b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular useTable 6: Incidences of Adverse Reactions 2% or More of INVEGASUSTENNA- Table 7: Extrapyramidal Symptoms (EPS) Assessed by Incidence of RatingTreated Patients (and Greater than Placebo) with Schizophrenia inScalesandUseofAnticholinergicMedicationSchizophrenia Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials (continued) Studies in AdultsINVEGASUSTENNA Percentage of SubjectsSystem OrganPlaceboa39 mg78 mg156 mg234/39 mgb 234/156 mgb 234/234 mgbINVEGASUSTENNAClass (N=510) (N=130) (N=302) (N=312) (N=160) (N=165) (N=163) Placebo39 mg78 mg156 mg Adverse Scale (N=262) (N=130) (N=223) (N=228)ReactionsPsychiatric disordersParkinsonisma 9 12 10 6Agitation 7 10 5 9 8 5 4Akathisiab 5 5 6 5Anxiety 7 8 5 3 5 6 6Dyskinesiac 3 4 6 4Nightmare 1 2 0 0 0 0 0Use of Anticholinergic Medicationsd 12 10 12 11 Respiratory, thoracic and mediastinal disordersFor parkinsonism, percent of subjects with Simpson-Angus Total score 0.3 at aCough 1 2 3 1 0 1 1 endpoint (Total score defined as total sum of items score divided by the numberVascular disorders of items)Hypertension 1 2 1 1 1 1 0 bFor Akathisia, percent of subjects with Barnes Akathisia Rating Scale global Percentages are rounded to whole numbers. Table includes adverse reactions thatc score2 at endpoint For Dyskinesia, percent of subjects with a score3 on any of the first 7 items orwere reported in 2% or more of subjects in any of the INVEGASUSTENNA dosea score2 on two or more of any of the first 7 items of the Abnormal Involuntary groups and which occurred at greater incidence than in the placebo group.Movement Scale at endpointa group is pooled from all studies and included either deltoid or glutealdPercent of subjects who received anticholinergic medications to treat EPSPlacebo injection depending on study design. Table 8:Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred b I nitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg everyTermSchizophrenia Studies in Adults4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1) inPercentage of SubjectsFull Prescribing Information] INVEGASUSTENNAAdverse reactions for which the INVEGASUSTENNA incidence was equal to orPlacebo39 mg 78 mg 156 mgless than placebo are not listed in the table, but included the following: dyspepsia,EPS Group (N=262) (N=130) (N=223) (N=228)psychoticdisorder,schizophrenia,andtremor.ThefollowingtermswereOverall percentage of subjects10 12 11 11combined:somnolence/sedation,breasttenderness/breastpain,abdominalwith EPS-related adverse events discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinusParkinsonism 5 6 6 4tachycardia/heart rate increased. All injection site reaction-related adverseHyperkinesia 2 2 2 4reactions were collapsed and are grouped under Injection site reactions. Tremor 3 2 2 3OtherAdverseReactionsObservedDuringtheClinicalTrialEvaluationofDyskinesia 1 2 3 1INVEGASUSTENNA Dystonia 0 1 1 2The following list does not include reactions: 1) already listed in previous tablesParkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal or elsewhere in labeling, 2) for which a drug cause was remote, 3) which werestiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesiaso general as to be uninformative, or 4) which were not considered to haveHyperkinesia group includes: Akathisia, restless legs syndrome, restlessnesssignificant clinical implications. Dyskinesiagroupincludes:Dyskinesia,choreoathetosis,muscletwitching, Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branchmyoclonus, tardive dyskinesiablock, palpitations, postural orthostatic tachycardia syndrome, tachycardia Dystonia group includes: Dystonia, muscle spasmsEar and labyrinth disorders: vertigo Theresultsacrossallphasesofthemaintenancetrialinsubjectswith Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, visionschizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blurred blind, placebo-controlled trial, the proportions of parkinsonism and akathisia Gastrointestinaldisorders:constipation,dyspepsia,flatulence,salivaryassessed by incidence of rating scales were higher in the INVEGASUSTENNA hypersecretion 156 mg group (18% and 11%, respectively) than in the INVEGASUSTENNA 78 mg Immune system disorders: hypersensitivity group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).Investigations: alanine aminotransferase increased, aspartate aminotransferaseIn the 13-week study in subjects with schizophrenia involving 234 mg initiation increased, electrocardiogram abnormal dosing, the incidence of any EPS was similar to that of the placebo group Metabolismandnutritiondisorders:decreasedappetite,hyperinsulinemia,(8%),butexhibitedadose-relatedpatternwith6%,10%,and11%inthe increased appetite INVEGASUSTENNA 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness,Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchalINVEGASUSTENNA 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a rigidity lower rate in the 234/39 mg group (1.3%).Nervous system disorders: bradykinesia, cerebrovascular accident, cogwheelIn the long-term study in subjects with schizoaffective disorder, EPS reported rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia,duringthe25-weekopen-labelINVEGASUSTENNAtreatmentincluded hypertonia,lethargy,oromandibulardystonia,parkinsonism,psychomotorhyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and hyperactivity, syncope dystonia (2.1%). During the 15-month double-blind treatment, the incidence of Psychiatric disorders: insomnia, libido decreased, restlessness any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). Reproductivesystemandbreastdisorders:amenorrhea,breastdischarge,Themostcommonlyreportedtreatment-emergentEPS-relatedadverse breast enlargement/breast swelling, breast tenderness/breast pain, ejaculationevents (2%) in any treatment group in the double-blind phase of the study disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder,(INVEGASUSTENNAversusplacebo)werehyperkinesia(3.7%vs.2.9%), menstruation delayed, menstruation irregular, sexual dysfunction parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 2.4%).Respiratory, thoracic and mediastinal disorders: nasal congestion DystoniaSkinandsubcutaneoustissuedisorders:drugeruption,pruritus,pruritusSymptoms of dystonia, prolonged abnormal contractions of muscle groups, generalized, rash, urticaria may occur in susceptible individuals during the first few days of treatment. Demographic Differences Dystonic symptoms include: spasm of the neck muscles, sometimes progressing An examination of population subgroups in the double-blind placebo-controlledto tightness of the throat, swallowing difficulty, difficulty breathing, and/or trials did not reveal any evidence of differences in safety on the basis of age,protrusion of the tongue. While these symptoms can occur at low doses, they gender, or race alone; however, there were few subjects 65 years of age andoccur more frequently and with greater severity with high potency and at higher older. doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.Extrapyramidal Symptoms (EPS) Pain Assessment and Local Injection Site ReactionsPooled data from the two double-blind, placebo-controlled, 13-week, fixed- In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-dose trials in adult subjects with schizophrenia provided information regardingcontrolledtrialsinsubjectswithschizophrenia,themeanintensityof EPS. Several methods were used to measure EPS: (1) the Simpson-Angusinjection pain reported by subjects using a visual analog scale (0 = no pain to global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia100 = unbearably painful) decreased in all treatment groups from the first to the Rating Scale global clinical rating score which evaluates akathisia, (3) thelast injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-(4) use of anticholinergic medications to treat EPS (Table 7), and (5) incidence ofcontrolled trial and the double-blind phase of the maintenance trial exhibited spontaneous reports of EPS (Table 8). comparable findings.'