b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular useData at all doses in both males and females. The above effects showed little or no Human Data reversibility in females after a 12-week drug-free recovery period.Published data from observational studies, birth registries, and case reportsThe long-term effects of INVEGASUSTENNA on growth and sexual maturation on the use of atypical antipsychotics during pregnancy do not report a clearhave not been fully evaluated in children and adolescents.associationwithantipsychoticsandmajorbirthdefects.AprospectiveGeriatric Useobservational study including 6 women treated with risperidone, the parentClinical studies of INVEGASUSTENNA did not include sufficient numbers compoundofpaliperidone,demonstratedplacentalpassageofrisperidoneof subjects aged 65 and over to determine whether they respond differently and paliperidone. A retrospective cohort study from a Medicaid database offrom younger subjects. Other reported clinical experience has not identified 9258womenexposedtoantipsychoticsduringpregnancydidnotindicatedifferences in responses between the elderly and younger patients.an overall increased risk for major birth defects. There was a small increaseThis drug is known to be substantially excreted by the kidney and clearance is 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 exposeddecreased in patients with renal impairment [see Clinical Pharmacology (12.3) to the parent compound of paliperidone, risperidone, during the first trimester ofin Full Prescribing Information], who should be given reduced doses. Because pregnancy; however, there is no mechanism of action to explain the differenceelderly patients are more likely to have decreased renal function, adjust dose in malformation rates.based on renal function [see Dosage and Administration (2.5) in Full Prescribing Animal Data Information].There were no treatment-related effects on the offspring when pregnant rats wereRenal Impairmentinjected intramuscularly with paliperidone palmitate extended-release injectableUse of INVEGASUSTENNA is not recommended in patients with moderate or suspension during the period of organogenesis at doses up to 250 mg/kg, which issevere renal impairment (creatinine clearance 50 mL/min). Dose reduction 10 times MRHD of 234 mg paliperidone based on mg/m2 body surface area. is recommended for patients with mild renal impairment (creatinine clearance In animal reproduction studies, there were no increases in fetal abnormalities 50 mL/min to 80 mL/min) [see Dosage and Administration (2.5) and Clinical when pregnant rats and rabbits were treated orally with paliperidone during thePharmacology (12.3) in Full Prescribing Information].2 Hepatic Impairment period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m INVEGASUSTENNA has not been studied in patients with hepatic impairment. body surface area. Based on a study with oral paliperidone, no dose adjustment is required in Additional reproduction toxicity studies were conducted with orally administeredpatients with mild or moderate hepatic impairment. Paliperidone has not been risperidone, which is extensively converted to paliperidone. Cleft palate wasstudied in patients with severe hepatic impairment [Clinical Pharmacology (12.3) observed in the offspring of pregnant mice treated with risperidone at 3 to 4in Full Prescribing Information].times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicityPatients with Parkinsons Disease or Lewy Body Dementiaoccurred at 4 times the MHRD. There was no evidence of teratogenicity inPatients with Parkinsons Disease or Dementia with Lewy Bodies can experience 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 bodyincreasedsensitivitytoINVEGA SUSTENNA .Manifestationscaninclude surface area. When the offspring of pregnant rats, treated with risperidone at 0.6confusion, obtundation, postural instability with frequent falls, extrapyramidal times the MRHD based on mg/m2 body surface area, reached adulthood, learningsymptoms, and clinical features consistent with neuroleptic malignant syndrome.was impaired. Increased neuronal cell death occurred in the fetal brains of theDRUG ABUSE AND DEPENDENCEoffspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatalControlled Substancedevelopment and growth of the offspring was delayed. INVEGASUSTENNA (paliperidone) is not a controlled substance.In rat reproduction studies with risperidone, pup deaths occurred at oral dosesAbusewhich are less than the MRHD of risperidone based on mg/m2 body surface area;Paliperidone has not been systematically studied in animals or humans for its it is not known whether these deaths were due to a direct effect on the fetuses orpotential for abuse.pups or, to effects on the dams (see RISPERDAL package insert). DependenceLactation Paliperidone has not been systematically studied in animals or humans for its Risk Summary potential for tolerance or physical dependence.LimiteddatafrompublishedliteraturereportthepresenceofpaliperidoneOVERDOSAGEin human breast milk. There is no information on the effects on the breastfedHuman Experienceinfant or the effects on milk production; however, there are reports of sedation,Nocasesofoverdosewerereportedinpremarketingstudieswith failuretothrive,jitteriness,andextrapyramidalsymptoms(tremorsandINVEGASUSTENNA. Because INVEGASUSTENNA is to be administered by abnormal muscle movements) in breastfed infants exposed to paliperidoneshealthcare professionals, the potential for overdosage by patients is low.parent compound, risperidone (see Clinical Considerations). Paliperidone hasWhile experience with paliperidone overdose is limited, among the few cases been detected in plasma in adult subjects up to 126 days after a single-doseof overdose reported in premarketing trials with oral paliperidone, the highest administration of INVEGASUSTENNA [see Clinical Pharmacology (12.3) in Fullestimatedingestionwas405mg.Observedsignsandsymptomsincluded Prescribing Information], and the clinical significance on the breastfed infant isextrapyramidal symptoms and gait unsteadiness. Other potential signs and not known. The developmental and health benefits of breastfeeding should besymptomsincludethoseresultingfromanexaggerationofpaliperidones considered along with the mothers clinical need for INVEGASUSTENNA andknownpharmacologicaleffects,i.e.,drowsinessandsedation,tachycardia any potential adverse effects on the breastfed child from INVEGASUSTENNAand hypotension, and QT prolongation. Torsades de pointes and ventricular or from the mothers underlying condition. fibrillation have been reported in a patient in the setting of overdose with oral Clinical Considerations paliperidone.Infants exposed to INVEGASUSTENNA through breastmilk should be monitoredPaliperidone is the major active metabolite of risperidone. Overdose experience for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptomsreported with risperidone can be found in the OVERDOSAGE section of the (tremors and abnormal muscle movements). risperidone package insert.Females and Males of Reproductive Potential Management of OverdosageInfertility Contact a Certified Poison Control Center for the most up to date information Females on the management of INVEGASUSTENNA overdosage (1-800-222-1222 or Based on the pharmacologic action of paliperidone (D2 receptor antagonism),www.poison.org). Provide supportive care, including close medical supervision treatmentwithINVEGA SUSTENNAmayresultinanincreaseinserumand monitoring. Treatment should consist of general measures employed in the prolactin levels, which may lead to a reversible reduction in fertility in females ofmanagement of overdosage with any drug. Consider the possibility of multiple reproductive potential [see Warnings and Precautions (5.10)]. drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Pediatric Use Monitorcardiacrhythmandvitalsigns.Usesupportiveandsymptomatic Safety and effectiveness of INVEGASUSTENNA in patients 18 years of agemeasures. There is no specific antidote to paliperidone.have not been established. Consider the prolonged-release characteristics of INVEGASUSTENNA and Juvenile Animal Studies the long apparent half-life of paliperidone when assessing treatment needs and In a study in which juvenile rats were treated with oral paliperidone from daysrecovery.24 to 73 of age, a reversible impairment of performance in a test of learningINVEGASUSTENNA(paliperidonepalmitate)Extended-ReleaseInjectable and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/ Suspensionday, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioralProduct of Irelandor reproductive development were seen up to the highest dose tested (2.5Manufactured by: mg/kg/day), which produced plasma levels of paliperidone 2-3 times those inJanssen Pharmaceutica NV adolescents. Beerse, BelgiumJuvenile dogs were treated for 40 weeks with oral risperidone, which is extensivelyManufactured for: metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, orJanssen Pharmaceuticals, Inc. 5 mg/kg/day. Decreased bone length and density were seen with a no-effectTitusville, NJ 08560dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus 2009 Janssen Pharmaceutical Companiespaliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seencp-78652v1'