b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular useInthe13-weekstudyinvolving234mginitiationdosinginsubjectswithTable9: Clinically Important Drug Interactions with INVEGA SUSTENNA schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over(continued)time, and similar in incidence between the INVEGASUSTENNA and placeboDopamineAgonistgroups. Investigator ratings of injection pain were similar for the placebo and INVEGASUSTENNA groups. Investigator evaluations of the injection site afterClinical Impact Paliperidone may antagonize the effect of levodopa the first injection for redness, swelling, induration, and pain were rated as absentand other dopamine agonistfor 69-100% of subjects in both the INVEGASUSTENNA and placebo groups. AtIntervention Monitor and manage patient as clinically appropriateDay 92, investigators rated absence of redness, swelling, induration, and pain inExamples Levodopa, bromocriptine, ropinirole and pramipexole95-100% of subjects in both the INVEGASUSTENNA and placebo groups.Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone Drugs Having No Clinically Important Interactions with INVEGASUSTENNAThe following is a list of additional adverse reactions that have been reported inClinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA clinical trials with oral paliperidone: and valproate (including valproic acid and divalproex sodium) is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment Cardiac disorders: bundle branch block left, sinus arrhythmia of INVEGA SUSTENNA is required when administered with valproate [see Gastrointestinal disorders: abdominal pain, small intestinal obstruction Clinical Pharmacology (12.3) in Full Prescribing Information]. Additionally, no General disorders and administration site conditions: edema, edema peripheral dosageadjustmentisnecessaryforvalproatewhenco-administeredwith Immune system disorders: anaphylactic reaction INVEGASUSTENNA[SeeClinicalPharmacology(12.3)inFullPrescribing Infections and infestations: rhinitis Information].Musculoskeletalandconnectivetissuedisorders:musculoskeletalpain,Pharmacokinetic interaction between lithium and INVEGA SUSTENNA is also torticollis, trismus unlikely.Nervous system disorders: grand mal convulsion, parkinsonian gait, transientPaliperidone is not expected to cause clinically important pharmacokinetic ischemic attack interactions with drugs that are metabolized by cytochrome P450 isozymes. Psychiatric disorders: sleep disorder In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone Reproductive system and breast disorders: breast engorgement metabolism; however, there is no evidence in vivo that inhibitors of these Respiratory,thoracicandmediastinaldisorders:pharyngolaryngealpain,enzymes significantly affect the metabolism of paliperidone. Paliperidone is pneumonia aspiration not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with Skin and subcutaneous tissue disorders: rash papular inhibitors or inducers of these isozymes is unlikely. [see Clinical Pharmacology Vascular disorders: hypotension, ischemia (12.3) in Full Prescribing Information]Postmarketing Experience USE IN SPECIFIC POPULATIONSThe following adverse reactions have been identified during postapproval usePregnancyof paliperidone; because these reactions were reported voluntarily from aPregnancy Exposure Registrypopulation of uncertain size, it is not always possible to reliably estimate theirThere is a pregnancy exposure registry that monitors pregnancy outcomes in frequency or establish a causal relationship to drug exposure: angioedema,women exposed to atypical antipsychotics, including INVEGA SUSTENNA, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura,during pregnancy. Healthcare providers are encouraged to register patients urinary incontinence, and urinary retention. bycontactingtheNationalPregnancyRegistryforAtypicalAntipsychotics Cases of anaphylactic reaction after injection with INVEGASUSTENNA haveat1-866-961-2388oronlineathttp://womensmentalhealth.org/clinical-and-been reported during postmarketing experience in patients who have previouslyresearch-programs/pregnancyregistry/.tolerated oral risperidone or oral paliperidone. Risk SummaryPaliperidone is the major active metabolite of risperidone. Adverse reactionsNeonatesexposedtoantipsychoticdrugsduringthethirdtrimesterof reported with oral risperidone and risperidone long-acting injection can be foundpregnancy are at risk for extrapyramidal and/or withdrawal symptoms following in the Adverse Reactions sections of the package inserts for those products. delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not DRUG INTERACTIONS establishedadrug-associatedriskformajorbirthdefects,miscarriage,or Drugs Having Clinically Important Interactions with INVEGA SUSTENNA adverse maternal or fetal outcomes (see Data). There are risks to the mother Becausepaliperidonepalmitateishydrolyzedtopaliperidone[seeClinicalassociated with untreated schizophrenia and with exposure to antipsychotics, Pharmacology (12.3) in Full Prescribing Information], results from studies withincluding INVEGASUSTENNA, during pregnancy (see Clinical Considerations). oral paliperidone should be taken into consideration when assessing drug-drugPaliperidone has been detected in plasma in adult subjects up to 126 days after a interaction potential. single-dose administration of INVEGASUSTENNA [see Clinical Pharmacology(12.3)inFullPrescribingInformation],andtheclinicalsignificanceof INVEGA SUSTENNA administeredbeforepregnancyoranytimeduring Table9: Clinically Important Drug Interactions with INVEGA SUSTENNA Drugs with Potential for Inducing Orthostatic Hypotension pregnancy is not known.Clinical Impact Because INVEGA SUSTENNA has the potential forThe estimated background risk of major birth defects and miscarriage for the inducing orthostatic hypotension, an additive effectindicated population is unknown. All pregnancies have a background risk of may occur when INVEGA SUSTENNA is administeredbirth defects, loss, or other adverse outcomes. In the U.S. general population, the with other therapeutic agents that have this potentialestimated background risk of major birth defects and miscarriage in clinically [see Warning and Precautions] recognized pregnancies is 2-4% and 15-20%, respectively.Intervention Monitor orthostatic vital signs in patients whoIn animal reproduction studies, there were no treatment related effects on the are vulnerable to hypotension [see Warnings andoffspring when pregnant rats were injected intramuscularly with paliperidone Precautions] palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on Examples Nitrates mg/m2 body surface area. There were no increases in fetal abnormalities when Antihypertensive medicines: thiazide diuretics (e.g.pregnant rats and rabbits were treated orally with paliperidone during the period hydrochlorothiazide); beta blockers (e.g. acebutolol);of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based angiotensin-converting enzyme (ACE) inhibitorson mg/m2 body surface area. Additional reproduction toxicity studies were (e.g. lisinopril); angiotensin II receptor blockersconducted with orally administered risperidone, which is extensively converted (ARBs) (e.g. candesartan); calcium channel blockersto paliperidone (see Animal data).(e.g.amlodipine); alpha-blockers (e.g. prazosin), alpha- Clinical Considerationsagonists (e.g. clonidine), other diuretics (e.g. loop,Disease-associated maternal and/or embryo/fetal riskK-sparing), vasodilators (e.g. hydralazine) There is a risk to the mother from untreated schizophrenia, including increased Strong Inducers of CYP3A4 and P-gp risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder Clinical Impact The concomitant use of paliperidone and strongare associated with increased adverse perinatal outcomes, including preterm inducers of CYP3A4 and P-gp may decrease thebirth. It is not known if this is a direct result of the illness or other comorbid exposure of paliperidone [see Clinical Pharmacologyfactors.(12.3) in Full Prescribing Information] Fetal/Neonatal Adverse ReactionsIntervention Avoid using CYP3A4 and/or P-gp inducers withExtrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, INVEGA SUSTENNA during the 1-month dosinghypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including interval, if possible. If administering a strong inducerINVEGASUSTENNA, during the third trimester of pregnancy. These symptoms is necessary, consider managing the patient usinghave varied in severity. Monitor neonates exhibiting extrapyramidal and/or paliperidone extended release tablets [see Dosagewithdrawal symptoms and manage symptoms appropriately. Some neonates and Administration (2.5) in Full Prescribing Information] recovered within hours or days without specific treatment; others required Examples Carbamazepine, rifampin, St Johns Wort prolonged hospitalization.'