b'INVEGA SUSTENNAINVEGA SUSTENNA (paliperidone palmitate)(paliperidone palmitate) extended-release injectable extended-release injectable suspension, for intramuscular usesuspension, for intramuscular use QT ProlongationBrief Summary Paliperidone causes a modest increase in the corrected QT (QTc) interval. The BEFORE PRESCRIBING INVEGASUSTENNA, PLEASE SEE FULL PRESCRIBINGuse of paliperidone should be avoided in combination with other drugs that INFORMATION, INCLUDING BOXED WARNING. are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or WARNING: INCREASED MORTALITY IN ELDERLY PATIENTSClass III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic WITH DEMENTIA-RELATED PSYCHOSIS medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, Elderly patients with dementia-related psychosis treated with antipsychoticmoxifloxacin), or any other class of medications known to prolong the QTc drugs are at an increased risk of death. INVEGA SUSTENNA is not approvedinterval. Paliperidone should also be avoided in patients with congenital long QT for use in patients with dementia-related psychosis. [see Warnings andsyndrome and in patients with a history of cardiac arrhythmias.Precautions]. Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong INDICATIONS AND USAGE the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; INVEGASUSTENNA (paliperidone palmitate) is indicated for the treatment of: (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence Schizophreniaof congenital prolongation of the QT interval.inadults[seeClinicalStudies(14.1)inFullPrescribing Information]. The effects of oral paliperidone on the QT interval were evaluated in a double-Schizoaffective disorder in adults as monotherapy and as an adjunct to moodblind,active-controlled(moxifloxacin400mgsingledose),multicenterQTstabilizers or antidepressants [see Clinical Studies (14.2) in Full Prescribingstudy in adults with schizophrenia and schizoaffective disorder, and in three Information]. placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with CONTRAINDICATIONS schizophrenia.INVEGASUSTENNAiscontraindicatedinpatientswithaknownhyper- In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone sensitivity to either paliperidone or risperidone, or to any of the excipients in(n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of theINVEGASUSTENNAformulation.Hypersensitivityreactions,including12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-anaphylactic reactions and angioedema, have been reported in patients treatedstate peak plasma concentration for this 8 mg dose of paliperidone immediate with risperidone and in patients treated with paliperidone. Paliperidone palmitaterelease (C max ss= 113 ng/mL) was more than 2-fold the exposure observed with is converted to paliperidone, which is a metabolite of risperidone. the maximum recommended 234 mg dose of INVEGASUSTENNA administered WARNINGS AND PRECAUTIONS in the deltoid muscle (predicted median C max ss= 50 ng/mL). In this same study, a Increased Mortality in Elderly Patients with Dementia-Related Psychosis 4 mg dose of the immediate-release oral formulation of paliperidone, for which Elderly patients with dementia-related psychosis treated with antipsychoticC max ss= 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials(90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.(modal duration of 10 weeks), largely in patients taking atypical antipsychoticIn the three fixed-dose efficacy studies of oral paliperidone extended release drugs, revealed a risk of death in drug-treated patients of between 1.6 toin subjects with schizophrenia, electrocardiogram (ECG) measurements taken 1.7 times the risk of death in placebo-treated patients. Over the course of aat various time points showed only one subject in the oral paliperidone 12 mg typical 10-week controlled trial, the rate of death in drug-treated patients wasgroup had a change exceeding 60 msec at one time-point on Day 6 (increase about 4.5%, compared to a rate of about 2.6% in the placebo group.of 62 msec).Although the causes of death were varied, most of the deaths appeared toIn the four fixed-dose efficacy studies of INVEGASUSTENNA in subjects be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g.,with schizophrenia and in the long-term study in subjects with schizoaffective pneumonia) in nature. Observational studies suggest that, similar to atypicaldisorder, no subject experienced a change in QTcLD exceeding 60 msec and no antipsychoticdrugs,treatmentwithconventionalantipsychoticdrugsmaysubject had a QTcLD value of 500 msec at any time point. In the maintenance increase mortality. The extent to which the findings of increased mortality instudy in subjects with schizophrenia, no subject had a QTcLD change 60 msec, observational studies may be attributed to the antipsychotic drug as opposedand one subject had a QTcLD value of 507 msec (Bazetts QT corrected interval to some characteristic(s) of the patients is not clear. INVEGASUSTENNA is[QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats not approved for the treatment of patients with dementia-related psychosis [seeper minute.Boxed Warning and Warnings and Precautions]. Tardive DyskinesiaCerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients withA syndrome of potentially irreversible, involuntary, dyskinetic movements may Dementia-Related Psychosis develop in patients treated with antipsychotic drugs. Although the prevalence In placebo-controlled trials with risperidone, aripiprazole, and olanzapine inof the syndrome appears to be highest among the elderly, especially elderly elderly subjects with dementia, there was a higher incidence of cerebrovascularwomen, it is impossible to predict which patients will develop the syndrome. adverse reactions (cerebrovascular accidents and transient ischemic attacks)Whether antipsychotic drug products differ in their potential to cause tardive including fatalities compared to placebo-treated subjects. No studies havedyskinesia is unknown.been conducted with oral paliperidone, INVEGA SUSTENNA, or the 3-monthThe risk of developing tardive dyskinesia and the likelihood that it will become paliperidonepalmitateextended-releaseinjectablesuspensioninelderlyirreversible appear to increase as the duration of treatment and the total patients with dementia. These medicines are not approved for the treatment ofcumulative dose of antipsychotic drugs administered to the patient increase, but patients with dementia-related psychosis [see Boxed Warning and Warningsthe syndrome can develop after relatively brief treatment periods at low doses, and Precautions]. although this is uncommon.Neuroleptic Malignant Syndrome The syndrome may remit, partially or completely, if antipsychotic treatment is A potentially fatal symptom complex sometimes referred to as Neurolepticwithdrawn. Antipsychotic treatment itself may suppress (or partially suppress) Malignant Syndrome (NMS) has been reported in association with antipsychoticthe signs and symptoms of the syndrome and may thus mask the underlying drugs, including paliperidone. process. The effect of symptomatic suppression on the long-term course of the Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mentalsyndrome is unknown.status, and evidence of autonomic instability (irregular pulse or blood pressure,Giventheseconsiderations,INVEGASUSTENNAshouldbeprescribedin tachycardia,diaphoresis,andcardiacdysrhythmia).Additionalsignsmaya manner that is most likely to minimize the occurrence of tardive dyskinesia. include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), andChronic antipsychotic treatment should generally be reserved for patients who acute renal failure. suffer from a chronic illness that is known to respond to antipsychotic drugs. In The diagnostic evaluation of patients with this syndrome is complicated. Inpatients who do require chronic treatment, the smallest dose and the shortest arriving at a diagnosis, it is important to identify cases in which the clinicalduration of treatment producing a satisfactory clinical response should be presentation includes both serious medical illness (e.g., pneumonia, systemicsought. The need for continued treatment should be reassessed periodically.infection, etc.) and untreated or inadequately treated extrapyramidal signs andIf signs and symptoms of tardive dyskinesia appear in a patient treated with symptoms (EPS). Other important considerations in the differential diagnosisINVEGASUSTENNA, drug discontinuation should be considered. However, include central anticholinergic toxicity, heat stroke, drug fever, and primarysome patients may require treatment with INVEGASUSTENNA despite the central nervous system pathology. presence of the syndrome.The management of NMS should include: (1) immediate discontinuation ofMetabolic Changesantipsychoticdrugsandotherdrugsnotessentialtoconcurrenttherapy;Atypical antipsychotic drugs have been associated with metabolic changes that (2) intensive symptomatic treatment and medical monitoring; and (3) treatmentmay increase cardiovascular/cerebrovascular risk. These metabolic changes of any concomitant serious medical problems for which specific treatmentsinclude hyperglycemia, dyslipidemia, and body weight gain. While all of the are available. There is no general agreement about specific pharmacologicaldrugs in the class have been shown to produce some metabolic changes, each treatment regimens for uncomplicated NMS. drug has its own specific risk profile.If a patient appears to require antipsychotic drug treatment after recoveryHyperglycemia and Diabetes Mellitusfrom NMS, reintroduction of drug therapy should be closely monitored, sinceHyperglycemia and diabetes mellitus, in some cases extreme and associated recurrences of NMS have been reported. with ketoacidosis or hyperosmolar coma or death, have been reported in patients'