b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular useLike other antipsychotic drugs, INVEGASUSTENNA should be used cautiouslyAdverse Reactions in Double-Blind, Placebo-Controlled Clinical Trialsin patients with a history of seizures or other conditions that potentially lowerCommonly Observed Adverse Reactions: The most common (at least 5% in the seizure threshold. Conditions that lower the seizure threshold may be moreanyINVEGASUSTENNAgroup)andlikelydrug-related(adverseevents prevalent in patients 65 years or older. for which the drug rate is at least twice the placebo rate) adverse reactions Dysphagia from the double-blind, placebo-controlled trials in subjects with schizophrenia Esophageal dysmotility and aspiration have been associated with antipsychoticwere injection site reactions, somnolence/sedation, dizziness, akathisia, and drug use. INVEGASUSTENNA and other antipsychotic drugs should be usedextrapyramidaldisorder.Nooccurrencesofadverseeventsreachedthis cautiously in patients at risk for aspiration pneumonia. threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.Priapism Discontinuation of Treatment Due to Adverse Events: The percentage of subjects Drugs with alpha-adrenergic blocking effects have been reported to inducewho discontinued due to adverse events in the four fixed-dose, double-blind, priapism. Although no cases of priapism have been reported in clinical trials withplacebo-controlled schizophrenia trials were similar for INVEGA SUSTENNA- INVEGASUSTENNA, priapism has been reported with oral paliperidone duringand placebo-treated subjects.postmarketing surveillance. Severe priapism may require surgical intervention. The percentage of subjects who discontinued due to adverse events in the open-Disruption of Body Temperature Regulation label period of the long-term study in subjects with schizoaffective disorder Disruption of the bodys ability to reduce core body temperature has beenwas 7.5%. During the double-blind, placebo-controlled period of that study, the attributed to antipsychotic agents. Appropriate care is advised when prescribingpercentages of subjects who discontinued due to adverse events were 5.5% and INVEGASUSTENNA to patients who will be experiencing conditions which1.8% in INVEGA SUSTENNA- and placebo-treated subjects, respectively.maycontributetoanelevationincorebodytemperature,e.g.,exercisingDose-Related Adverse Reactions: Based on the pooled data from the four fixed-strenuously, exposure to extreme heat, receiving concomitant medication withdose, double-blind, placebo-controlled trials in subjects with schizophrenia, anticholinergic activity, or being subject to dehydration. among the adverse reactions that occurred with2% incidence in the subjects ADVERSE REACTIONS treatedwithINVEGASUSTENNA,onlyakathisiaincreasedwithdose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at2% The following are discussed in more detail in other sections of the labeling: incidence in INVEGA SUSTENNA-treated subjects from the four fixed-dose Increased mortality in elderly patients with dementia-related psychosis [seestudies. Boxed Warning and Warnings and Precautions] AdverseReactionsOccurringatanIncidenceof2%orMorein INVEGASUSTENNA-TreatedPatients:Table6liststheadversereactions Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions] reported in 2% or more of INVEGASUSTENNA-treated subjects and at a greater Neuroleptic malignant syndrome [see Warnings and Precautions] proportion than in the placebo group with schizophrenia in the four fixed-dose, QT prolongation [see Warnings and Precautions] double-blind, placebo-controlled trials. Tardive dyskinesia [see Warnings and Precautions] Table 6: Incidences of Adverse Reactions 2% or More of INVEGASUSTENNA-Metabolic changes [see Warnings and Precautions] Treated Patients (and Greater than Placebo) with Schizophrenia in Orthostatic hypotension and syncope [see Warnings and Precautions] Four Fixed-Dose, Double-Blind, Placebo-Controlled TrialsFalls [see Warnings and Precautions] INVEGASUSTENNASystem OrganPlaceboa39 mg78 mg156 mg234/39 mgb 234/156 mgb 234/234 mgb Leukopenia,neutropenia,andagranulocytosis[seeWarningsand Precautions] Class (N=510) (N=130) (N=302) (N=312) (N=160) (N=165) (N=163)AdverseHyperprolactinemia [see Warnings and Precautions] Reactions Potential for cognitive and motor impairment [see Warnings and Precautions] Total percentage70 75 68 69 63 60 63Seizures [see Warnings and Precautions] of subjects Dysphagia [see Warnings and Precautions] with adverse reactionsPriapism [see Warnings and Precautions] Gastrointestinal disordersDisruption of body temperature regulation [see Warnings and Precautions] Abdominal2 2 4 4 1 2 4 Clinical Trials Experience discomfort/Because clinical trials are conducted under widely varying conditions, adverseabdominal pain reactionratesobservedintheclinicaltrialsofadrugcannotbedirectlyuppercompared to rates in the clinical trials of another drug and may not reflect theDiarrhea 2 0 3 2 1 2 2rates observed in clinical practice. Dry mouth 1 3 1 0 1 1 1Patient Exposure Nausea 3 4 4 3 2 2 2The data described in this section are derived from a clinical trial databaseToothache 1 1 1 3 1 2 3consisting of a total of 3817 subjects (approximately 1705 patient-years exposure)Vomiting 4 5 4 2 3 2 2with schizophrenia who received at least one dose of INVEGA SUSTENNA inGeneral disorders and administration site conditionsthe recommended dose range of 39 mg to 234 mg and a total of 510 subjects withAsthenia 0 2 1 1 0 1 1schizophrenia who received placebo. Among the 3817 INVEGA SUSTENNA-Fatigue 1 1 2 2 1 2 1treated subjects, 1293 received INVEGA SUSTENNA in four fixed-dose, double- Injection site2 0 4 6 9 7 10 blind, placebo-controlled trials (one 9-week and three 13-week studies), 849reactionsreceivedINVEGASUSTENNAinthemaintenancetrial(medianexposureInfections and infestations229 days during the initial 33-week open-label phase of this study, of whom 205Nasopharyngitis 2 0 2 2 4 2 2continued to receive INVEGA SUSTENNA during the double-blind placebo- Upper2 2 2 2 1 2 4 controlled phase of this study [median exposure 171 days]), and 1675 receivedrespiratory tract INVEGA SUSTENNA in five non-placebo controlled trials (three noninferiorityinfectionUrinary tract1 0 1 1 1 1 2active-comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoid-gluteal] cross-over trial). One of the 13-weekinfectionstudies included a 234 mg INVEGA SUSTENNA initiation dose followed byInvestigationstreatment with either 39 mg, 156 mg, or 234 mg every 4 weeks. Weight1 4 4 1 1 1 2increasedThe safety of INVEGA SUSTENNA was also evaluated in a 15-month, long- Musculoskeletal and connective tissue disordersterm study comparing INVEGA SUSTENNA to selected oral antipsychoticBack pain 2 2 1 3 1 1 1therapies in adult subjects with schizophrenia. A total of 226 subjects received Musculoskeletal1 1 1 1 1 1 2INVEGASUSTENNA during the 15-month, open-label period of this study;stiffness218subjectsreceivedselectedoralantipsychotictherapies.ThesafetyofMyalgia 1 2 1 1 1 0 2INVEGASUSTENNA was similar to that seen in previous double-blind, placebo- Pain in1 0 2 2 2 3 0 controlled clinical trials in adult subjects with schizophrenia. The safety of INVEGAextremitySUSTENNA was also evaluated in a long-term study in adult subjects withNervous system disordersschizoaffective disorder. A total of 667 subjects received INVEGA SUSTENNAAkathisia 3 2 2 3 1 5 6during the initial 25-week open-label period of this study (median exposureDizziness 1 6 2 4 1 4 2147days);164subjectscontinuedtoreceiveINVEGASUSTENNA duringExtrapyramidal1 5 2 3 1 0 0the15-monthdouble-blindplacebo-controlledperiodofthisstudy(median exposure 446 days). Adverse reactions that occurred more frequently in thedisorderINVEGA SUSTENNA than the placebo group (a 2% difference or more betweenHeadache 12 11 11 15 11 7 6Somnolence/ 3 5 7 4 1 5 5groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia. sedation'