine, the dose of INVEGA 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 INVEGA 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 INVEGA 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Dosage reduction for INVEGA should be considered when INVEGA is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and INVEGA is unlikely.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA, 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 INVEGA, 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 INVEGA, during the third trimester of pregnancy.

These symptoms have varied in severity.…