PALIPERIDONE: Package Insert and Label Information (Page 4 of 6)

6.8 Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia and from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between paliperidone and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between paliperidone and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, paliperidone was associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

6.9 Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone

The following additional adverse reactions occurred in < 2% of Paliperidone-treated subjects in the above schizophrenia clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by paliperidone-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare

Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation

Respiratory , thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

The safety of paliperidone was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone in adults with schizophrenia [see Clinical Studies (14)]. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

6.10 Postmarketing Experience

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

6.11 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 to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], paliperidone 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 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 is unlikely.

In a drug interaction study, co-administration of paliperidone (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 (AUC24h and Cmax ,ss ) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on a stable dose of valproate showed comparable valproate average plasma concentrations when paliperidone 3-15 mg of paliperidone was added to their existing valproate treatment.

7.2 Potential for Other Drugs to Affect Paliperidopne

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 6 mg once daily with carbamazepine 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 should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone 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 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 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 should be considered when paliperidone is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and paliperidone 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 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/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 INVEGA®, 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/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).

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parentcompound,risperidone (see CLINICAL CONSIDERATIONS). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paliperidone and any potential adverse effects on the breastfed child from paliperidone or from the mother’s underlying condition.Clinical Considerations

Infants exposed to paliperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with paliperidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential[see WARNINGS AND PRECAUTIONS (5.7)].

8.4 Pediatric Use

Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of paliperidone for the treatment of schizophrenia in patients < 12 years of age have not been established Safety and effectiveness of paliperidone for the treatment of schizoaffective disorder in patients< 18 years of age have not studied.

In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

8.5 Geriatric Use

The safety, tolerability, and efficacy of paliperidone were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of paliperidone (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of paliperidone (3 mg to 15 mg once daily) [see Clinical Studies (14)]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone (n = 1796), including those who received paliperidone or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)].

8.6 Renal Impairment

Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration (2.5)].

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