b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular usetreated with all atypical antipsychotics. These cases were, for the most part,Table 2: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week,seen in post-marketing clinical use and epidemiologic studies, not in clinicalFixed-Dose Studies in Subjects with Schizophrenia (continued)trials. Hyperglycemia and diabetes have been reported in trial subjects treatedINVEGASUSTENNAwith INVEGA SUSTENNA. Assessment of the relationship between atypicalPlacebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mgaantipsychotic use and glucose abnormalities is complicated by the possibility ofProportion of Patients with Shiftsan increased background risk of diabetes mellitus in patients with schizophreniaCholesterol and the increasing incidence of diabetes mellitus in the general population.Normal to High3.2% 2.0% 2.0% 2.1% 0% 3.1% 7.1%Giventheseconfounders,therelationshipbetweenatypicalantipsychotic(200 mg/dL to(7/222) (1/51) (3/147) (3/141) (0/69) (2/65) (6/84)use and hyperglycemia-related adverse events is not completely understood.240 mg/dL)However, epidemiological studies suggest an increased risk of hyperglycemia- LDLrelated adverse reactions in patients treated with the atypical antipsychotics. Normal to High 1.1% 0% 0% 0% 0% 0% 0%Patients with an established diagnosis of diabetes mellitus who are started on(100 mg/dL to(1/95) (0/29) (0/67) (0/46) (0/41) (0/37) (0/44)atypical antipsychotics should be monitored regularly for worsening of glucose160 mg/dL)control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history ofHDLdiabetes) who are starting treatment with atypical antipsychotics should undergoNormal to Low13.8% 14.8% 9.6% 14.2% 12.7% 10.5% 16.0%fasting blood glucose testing at the beginning of treatment and periodically during(40 mg/dL to(28/203) (9/61) (11/115) (15/106) (9/71) (8/76) (13/81)treatment. Any patient treated with atypical antipsychotics should be monitored40 mg/dL)for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, andTriglycerides weakness. Patients who develop symptoms of hyperglycemia during treatmentNormal to High3.6% 6.1% 9.2% 7.2% 1.3% 3.7% 10.7%with atypical antipsychotics should undergo fasting blood glucose testing. In(150 mg/dL to(8/221) (3/49) (14/153) (10/139) (1/79) (3/82) (9/84)some cases, hyperglycemia has resolved when the atypical antipsychotic was200 mg/dL)discontinued;however,somepatientsrequiredcontinuationofanti-diabeticatreatment despite discontinuation of the suspect drug. Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg Pooled data from the four placebo-controlled (one 9-week and three 13-week),every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, fixed-dose studies in subjects with schizophrenia are presented in Table 1. and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1) in Full Prescribing Information].Table 1: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, In a long-term open-label pharmacokinetic and safety study in subjects with Fixed-Dose Studies in Subjects with Schizophrenia schizophrenia in which the highest dose available (234 mg) was evaluated, the INVEGASUSTENNA mean changes from baseline in lipid values are presented in Table 3.Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga Table 3: Change in Fasting Lipids from Long-term Open-label PharmacokineticMean change from baseline (mg/dL) and Safety Study in Subjects with Schizophrenian=367 n=86 n=244 n=238 n=110 n=126 n=115 INVEGASUSTENNA 234 mgSerum Glucose Change from-1.3 1.3 3.5 0.1 3.4 1.8 -0.2 Week 29 Week 53baseline Mean change from baseline (mg/dL)Proportion of Patients with Shifts Cholesterol n=112 n=100Serum GlucoseChange from baseline -1.2 0.1Normal to High 4.6% 6.3% 6.4% 3.9% 2.5% 7.0% 6.6%(100 mg/dL to (11/241) (4/64) (11/173) (6/154) (2/79) (6/86) (5/76) LDL n=107 n=89126 mg/dL) Change from baseline -2.7 -2.3a HDL n=112 n=98Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, andChange from baseline -0.8 -2.6156 mg) are from studies involving only gluteal injection. [see Clinical StudiesTriglycerides n=112 n=100(14.1) in Full Prescribing Information]. Change from baseline 16.2 37.4In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated,The mean changes from baseline in lipid values during the initial 25-week open-INVEGASUSTENNAwasassociatedwithameanchangeinglucoseoflabel period and at the endpoint of the subsequent 15-month double-blind period -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100). in a long-term study in subjects with schizoaffective disorder are presented in During the initial 25-week open-label period of a long-term study in subjectsTable 4.with schizoaffective disorder, INVEGASUSTENNA was associated with meanTable 4: Change in Fasting Lipids from an Open-Label and Double-Blind Periods change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGASUSTENNA was associatedof a Long-Term Study in Subjects with Schizoaffective Disorderwith a mean change in glucose of +0.3 mg/dL (n=131) compared with a meanOpen-Label Period Double-Blind Periodchange of +4.0 mg/dL in the placebo group (n=120). INVEGASUSTENNA Placebo INVEGASUSTENNADyslipidemia Mean change from baseline (mg/dL)Undesirable alterations in lipids have been observed in patients treated withCholesterol n=198 n=119 n=132atypical antipsychotics.Pooled data from the four placebo-controlled (one 9-week and three 13-week),Change from-3.9 -4.2 2.3fixed-dose studies in subjects with schizophrenia are presented in Table 2. baselineTable 2: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week,LDL n=198 n=117 n=130 Fixed-Dose Studies in Subjects with Schizophrenia Change from-2.7 -2.8 5.9INVEGASUSTENNA baselinePlacebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga HDL n=198 n=119 n=131Mean change from baseline (mg/dL) Change from-2.7 -0.9 -0.7Cholesteroln=366 n=89 n=244 n=232 n=105 n=119 n=120 baselineChange from-6.6 -6.4 -5.8 -7.1 -0.9 -4.2 9.4baseline Triglycerides n=198 n=119 n=132LDL Change from7.0 2.5 -12.3Change fromn=275 n=80 n=164 n=141 n=104 n=117 n=108 baselinebaseline -6.0 -4.8 -5.6 -4.8 0.9 -2.4 5.2Weight GainHDL n=286 n=89 n=165 n=150 n=105 n=118 n=115 Weightgainhasbeenobservedwithatypicalantipsychoticuse.Clinical Change from0.7 2.1 0.6 0.3 1.5 1.1 0.0 monitoring of weight is recommended.baselineTriglycerides Data on mean changes in body weight and the proportion of subjects meeting a Change fromn=366 n=89 n=244 n=232 n=105 n=119 n=120 weight gain criterion of7% of body weight from the four placebo-controlled (one baseline -16.7 7.6 -9.0 -11.5 -14.1 -20.0 11.9 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 5.'