WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack). (5.2)Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3)QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. (5.4)Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5)Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain. (5.6)Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. (5.7)Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing INVEGA SUSTENNA(R) if clinically significant decline in WBC in the absence of other causative factors. (5.9)Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.10)Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.11)Seizures: Use cautiously in patients with history of seizures or with conditions that lower the seizure threshold. (5.12). Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack). (5.2). Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3). QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. (5.4). Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5). Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain. (5.6). Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. (5.7). Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing INVEGA SUSTENNA(R) if clinically significant decline in WBC in the absence of other causative factors. (5.9). Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.10). Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.11). Seizures: Use cautiously in patients with history of seizures or with conditions that lower the seizure threshold. (5.12). 5.1Increased Mortality in Elderly Patients with Dementia-Related Psychosis. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA SUSTENNA(R) is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].. 5.2Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis. In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA(R), or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].. 5.3Neuroleptic Malignant Syndrome. Neuroleptic Malignant Syndrome (NMS), potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.If NMS is suspected, immediately discontinue INVEGA SUSTENNA(R) and provide symptomatic treatment and monitoring.. 5.4QT Prolongation. Paliperidone causes modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with history of cardiac arrhythmias.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 the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.The effects of oral paliperidone on the QT interval were evaluated in double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.In the QT study (n=141), the mg dose of immediate-release oral paliperidone (n=50) showed mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this mg dose of paliperidone immediate release (Cmax ss 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of INVEGA SUSTENNA(R) administered in the deltoid muscle (predicted median Cmax ss 50 ng/mL). In this same study, 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day at 1.5 hours post-dose.In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had change exceeding 60 msec at one time-point on Day (increase of 62 msec).In the four fixed-dose efficacy studies of INVEGA SUSTENNA(R) in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced change in QTcLD exceeding 60 msec and no subject had QTcLD value of 500 msec at any time point. In the maintenance study in subjects with schizophrenia, no subject had QTcLD change 60 msec, and one subject had QTcLD value of 507 msec (Bazetts QT corrected interval [QTcB] value of 483 msec); this latter subject also had heart rate of 45 beats per minute.. 5.5Tardive Dyskinesia. Tardive dyskinesia, syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.Given these considerations, INVEGA SUSTENNA(R) should be prescribed in manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing satisfactory clinical response. Periodically reassess the need for continued treatment.If signs and symptoms of tardive dyskinesia appear in patient on INVEGA SUSTENNA(R), drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA(R) despite the presence of the syndrome.. 5.6Metabolic Changes. Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.. Hyperglycemia and Diabetes MellitusHyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA SUSTENNA(R). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 5.Table 5:Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with SchizophreniaINVEGA SUSTENNA(R) Placebo39 mg78 mg156 mg234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 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)]. 234/156 mg 234/234 mg Mean change from baseline (mg/dL)n=367n=86n=244n=238n=110n=126n=115Serum GlucoseChange from baseline-1.31.33.50.13.41.8-0.2Proportion of Patients with ShiftsSerum GlucoseNormal to High4.6%6.3%6.4%3.9%2.5%7.0%6.6%(<100 mg/dL to >=126 mg/dL)(11/241)(4/64)(11/173)(6/154)(2/79)(6/86)(5/76)In long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA(R) was associated with mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).During the initial 25-week open-label period of long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA(R) was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA(R) was associated with mean change in glucose of +0.3 mg/dL (n=131) compared with mean change of +4.0 mg/dL in the placebo group (n=120).. DyslipidemiaUndesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 6.Table 6:Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with SchizophreniaINVEGA SUSTENNA(R) Placebo39 mg78 mg156 mg234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 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)]. 234/156 mg 234/234 mg Mean change from baseline (mg/dL)Cholesteroln=366n=89n=244n=232n=105n=119n=120Change from baseline-6.6-6.4-5.8-7.1-0.9-4.29.4LDL n=275n=80n=164n=141n=104n=117n=108 Change from baseline-6.0-4.8-5.6-4.80.9-2.45.2HDLn=286n=89n=165n=150n=105n=118n=115Change from baseline0.72.10.60.31.51.10.0Triglycerides n=366n=89n=244n=232n=105n=119n=120Change from baseline-16.77.6-9.0-11.5-14.1-20.011.9Proportion of Patients with ShiftsCholesterolNormal to High3.2%2.0%2.0%2.1%0%3.1%7.1%(<200 mg/dL to >=240 mg/dL)(7/222)(1/51)(3/147)(3/141)(0/69)(2/65)(6/84)LDLNormal to High1.1%0%0%0%0%0%0%(<100 mg/dL to >=160 mg/dL)(1/95)(0/29)(0/67)(0/46)(0/41)(0/37)(0/44)HDLNormal to Low13.8%14.8%9.6%14.2%12.7%10.5%16.0%(>=40 mg/dL to <40 mg/dL)(28/203)(9/61)(11/115)(15/106)(9/71)(8/76)(13/81)TriglyceridesNormal to High3.6%6.1%9.2%7.2%1.3%3.7%10.7%(<150 mg/dL to >=200 mg/dL)(8/221)(3/49)(14/153)(10/139)(1/79)(3/82)(9/84)In 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 are presented in Table 7.Table 7:Change in Fasting Lipids from Long-term Open-label Pharmacokinetic and Safety Study in Subjects with SchizophreniaINVEGA SUSTENNA(R) 234 mgWeek 29Week 53Mean change from baseline (mg/dL)Cholesterol n=112n=100 Change from baseline-1.20.1LDL n=107n=89 Change from baseline-2.7-2.3HDLn=112n=98 Change from baseline-0.8-2.6Triglycerides n=112n=100 Change from baseline16.237.4The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in long-term study in subjects with schizoaffective disorder are presented in Table 8.Table 8:Change in Fasting Lipids from an Open-Label and Double-Blind Periods of Long-Term Study in Subjects with Schizoaffective DisorderOpen-Label PeriodDouble-Blind PeriodINVEGA SUSTENNA(R) PlaceboINVEGA SUSTENNA(R) Mean change from baseline (mg/dL)Cholesteroln=198n=119n=132Change from baseline-3.9-4.22.3LDL n=198n=117n=130Change from baseline-2.7-2.85.9HDLn=198n=119n=131Change from baseline-2.7-0.9-0.7Triglycerides n=198n=119n=132Change from baseline7.02.5-12.3. Weight GainWeight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.Data on mean changes in body weight and the proportion of subjects meeting weight gain criterion of >= 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 9.Table 9:Mean Change in Body Weight (kg) and the Proportion of Subjects with >= 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with SchizophreniaINVEGA SUSTENNA(R) Placebo39 mg78 mg156 mg234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 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)]. 234/156 mg 234/234 mg n=451n=116n=280n=267n=137n=144n=145Weight (kg) Change from baseline-0.40.40.81.40.40.71.4Weight Gain >= 7% increase from baseline3.3%6.0%8.9%9.0%5.8%8.3%13.1%In long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA(R) was associated with mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).During the initial 25-week open-label period of long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA(R) was associated with mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of >= 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA(R) was associated with mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of >= 7% (n=161); the placebo group had mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of >= 7% (n=168).. 5.7Orthostatic Hypotension and Syncope. Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. Syncope was reported in 1% (4/1293) of subjects treated with INVEGA SUSTENNA(R) in the recommended dose range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by 1% (2/1293) of INVEGA SUSTENNA(R)-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.INVEGA SUSTENNA(R) should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.. 5.8 Falls. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA(R), which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.. 5.9Leukopenia, Neutropenia, and Agranulocytosis. In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA SUSTENNA(R). Agranulocytosis has also been reported.Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with history of clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA SUSTENNA(R) at the first sign of clinically significant decline in WBC in the absence of other causative factors.Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA SUSTENNA(R) in patients with severe neutropenia (absolute neutrophil count 1000/mm3) and follow their WBC until recovery.. 5.10 Hyperprolactinemia. Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has prolactin-elevating effect similar to that seen with risperidone, drug that is associated with higher levels of prolactin than other antipsychotic drugs.Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, factor of potential importance if the prescription of these drugs is considered in patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.Prolactin data from two long-term, double-blind, placebo-controlled studies with INVEGA SUSTENNA(R) are presented below; one study was in population of patients with schizophrenia; the second study was in patients with schizoaffective disorder. Schizophrenia In long-term maintenance trial of INVEGA SUSTENNA(R) in schizophrenia patients (Study PSY-3001), see Clinical Studies (14.1), elevations of prolactin to above the reference range (> 18 ng/mL in males and 30 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in higher percentage of the patients in the INVEGA SUSTENNA(R) group than those in the placebo group in males (51.9% vs. 29.0%) and in females (50.5% vs. 42.9%). During the double-blind phase, females (4.2%) in the INVEGA SUSTENNA(R) group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the INVEGA SUSTENNA(R) group experienced erectile dysfunction and male (0.9%) in placebo group experienced gynecomastia. Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with rate greater than 2%. Schizoaffective Disorder In long-term maintenance trial of INVEGA SUSTENNA(R) in patients with schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations of prolactin to above the reference range (> 13.13 ng/mL in males and 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in higher percentage of patients in the INVEGA SUSTENNA(R) group than those in the placebo group in males (55.6% vs. 23.2%) and in females (44.3% vs. 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the INVEGA SUSTENNA(R) group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while females (5.8%) in the placebo group had potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the INVEGA SUSTENNA(R) group experienced potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased. Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% vs. 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with rate greater than 2%. 5.11 Potential for Cognitive and Motor Impairment. Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA(R) [see Adverse Reactions (6.1)]. Antipsychotics, including INVEGA SUSTENNA(R), have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.. 5.12 Seizures. In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with INVEGA SUSTENNA(R) in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.Like other antipsychotic drugs, INVEGA SUSTENNA(R) should be used cautiously in patients with history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.. 5.13 Dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA SUSTENNA(R) and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.. 5.14 Priapism. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA SUSTENNA(R), priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.. 5.15 Disruption of Body Temperature Regulation. Disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA SUSTENNA(R) to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following are discussed in more detail in other sections of the labeling:Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)] QT prolongation [see Warnings and Precautions (5.4)] Tardive dyskinesia [see Warnings and Precautions (5.5)] Metabolic changes [see Warnings and Precautions (5.6)] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7)] Falls [see Warnings and Precautions (5.8)] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)] Hyperprolactinemia [see Warnings and Precautions (5.10)] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)] Seizures [see Warnings and Precautions (5.12)] Dysphagia [see Warnings and Precautions (5.13)] Priapism [see Warnings and Precautions (5.14)] Disruption of body temperature regulation [see Warnings and Precautions (5.15)] Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)] QT prolongation [see Warnings and Precautions (5.4)] Tardive dyskinesia [see Warnings and Precautions (5.5)] Metabolic changes [see Warnings and Precautions (5.6)] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7)] Falls [see Warnings and Precautions (5.8)] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)] Hyperprolactinemia [see Warnings and Precautions (5.10)] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)] Seizures [see Warnings and Precautions (5.12)] Dysphagia [see Warnings and Precautions (5.13)] Priapism [see Warnings and Precautions (5.14)] Disruption of body temperature regulation [see Warnings and Precautions (5.15)] The most common adverse reactions (incidence >= 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. (6)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Patient ExposureThe data described in this section are derived from clinical trial database consisting of total of 3817 subjects (approximately 1705 patient-years exposure) with schizophrenia who received at least one dose of INVEGA SUSTENNA(R) in the recommended dose range of 39 mg to 234 mg and total of 510 subjects with schizophrenia who received placebo. Among the 3817 INVEGA SUSTENNA(R)-treated subjects, 1293 received INVEGA SUSTENNA(R) in four fixed-dose, double-blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received INVEGA SUSTENNA(R) in the maintenance trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive INVEGA SUSTENNA(R) during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1675 received INVEGA SUSTENNA(R) in five non-placebo controlled trials (three noninferiority active-comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoid-gluteal] cross-over trial). One of the 13-week studies included 234 mg INVEGA SUSTENNA(R) initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every weeks.The safety of INVEGA SUSTENNA(R) was also evaluated in 15-month, long-term study comparing INVEGA SUSTENNA(R) to selected oral antipsychotic therapies in adult subjects with schizophrenia. total of 226 subjects received INVEGA SUSTENNA(R) during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of INVEGA SUSTENNA(R) was similar to that seen in previous double-blind, placebo-controlled clinical trials in adult subjects with schizophrenia.The safety of INVEGA SUSTENNA(R) was also evaluated in long-term study in adult subjects with schizoaffective disorder. total of 667 subjects received INVEGA SUSTENNA(R) during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive INVEGA SUSTENNA(R) during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the INVEGA SUSTENNA(R) than the placebo group (a 2% difference or more between groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.. Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials. Commonly Observed Adverse Reactions: The most common (at least 5% in any INVEGA SUSTENNA(R) group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.. Discontinuation of Treatment Due to Adverse Events: The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for INVEGA SUSTENNA(R)- and placebo-treated subjects.The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% in INVEGA SUSTENNA(R)- and placebo-treated subjects, respectively.. Dose-Related Adverse Reactions: Based on the pooled data from the four fixed-dose, double-blind, placebo-controlled trials in subjects with schizophrenia, among the adverse reactions that occurred with >= 2% incidence in the subjects treated with INVEGA SUSTENNA(R), only akathisia increased with dose. Hyperprolactinemia also exhibited dose relationship, but did not occur at >= 2% incidence in INVEGA SUSTENNA(R)-treated subjects from the four fixed-dose studies.. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA SUSTENNA(R)-Treated Patients: Table 10 lists the adverse reactions reported in 2% or more of INVEGA SUSTENNA(R)-treated subjects and at greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.Table 10: Incidences of Adverse Reactions 2% or More of INVEGA SUSTENNA(R)-Treated Patients (and Greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled TrialsINVEGA SUSTENNA(R) System Organ ClassPlaceboPlacebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design. 39 mg78 mg156 mg234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 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)] 234/156 mg 234/234 mg Adverse Reactions(N=510)(N=130)(N=302)(N=312)(N=160)(N=165)(N=163)Percentages are rounded to whole numbers. Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA SUSTENNA(R) dose groups and which occurred at greater incidence than in the placebo group.Total percentage of subjects with adverse reactions70756869636063Gastrointestinal disorders Abdominal discomfort/abdominal pain upper2244124 Diarrhea2032122 Dry mouth1310111 Nausea3443222 Toothache1113123 Vomiting4542322General disorders and administration site conditions Asthenia021<1011 Fatigue1122121 Injection site reactions20469710Infections and infestations Nasopharyngitis2022422 Upper respiratory tract infection2222124 Urinary tract infection101<1112Investigations Weight increased1441112Musculoskeletal and connective tissue disorders Back pain2213111 Musculoskeletal stiffness11<1<1112 Myalgia121<1102 Pain in extremity1022230Nervous system disorders Akathisia3223156 Dizziness1624142 Extrapyramidal disorder1523100 Headache121111151176 Somnolence/sedation3574155Psychiatric disorders Agitation71059854 Anxiety7853566 Nightmare<1200000Respiratory, thoracic and mediastinal disorders Cough1231011Vascular disorders Hypertension1211110. Adverse reactions for which the INVEGA SUSTENNA(R) incidence was equal to or less than placebo are not listed in the table, but included the following: dyspepsia, psychotic disorder, schizophrenia, and tremor. The following terms were combined: somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse reactions were collapsed and are grouped under Injection site reactions.Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA SUSTENNA(R) The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardiaEar and labyrinth disorders: vertigoEye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurredGastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretionImmune system disorders: hypersensitivityInvestigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormalMetabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetiteMusculoskeletal and connective tissue disorders: arthralgia, joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidityNervous system disorders: bradykinesia, cerebrovascular accident, cogwheel rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncopePsychiatric disorders: insomnia, libido decreased, restlessnessReproductive system and breast disorders: amenorrhea, breast discharge, breast enlargement/breast swelling, breast tenderness/breast pain, ejaculation disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunctionRespiratory, thoracic and mediastinal disorders: nasal congestionSkin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria. Demographic DifferencesAn examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.. Extrapyramidal Symptoms (EPS)Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in adult subjects with schizophrenia provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 11), and (5) incidence of spontaneous reports of EPS (Table 12).Table 11: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication Schizophrenia Studies in AdultsPercentage of SubjectsINVEGA SUSTENNA(R) ScalePlacebo(N=262)39 mg(N=130)78 mg(N=223)156 mg(N=228)ParkinsonismFor parkinsonism, percent of subjects with Simpson-Angus Total score 0.3 at endpoint (Total score defined as total sum of texts score divided by the number of texts) 912106AkathisiaFor Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score >= at endpoint 5565DyskinesiaFor Dyskinesia, percent of subjects with score >= on any of the first texts or score >= on two or more of any of the first texts of the Abnormal Involuntary Movement Scale at endpoint 3464Use of Anticholinergic MedicationsPercent of subjects who received anticholinergic medications to treat EPS 12101211Table 12: Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Schizophrenia Studies in AdultsPercentage of SubjectsINVEGA SUSTENNA(R) EPS GroupPlacebo(N=262)39 mg(N=130)78 mg(N=223)156 mg(N=228)Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesiaHyperkinesia group includes: Akathisia, restless legs syndrome, restlessnessDyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesiaDystonia group includes: Dystonia, muscle spasmsOverall percentage of subjects with EPS-related adverse events10121111Parkinsonism5664Hyperkinesia2224Tremor3223Dyskinesia1231Dystonia0112The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of parkinsonism and akathisia assessed by incidence of rating scales were higher in the INVEGA SUSTENNA(R) 156 mg group (18% and 11%, respectively) than in the INVEGA SUSTENNA(R) 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).In the 13-week study in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS was similar to that of the placebo group (8%), but exhibited dose-related pattern with 6%, 10%, and 11% in the INVEGA SUSTENNA(R) 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at similar rate between the placebo (4.9%) and INVEGA SUSTENNA(R) 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at lower rate in the 234/39 mg group (1.3%).In the long-term study in subjects with schizoaffective disorder, EPS reported during the 25-week open-label INVEGA SUSTENNA(R) treatment included hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events (> 2%) in any treatment group in the double-blind phase of the study (INVEGA SUSTENNA(R) versus placebo) were hyperkinesia (3.7% vs. 2.9%), parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 2.4%).. DystoniaSymptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.. Pain Assessment and Local Injection Site ReactionsIn the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials in subjects with schizophrenia, the mean intensity of injection pain reported by subjects using visual analog scale (0 no pain to 100 unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.In the 13-week study involving 234 mg initiation dosing in subjects with schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the INVEGA SUSTENNA(R) and placebo groups. Investigator ratings of injection pain were similar for the placebo and INVEGA SUSTENNA(R) groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the INVEGA SUSTENNA(R) and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the INVEGA SUSTENNA(R) and placebo groups.. Additional Adverse Reactions Reported in Clinical Trials with Oral PaliperidoneThe following is list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:Cardiac disorders: bundle branch block left, sinus arrhythmiaGastrointestinal disorders: abdominal pain, small intestinal obstructionGeneral disorders and administration site conditions: edema, edema peripheralImmune system disorders: anaphylactic reactionInfections and infestations: rhinitisMusculoskeletal and connective tissue disorders: musculoskeletal pain, torticollis, trismusNervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attackPsychiatric disorders: sleep disorderReproductive system and breast disorders: breast engorgementRespiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, pneumonia aspirationSkin and subcutaneous tissue disorders: rash papularVascular disorders: hypotension, ischemia. 6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.Cases of anaphylactic reaction after injection with INVEGA SUSTENNA(R) have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) sections of the package inserts for those products.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, the drugs therapeutic effect in schizophrenia could be mediated through combination of central dopamine Type (D2) and serotonin Type (5HT2A) receptor antagonism.. 12.2 Pharmacodynamics. In vitro, paliperidone acts as an antagonist at the central dopamine Type (D2) and serotonin Type (5HT2A) receptors with binding affinities (Ki values) of 1.6-2.8 nM for D2 and 0.8-1.2 nM for 5HT2A receptors. Paliperidone is also active as an antagonist at the and adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or 1- and 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro. 12.3 Pharmacokinetics. Absorption and DistributionDue to its extremely low water solubility, the 1-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at median Tmax of 13 days. The release of the drug starts as early as day and lasts for as long as 126 days.Following intramuscular injection of single doses (39 mg 234 mg) in the deltoid muscle, on average, 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day and 156 mg on day help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA SUSTENNA(R) results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA SUSTENNA(R) administration was dose-proportional over 39 mg-234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an INVEGA SUSTENNA(R) dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6-1.8.Based on population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.. Metabolism and EliminationIn study with oral immediate-release 14C-paliperidone, one week following administration of single oral dose of mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.The median apparent half-life of paliperidone following INVEGA SUSTENNA(R) single-dose administration over the dose range of 39 mg 234 mg ranged from 25 days 49 days.. Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release PaliperidoneINVEGA SUSTENNA(R) is designed to deliver paliperidone over monthly period while extended-release oral paliperidone is administered on daily basis. The initiation regimen for INVEGA SUSTENNA(R) (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.In general, overall initiation plasma levels with INVEGA SUSTENNA(R) were within the exposure range observed with 6-12 mg extended-release oral paliperidone. The use of the INVEGA SUSTENNA(R) initiation regimen allowed patients to stay in this exposure window of 6-12 mg extended-release oral paliperidone even on trough pre-dose days (Day and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from INVEGA SUSTENNA(R) was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making direct comparison of their pharmacokinetic properties.. Drug Interaction StudiesNo specific drug interaction studies have been performed with INVEGA SUSTENNA(R). The information below is obtained from studies with oral paliperidone.Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean Cmax and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to substantial degree, by 35% increase in renal clearance of paliperidone.Figure 1: The effects of other drugs on paliperidone pharmacokinetics.Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA(R) and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone.After oral administration of paliperidone, the steady-state Cmax and AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended-release tablets. In clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)].In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only small fraction of total body clearance. In vitro studies demonstrated that paliperidone is substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.Paliperidone is weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.. Figure 1. Studies in Specific PopulationsNo specific pharmacokinetic studies have been performed with INVEGA SUSTENNA(R) in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA SUSTENNA(R). Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].After oral administration of paliperidone in elderly subjects, the Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].Figure 2: Effects of intrinsic factors on paliperidone pharmacokinetics.Based on in vitro studies utilizing human liver enzymes, paliperidone is not substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.Slower absorption was observed in females in population pharmacokinetic analysis. At apparent steady-state with INVEGA SUSTENNA(R), the trough concentrations were similar between males and females.Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with INVEGA SUSTENNA(R), the trough concentrations were similar among normal, overweight, and obese subjects.. Figure 2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Schizophrenia. Short-Term Monotherapy (Studies 1, 2, 3, 4)The efficacy of INVEGA SUSTENNA(R) in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of INVEGA SUSTENNA(R) in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies, i.e., at weekly interval for the initial two doses and then every weeks for maintenance.Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is 30-text scale that measures positive symptoms of schizophrenia (7 texts), negative symptoms of schizophrenia (7 texts), and general psychopathology (16 texts), each rated on scale of (absent) to (extreme); total PANSS scores range from 30 to 210.In Study (PSY-3007), 13-week study (n=636) comparing three fixed doses of INVEGA SUSTENNA(R) (initial deltoid injection of 234 mg followed by gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA(R) were superior to placebo in improving the PANSS total score.In Study (PSY-3003), another 13-week study (n=349) comparing three fixed doses of INVEGA SUSTENNA(R) (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of INVEGA SUSTENNA(R) was superior to placebo in improving the PANSS total score.In Study (PSY-3004), third 13-week study (n=513) comparing three fixed doses of INVEGA SUSTENNA(R) (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA(R) were superior to placebo in improving the PANSS total score.In Study (SCH-201), the 9-week study (n=197) comparing two fixed doses of INVEGA SUSTENNA(R) (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of INVEGA SUSTENNA(R) were superior to placebo in improving PANSS total score.A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 14.Table 14: Schizophrenia Short-term StudiesStudy NumberTreatment GroupPrimary Efficacy Measure: PANSS Total ScoreMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted DifferenceDifference (drug minus placebo) in least-squares mean change from baseline. (95% CI)SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.Study 1INVEGA SUSTENNA(R) (39 mg/4 weeks)p<0.05 (Doses statistically significantly superior to placebo). 86.9 (11.99)-11.2 (1.69)-5.1 (-9.01, -1.10)INVEGA SUSTENNA(R) (156 mg/4 weeks) 86.2 (10.77)-14.8 (1.68)-8.7 (-12.62, -4.78)INVEGA SUSTENNA(R) (234 mg/4 weeks) 88.4 (11.70)-15.9 (1.70)-9.8 (-13.71, -5.85)Placebo86.8 (10.31)-6.1 (1.69)--Study 2Because an insufficient number of subjects received the 234 mg/4 weeks dose, results from this group are not included.INVEGA SUSTENNA(R) (78 mg/4 weeks)89.9 (10.78)-6.9 (2.50)-3.5 (-8.73, 1.77)INVEGA SUSTENNA(R) (156 mg/4 weeks) 90.1 (11.66)-10.4 (2.47)-6.9 (-12.12, -1.68)Placebo92.4 (12.55)-3.5 (2.15)--Study 3INVEGA SUSTENNA(R) (39 mg/4 weeks) 90.7 (12.25)-19.8 (2.19)-6.6 (-11.40, -1.73)INVEGA SUSTENNA(R) (78 mg/4 weeks) 91.2 (12.02)-19.2 (2.19)-5.9 (-10.76, -1.07)INVEGA SUSTENNA(R) (156 mg/4 weeks) 90.8 (11.70)-22.5 (2.18)-9.2 (-14.07, -4.43)Placebo90.7 (12.22)-13.3 (2.21)--Study 4INVEGA SUSTENNA(R) (78 mg/4 weeks) 88.0 (12.39)-4.6 (2.43)-11.2 (-16.85, -5.57)INVEGA SUSTENNA(R) (156 mg/4 weeks) 85.2 (11.09)-7.4 (2.45)-14.0 (-19.51, -8.58)Placebo87.8 (13.90)6.6 (2.45)--. Maintenance Monotherapy Treatment (Study 5: PSY-3001)The efficacy of INVEGA SUSTENNA(R) in maintaining symptomatic control in schizophrenia was established in longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included minimum 12-week, fixed-dose stabilization phase, and randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of INVEGA SUSTENNA(R) they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every weeks, or to placebo. total of 410 stabilized patients were randomized to either INVEGA SUSTENNA(R) or to placebo until they experienced relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, >= 25% increase (if the baseline score was 40) or 10-point increase (if the baseline score was <= 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or score of >= (if the maximum baseline score was <= 3) or >= (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS texts. The primary efficacy variable was time to relapse. pre-planned interim analysis showed statistically significantly longer time to relapse in patients treated with INVEGA SUSTENNA(R) compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the INVEGA SUSTENNA(R) group experienced relapse event. There was statistically significant difference between the treatment groups in favor of INVEGA SUSTENNA(R). Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 3. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the INVEGA SUSTENNA(R) group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.Figure 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5). Figure 3. Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic Therapy (Study 6: SCH-3006)The efficacy of INVEGA SUSTENNA(R) in delaying time to treatment failure compared with selected oral antipsychotic medications was established in long-term, randomized, flexible-dose study in subjects with schizophrenia and history of incarceration. Subjects were screened for up to 14 days followed by 15-month treatment phase during which they were observed for treatment failure.The primary endpoint was time to first treatment failure. Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide. Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment. total of 444 subjects were randomly assigned to either INVEGA SUSTENNA(R) (N 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N 218; aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone). The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator. statistically significantly longer time to first treatment failure was seen for INVEGA SUSTENNA(R) compared with oral antipsychotic medications. The median time to treatment failure was 416 days and 226 days for INVEGA SUSTENNA(R) and antipsychotic medications, respectively. Kaplan-Meier plot of time to first treatment failure is shown in Figure 4. The frequencies of first treatment failure events by type are shown in Table 15. The time to first arrest and/or incarceration or psychiatric hospitalization was also statistically significantly longer for the INVEGA SUSTENNA(R) group compared to the oral antipsychotic group.Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and History of Incarceration (Schizophrenia Study 6) Median time to first treatment failure: 416 days with INVEGA SUSTENNA(R); 226 days with oral antipsychoticsTable 15: Components of Composite Endpoint in Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and History of Incarceration (Schizophrenia Study 6)Event TypeINVEGA SUSTENNA(R) N=226frequency (%)Oral AntipsychoticsN=218frequency (%)Hazard RatioHazard ratio of INVEGA SUSTENNA(R) to Oral Antipsychotics based on Cox regression model for time-to-event analysis. Note that the hazard ratio did not appear constant throughout the trial. [95% CI]First Treatment Failures90 (39.8%)117 (53.7%)0.70 [0.53, 0.92]First Treatment Failure Component EventsArrest and/or incarceration48 (21.2%)64 (29.4%)Psychiatric hospitalization18 (8.0%)26 (11.9%)Discontinuation of antipsychotic treatment because of safety or tolerability15 (6.6%)8 (3.7%)Treatment supplementation with another antipsychotic because of inadequate efficacy5 (2.2%)6 (2.8%)Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization3 (1.3%)4 (1.8%)Discontinuation of antipsychotic treatment because of inadequate efficacy1 (0.4%)9 (4.1%)Suicide00Arrest and/or Incarceration or Psychiatric Hospitalization Events, regardless of whether they were first eventsAnalysis results, which incorporated relevant events collected after discontinuation for those who discontinued, were consistent with the results from the pre-specified analysis of this secondary endpoint.76 (33.6%)98 (45.0%)0.70[0.52, 0.94]. Arrest and/or incarceration. Psychiatric hospitalization. Discontinuation of antipsychotic treatment because of safety or tolerability. Treatment supplementation with another antipsychotic because of inadequate efficacy. Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization. Discontinuation of antipsychotic treatment because of inadequate efficacy. Suicide. Figure 4. 14.2 Schizoaffective Disorder. Maintenance Treatment Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004)The efficacy of INVEGA SUSTENNA(R) in maintaining symptom control in schizoaffective disorder was established in long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received INVEGA SUSTENNA(R) either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers.This study included 13-week, open-label, flexible-dose (INVEGA SUSTENNA(R) 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score >=4 on >=3 PANSS texts of delusions, conceptual disorganization, hallucinatory behavior, exctextent, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms >=16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-text version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years) and 53.5% were male. The mean scores at open-label enrollment of PANSS total was 85.8 (range 42 to 128), HAM-D-21 was 20.4 (range to 43), YMRS was 18.6 (range to 50), and CGI-S-SCA was 4.4 (range to 6).After the 13-week open-label flexible-dose INVEGA SUSTENNA(R) treatment, 432 subjects met stabilization criteria (PANSS total score <=70, YMRS <=12, and HAM-D-21 <=12) and continued into the 12-week open-label fixed-dose stabilization period.A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of INVEGA SUSTENNA(R) or to placebo in the 15-month, double-blind, maintenance period. For the 164 subjects who were randomized to INVEGA SUSTENNA(R), dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to relapse. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) score of >=6 (if the score was <=4 at randomization) of any of the individual PANSS texts: delusions, conceptual disorganization, hallucinatory behavior, exctextent, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within days: >=25% increase (if the score at randomization was >45) or >=10-point increase (if the score at randomization was <=45) in total PANSS score; score of >=5 (if the score was <=3 at randomization) of any of the individual PANSS texts: delusions, conceptual disorganization, hallucinatory behavior, exctextent, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of >=2 points (if the score was [not ill] to [mildly ill] at randomization) or increase of >=1 point (if the score was >=4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score.There was statistically significant difference in time to relapse between the treatment groups in favor of INVEGA SUSTENNA(R). Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 5.Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1)Table 16 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy vs. adjunctive therapy), and by symptom type at the first occurrence of relapse.Table 16: Summary of Relapse Rates (SAff Study 1).Number (Percent) of Subjects Who RelapsedPlaceboN=170INVEGA SUSTENNA(R) N=164All Subjects57 (33.5%)25 (15.2%) Monotherapy subsetN=7324 (32.9%)N=789 (11.5%) Adjunct to Antidepressants or Mood Stabilizer subsetN=9733 (34.0%)N=8616 (18.6%)Psychotic Symptoms8 subjects experienced relapse without psychotic symptoms.53 (31.2%)21 (12.8%)Mood Symptoms16 subjects experienced relapse without any mood symptoms. Any Mood Symptoms48 (28.2%)18 (11.0%) Manic16 (9.4%)5 (3.0%) Depressive23 (13.5%)8 (4.9%) Mixed9 (5.3%)5 (3.0%). Figure 4.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intramuscular injection only. (2.1)Each injection must be administered only by healthcare professional. (2.1)For deltoid injection, use 1-inch 23G needle for patients weighing less than 90 kg or 1/2 -inch 22G needle for patients weighing 90 kg or more. For gluteal injection, use 1/2 -inch 22G needle regardless of patient weight. (2.1)IndicationInitiation Dosing(deltoid)Monthly Maintenance DoseAdministered weeks after the first injection. (deltoid or gluteal)Maximum Monthly DoseDay 1Day 8Schizophrenia (2.2)234 mg156 mg39-234 mgThe recommended maintenance dose for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 234 mgSchizoaffective disorder (2.2)234 mg156 mg78-234 mgAdjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not studied in the long-term schizoaffective disorder study. 234 mgFor patients naive to oral paliperidone or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA(R). (2.2)Missed Doses: To manage either missed second initiation dose or missed monthly maintenance dose, refer to the Full Prescribing Information. (2.3)Moderate to severe renal impairment (creatinine clearance 50 mL/min): INVEGA SUSTENNA(R) is not recommended. (2.5)Mild renal impairment (creatinine clearance >= 50 mL/min to 80 mL/min): Administer 156 mg on treatment day and 117 mg one week later, both administered in the deltoid muscle. Follow with monthly injections of 78 mg in either the deltoid or gluteal muscle. (2.5). For intramuscular injection only. (2.1). Each injection must be administered only by healthcare professional. (2.1). For deltoid injection, use 1-inch 23G needle for patients weighing less than 90 kg or 1/2 -inch 22G needle for patients weighing 90 kg or more. For gluteal injection, use 1/2 -inch 22G needle regardless of patient weight. (2.1). For patients naive to oral paliperidone or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA(R). (2.2). Missed Doses: To manage either missed second initiation dose or missed monthly maintenance dose, refer to the Full Prescribing Information. (2.3). Moderate to severe renal impairment (creatinine clearance 50 mL/min): INVEGA SUSTENNA(R) is not recommended. (2.5). Mild renal impairment (creatinine clearance >= 50 mL/min to 80 mL/min): Administer 156 mg on treatment day and 117 mg one week later, both administered in the deltoid muscle. Follow with monthly injections of 78 mg in either the deltoid or gluteal muscle. (2.5). 2.1Administration Instructions. Each injection must be administered only by healthcare professional.Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration, whenever product and container permit.INVEGA SUSTENNA(R) is intended for intramuscular use only. Do not administer by any other route. Avoid inadvertent injection into blood vessel. Administer the dose in single injection; do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal muscle.INVEGA SUSTENNA(R) must be administered using only the needles that are provided in the INVEGA SUSTENNA(R) kit.The recommended needle size for administration of INVEGA SUSTENNA(R) into the deltoid muscle is determined by the patients weight:For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.For patients weighing 90 kg or more, the 1/2 -inch, 22 gauge needle is recommended.Deltoid injections should be alternated between the two deltoid muscles.The recommended needle size for administration of INVEGA SUSTENNA(R) into the gluteal muscle is the 1/2 -inch, 22 gauge needle regardless of patient weight.Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.. For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.. For patients weighing 90 kg or more, the 1/2 -inch, 22 gauge needle is recommended.. 2.2Schizophrenia and Schizoaffective Disorder. For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA(R).The recommended dosing of INVEGA SUSTENNA(R) for each approved indication is displayed in Table 1. The recommended initiation of INVEGA SUSTENNA(R) is with dose of 234 mg on treatment day and 156 mg one week later, both administered in the deltoid muscle. Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.Table 1:Recommended Dosing of INVEGA SUSTENNA(R) for Adults with Schizophrenia or Schizoaffective DisorderIndicationInitiation Dosing(deltoid)Monthly Maintenance DoseAdministered weeks after the first injection. (deltoid or gluteal)Maximum Monthly DoseDay 1Day 8Schizophrenia234 mg156 mg39-234 mgThe recommended maintenance dose for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 234 mgSchizoaffective disorder234 mg156 mg78-234 mgAdjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not studied in the long-term schizoaffective disorder study. 234 mgAdjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of INVEGA SUSTENNA(R) should be considered [see Clinical Pharmacology (12.3)], as the full effect of the dose adjustment may not be evident for several months.. 2.3Missed Doses. Avoiding Missed DosesIt is recommended that the second initiation dose of INVEGA SUSTENNA(R) be given one week after the first dose. To avoid missed dose, patients may be given the second dose days before or after the one-week time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid missed monthly dose, patients may be given the injection up to days before or after the monthly time point.. Management of Missed Second Initiation DoseIf the target date for the second INVEGA SUSTENNA(R) injection (one week +- days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patients first injection. In case of missed second initiation dose follow the dosing instructions provided in Table 2.Table 2:Management of Missed Second Initiation DoseTIMING OF MISSED SECOND INITIATION DOSEDOSINGLess than weeks since first injectionAdminister the second initiation dose of 156 mg in the deltoid muscle as soon as possible.It is recommended to administer third injection of 117 mg in either the deltoid or gluteal muscle weeks after the first injection (regardless of the timing of the second injection).Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.4 to weeks since first injectionResume dosing with two injections of 156 mg in the following manner:Administer deltoid injection as soon as possible.Administer second deltoid injection week later.Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.More than weeks since first injectionRestart dosing with recommended initiation (see Section 2.2, Table 1): Administer 234 mg deltoid injection on Day 1.Administer 156 mg deltoid injection week later.Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.. It is recommended to administer third injection of 117 mg in either the deltoid or gluteal muscle weeks after the first injection (regardless of the timing of the second injection).. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.. Administer deltoid injection as soon as possible.. Administer second deltoid injection week later.. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.. Administer 234 mg deltoid injection on Day 1.. Administer 156 mg deltoid injection week later.. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.. Management of Missed Maintenance DoseIn case of missed maintenance dose follow the dosing instructions provided in Table 3.Table 3:Management of Missed Maintenance DoseTIMING OF MISSED MAINTENANCE DOSEDOSING4 to weeks since last injectionResume regular monthly dosing as soon as possible at the patients previously stabilized dose, followed by injections at monthly intervals.More than weeks to months since last injectionResume the same dose the patient was previously stabilized on (unless the patient was stabilized on dose of 234 mg, then the first injections should each be 156 mg) in the following manner:Administer deltoid injection as soon as possible.Administer second deltoid injection week later at the same dose.Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle month after the second injection.More than months since last injectionRestart dosing with recommended initiation (see Section 2.2, Table ): Administer 234 mg deltoid injection on Day 1.Administer 156 mg deltoid injection week later.Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle month after the second injection. Administer deltoid injection as soon as possible.. Administer second deltoid injection week later at the same dose.. Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle month after the second injection.. Administer 234 mg deltoid injection on Day 1.. Administer 156 mg deltoid injection week later.. Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle month after the second injection.. 2.4Use with Risperidone or with Oral Paliperidone. Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA SUSTENNA(R) is coadministered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA SUSTENNA(R) with other antipsychotics is limited.. 2.5Dosage Adjustments. Renal ImpairmentINVEGA SUSTENNA(R) has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)]. For patients with mild renal impairment (creatinine clearance >= 50 mL/min to 80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA(R) with dose of 156 mg on treatment day and 117 mg one week later. Administer both doses in the deltoid muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].INVEGA SUSTENNA(R) is not recommended in patients with moderate or severe renal impairment (creatinine clearance 50 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers Avoid using strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St Johns Wort) during the 1-month dosing interval for INVEGA SUSTENNA(R), if possible. If administering strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 2.6Switching from Other Antipsychotics. There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to INVEGA SUSTENNA(R), or concerning concomitant administration with other antipsychotics.. Switching from Oral AntipsychoticsFor patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA(R).Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with INVEGA SUSTENNA(R). Recommended initiation of INVEGA SUSTENNA(R) is with dose of 234 mg on treatment day and 156 mg one week later, both administered in the deltoid muscle [see Dosage and Administration (2.2)]. Patients previously stabilized on different doses of INVEGA(R) Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with INVEGA SUSTENNA(R) monthly doses as depicted in Table 4.Table 4:Doses of INVEGA(R) and INVEGA SUSTENNA(R) Needed to Attain Similar Steady-State Paliperidone Exposure During Maintenance TreatmentFormulationINVEGA(R) Extended-Release TabletINVEGA SUSTENNA(R) InjectionDosing FrequencyOnce DailyOnce every weeksDose (mg)1223491566117339-78. Switching from Long-Acting Injectable AntipsychoticsFor patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA(R).When switching patients currently at steady-state on long-acting injectable antipsychotic, initiate INVEGA SUSTENNA(R) therapy in place of the next scheduled injection. INVEGA SUSTENNA(R) should then be continued at monthly intervals. The one-week initiation dosing regimen as described in Section 2.2 is not required. See Table above for recommended monthly maintenance dosing. Based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg). The 39 mg strength was not studied in the long-term schizoaffective disorder study. Monthly maintenance doses can be administered in either the deltoid or gluteal muscle [see Dosage and Administration (2.2)].If INVEGA SUSTENNA(R) is discontinued, its prolonged-release characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.. 2.7Instructions for Use. Each injection must be administered only by healthcare professional.The kit contains prefilled syringe and safety needles (a 1/2 -inch 22 gauge needle and 1-inch 23 gauge needle) for intramuscular injection.INVEGA SUSTENNA(R) is for single use only.a.Shake the syringe vigorously for minimum of 10 seconds to ensure homogeneous suspension.b.Select the appropriate needle.For DELTOID injection:If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub).If the patient weighs 90 kg or more, use the 1/2 -inch 22 gauge needle (needle with gray colored hub).For GLUTEAL injection:Use the 1/2 -inch 22 gauge needle (needle with gray colored hub) regardless of patients weight.c.While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting motion.d.Peel the safety needle pouch half way open. Grasp the needle sheath using the plastic peel pouch. Attach the safety needle to the luer connection of the syringe with an easy clockwise twisting motion.e.Pull the needle sheath away from the needle with straight pull. Do not twist the sheath as the needle may be loosened from the syringe.f.Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.g.Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. Do not administer by any other route.h.After the injection is complete, use either thumb or finger of one hand (h1, h2) or flat surface (h3) to activate the needle protection system. The needle protection system is fully activated when click is heard. Discard the syringe with needle appropriately.h1h2h3. a.Shake the syringe vigorously for minimum of 10 seconds to ensure homogeneous suspension.. b.Select the appropriate needle.For DELTOID injection:If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub).If the patient weighs 90 kg or more, use the 1/2 -inch 22 gauge needle (needle with gray colored hub).For GLUTEAL injection:Use the 1/2 -inch 22 gauge needle (needle with gray colored hub) regardless of patients weight.. If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub).. If the patient weighs 90 kg or more, use the 1/2 -inch 22 gauge needle (needle with gray colored hub).. c.While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting motion.. d.Peel the safety needle pouch half way open. Grasp the needle sheath using the plastic peel pouch. Attach the safety needle to the luer connection of the syringe with an easy clockwise twisting motion.. e.Pull the needle sheath away from the needle with straight pull. Do not twist the sheath as the needle may be loosened from the syringe.. f.Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.. g.Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. Do not administer by any other route.. h.After the injection is complete, use either thumb or finger of one hand (h1, h2) or flat surface (h3) to activate the needle protection system. The needle protection system is fully activated when click is heard. Discard the syringe with needle appropriately.. Figure. Figure. Figure. Figure. Figure. Figure. h1. h2. h3.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and DistributionDue to its extremely low water solubility, the 1-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at median Tmax of 13 days. The release of the drug starts as early as day and lasts for as long as 126 days.Following intramuscular injection of single doses (39 mg 234 mg) in the deltoid muscle, on average, 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day and 156 mg on day help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA SUSTENNA(R) results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA SUSTENNA(R) administration was dose-proportional over 39 mg-234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an INVEGA SUSTENNA(R) dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6-1.8.Based on population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.. Metabolism and EliminationIn study with oral immediate-release 14C-paliperidone, one week following administration of single oral dose of mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.The median apparent half-life of paliperidone following INVEGA SUSTENNA(R) single-dose administration over the dose range of 39 mg 234 mg ranged from 25 days 49 days.. Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release PaliperidoneINVEGA SUSTENNA(R) is designed to deliver paliperidone over monthly period while extended-release oral paliperidone is administered on daily basis. The initiation regimen for INVEGA SUSTENNA(R) (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.In general, overall initiation plasma levels with INVEGA SUSTENNA(R) were within the exposure range observed with 6-12 mg extended-release oral paliperidone. The use of the INVEGA SUSTENNA(R) initiation regimen allowed patients to stay in this exposure window of 6-12 mg extended-release oral paliperidone even on trough pre-dose days (Day and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from INVEGA SUSTENNA(R) was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making direct comparison of their pharmacokinetic properties.. Drug Interaction StudiesNo specific drug interaction studies have been performed with INVEGA SUSTENNA(R). The information below is obtained from studies with oral paliperidone.Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean Cmax and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to substantial degree, by 35% increase in renal clearance of paliperidone.Figure 1: The effects of other drugs on paliperidone pharmacokinetics.Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA(R) and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone.After oral administration of paliperidone, the steady-state Cmax and AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended-release tablets. In clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)].In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only small fraction of total body clearance. In vitro studies demonstrated that paliperidone is substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.Paliperidone is weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.. Figure 1. Studies in Specific PopulationsNo specific pharmacokinetic studies have been performed with INVEGA SUSTENNA(R) in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA SUSTENNA(R). Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].After oral administration of paliperidone in elderly subjects, the Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].Figure 2: Effects of intrinsic factors on paliperidone pharmacokinetics.Based on in vitro studies utilizing human liver enzymes, paliperidone is not substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.Slower absorption was observed in females in population pharmacokinetic analysis. At apparent steady-state with INVEGA SUSTENNA(R), the trough concentrations were similar between males and females.Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with INVEGA SUSTENNA(R), the trough concentrations were similar among normal, overweight, and obese subjects.. Figure 2.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA SUSTENNA(R), during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk SummaryNeonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA SUSTENNA(R), during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 126 days after single-dose administration of INVEGA SUSTENNA(R) [see Clinical Pharmacology (12.3)], and the clinical significance of INVEGA SUSTENNA(R) administered before pregnancy or anytime during pregnancy is not known.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to times the MRHD of 12 mg of paliperidone based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskThere is risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is direct result of the illness or other comorbid factors.. Fetal/Neonatal Adverse ReactionsExtrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA SUSTENNA(R), during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.. Data. Human DataPublished data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report clear association with antipsychotics and major birth defects. prospective observational study including women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. retrospective cohort study from Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.. Animal DataThere were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone based on mg/m2 body surface area.In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to times the MRHD of 12 mg based on mg/m2 body surface area.Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at to times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL(R) package insert).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONINVEGA SUSTENNA(R) (in-VAY-guh suss-TEN-uh)(paliperidone palmitate)Extended-Release Injectable SuspensionWhat is the most important information should know about INVEGA SUSTENNA(R)INVEGA SUSTENNA(R) can cause serious side effects, including:Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). INVEGA SUSTENNA(R) is not for treating dementia-related psychosis. What is INVEGA SUSTENNA(R)INVEGA SUSTENNA(R) is prescription medicine given by injection by healthcare professional and used to treat:schizophrenia in adultsschizoaffective disorder in adults either alone or with other medicines such as mood stabilizers or antidepressantsIt is not known if INVEGA SUSTENNA(R) is safe and effective in children under 18 years of age.Who should not receive INVEGA SUSTENNA(R)Do not receive INVEGA SUSTENNA(R) if you:are allergic to paliperidone, paliperidone palmitate, risperidone, or any of the ingredients in INVEGA SUSTENNA(R). See the end of this Patient Information leaflet for complete list of ingredients in INVEGA SUSTENNA(R).What should tell my healthcare provider before receiving INVEGA SUSTENNA(R)Before you receive INVEGA SUSTENNA(R), tell your healthcare provider about all your medical conditions, including if you:have had Neuroleptic Malignant Syndrome (NMS)have or have had heart problems, including heart attack, heart failure, abnormal heart rhythm, or long QT syndromehave or have had low levels of potassium or magnesium in your bloodhave or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)have or have had kidney or liver problemshave diabetes or have family history of diabeteshave had low white blood cell counthave had problems with dizziness or fainting or are being treated for high blood pressurehave or have had seizures or epilepsyhave any other medical conditionsare pregnant or plan to become pregnant. It is not known if INVEGA SUSTENNA(R) will harm your unborn baby.If you become pregnant while taking INVEGA SUSTENNA(R), talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.Infants born to women who are treated with INVEGA SUSTENNA(R) may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur. are breastfeeding or plan to breastfeed. INVEGA SUSTENNA(R) can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive INVEGA SUSTENNA(R).Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them to show to your healthcare provider or pharmacist when you get new medicine.How will receive INVEGA SUSTENNA(R)Follow your INVEGA SUSTENNA(R) treatment schedule exactly as your healthcare provider tells you to.Your healthcare provider will tell you how much INVEGA SUSTENNA(R) you will receive and when you will receive it.INVEGA SUSTENNA(R) is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks.When you receive your first dose of INVEGA SUSTENNA(R) you will need to get second dose week later. After that you will only need to get dose time month.What should avoid while receiving INVEGA SUSTENNA(R)INVEGA SUSTENNA(R) may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA SUSTENNA(R) affects you.Avoid getting overheated or dehydrated.What are the possible side effects of INVEGA SUSTENNA(R)INVEGA SUSTENNA(R) may cause serious side effects, including:See What is the most important information should know about INVEGA SUSTENNA(R) stroke in elderly people (cerebrovascular problems) that can lead to deathNeuroleptic Malignant Syndrome (NMS). NMS is rare but very serious problem that can happen in people who receive INVEGA SUSTENNA(R). NMS can cause death and must be treated in hospital. Call your healthcare provider right away if you become severely ill and have any of these symptoms:high feversevere muscle stiffnessconfusionloss of consciousnesschanges in your breathing, heartbeat and blood pressure problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms:passing out or feeling like you will pass outdizzinessfeeling as if your heart is pounding or missing beats uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)metabolic changes. Metabolic changes may include high blood sugar (hyperglycemia), diabetes mellitus and changes in the fat levels in your blood (dyslipidemia), and weight gain.low blood pressure and faintingchanges in your blood cell countshigh level of prolactin in your blood (hyperprolactinemia). INVEGA SUSTENNA(R) may cause rise in the blood levels of hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, leakage of milk from the breasts, development of breasts in men, or problems with erection.problems thinking clearly and moving your bodyseizuresdifficulty swallowing that can cause food or liquid to get into your lungsprolonged or painful erection lasting more than hours. Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than hours.problems with control of your body temperature especially when you exercise lot or spend time doing things that make you warm. It is important for you to drink water to avoid dehydration.The most common side effects of INVEGA SUSTENNA(R) include: injection site reactions, sleepiness or drowsiness, dizziness, feeling restlessness or needing to be constantly moving, abnormal muscle movements including tremor (shaking), shuffling, uncontrolled involuntary movements, and abnormal movements of your eyes.Tell your healthcare provider if you have any side effect that bothers you or does not go away.These are not all the possible side effects of INVEGA SUSTENNA(R). For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of INVEGA SUSTENNA(R).Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use INVEGA SUSTENNA(R) for condition for which it was not prescribed. Do not give INVEGA SUSTENNA(R) to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVEGA SUSTENNA(R) that is written for healthcare professionals.This Patient Information leaflet summarizes the most important information about INVEGA SUSTENNA(R). If you would like more information, talk with your healthcare provider.You can ask your healthcare provider or pharmacist for more information that is written for healthcare professionals. For more information, go to www.invegasustenna.com or call 1-800-526-7736.What are the ingredients in INVEGA SUSTENNA(R)Active ingredient: paliperidone palmitateInactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injectionRevised: 07/2018Manufactured by: Janssen Pharmaceutica NV, Beerse, BelgiumManufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560(C) 2009 Janssen Pharmaceutical Companies. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). INVEGA SUSTENNA(R) is not for treating dementia-related psychosis. schizophrenia in adults. schizoaffective disorder in adults either alone or with other medicines such as mood stabilizers or antidepressants. are allergic to paliperidone, paliperidone palmitate, risperidone, or any of the ingredients in INVEGA SUSTENNA(R). See the end of this Patient Information leaflet for complete list of ingredients in INVEGA SUSTENNA(R).. have had Neuroleptic Malignant Syndrome (NMS). have or have had heart problems, including heart attack, heart failure, abnormal heart rhythm, or long QT syndrome. have or have had low levels of potassium or magnesium in your blood. have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia). have or have had kidney or liver problems. have diabetes or have family history of diabetes. have had low white blood cell count. have had problems with dizziness or fainting or are being treated for high blood pressure. have or have had seizures or epilepsy. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if INVEGA SUSTENNA(R) will harm your unborn baby.If you become pregnant while taking INVEGA SUSTENNA(R), talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.Infants born to women who are treated with INVEGA SUSTENNA(R) may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur. If you become pregnant while taking INVEGA SUSTENNA(R), talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Infants born to women who are treated with INVEGA SUSTENNA(R) may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur.. are breastfeeding or plan to breastfeed. INVEGA SUSTENNA(R) can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive INVEGA SUSTENNA(R).. Follow your INVEGA SUSTENNA(R) treatment schedule exactly as your healthcare provider tells you to.. Your healthcare provider will tell you how much INVEGA SUSTENNA(R) you will receive and when you will receive it.. INVEGA SUSTENNA(R) is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks.. When you receive your first dose of INVEGA SUSTENNA(R) you will need to get second dose week later. After that you will only need to get dose time month.. INVEGA SUSTENNA(R) may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA SUSTENNA(R) affects you.. Avoid getting overheated or dehydrated.. See What is the most important information should know about INVEGA SUSTENNA(R) stroke in elderly people (cerebrovascular problems) that can lead to death. Neuroleptic Malignant Syndrome (NMS). NMS is rare but very serious problem that can happen in people who receive INVEGA SUSTENNA(R). NMS can cause death and must be treated in hospital. Call your healthcare provider right away if you become severely ill and have any of these symptoms:high feversevere muscle stiffnessconfusionloss of consciousnesschanges in your breathing, heartbeat and blood pressure high fever. severe muscle stiffness. confusion. loss of consciousness. changes in your breathing, heartbeat and blood pressure. problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms:passing out or feeling like you will pass outdizzinessfeeling as if your heart is pounding or missing beats passing out or feeling like you will pass out. dizziness. feeling as if your heart is pounding or missing beats. uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia). metabolic changes. Metabolic changes may include high blood sugar (hyperglycemia), diabetes mellitus and changes in the fat levels in your blood (dyslipidemia), and weight gain.. low blood pressure and fainting. changes in your blood cell counts. high level of prolactin in your blood (hyperprolactinemia). INVEGA SUSTENNA(R) may cause rise in the blood levels of hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, leakage of milk from the breasts, development of breasts in men, or problems with erection.. problems thinking clearly and moving your body. seizures. difficulty swallowing that can cause food or liquid to get into your lungs. prolonged or painful erection lasting more than hours. Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than hours.. problems with control of your body temperature especially when you exercise lot or spend time doing things that make you warm. It is important for you to drink water to avoid dehydration.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA SUSTENNA(R), during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk SummaryNeonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA SUSTENNA(R), during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 126 days after single-dose administration of INVEGA SUSTENNA(R) [see Clinical Pharmacology (12.3)], and the clinical significance of INVEGA SUSTENNA(R) administered before pregnancy or anytime during pregnancy is not known.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to times the MRHD of 12 mg of paliperidone based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskThere is risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is direct result of the illness or other comorbid factors.. Fetal/Neonatal Adverse ReactionsExtrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA SUSTENNA(R), during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.. Data. Human DataPublished data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report clear association with antipsychotics and major birth defects. prospective observational study including women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. retrospective cohort study from Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.. Animal DataThere were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone based on mg/m2 body surface area.In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to times the MRHD of 12 mg based on mg/m2 body surface area.Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at to times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL(R) package insert).. 8.2Lactation. Risk SummaryLimited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidones parent compound, risperidone (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 126 days after single-dose administration of INVEGA SUSTENNA(R) [see Clinical Pharmacology (12.3)], and the clinical significance on the breastfed infant is not known. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for INVEGA SUSTENNA(R) and any potential adverse effects on the breastfed child from INVEGA SUSTENNA(R) or from the mothers underlying condition.. Clinical ConsiderationsInfants exposed to INVEGA SUSTENNA(R) through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).. 8.3Females and Males of Reproductive Potential. Infertility. FemalesBased on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with INVEGA SUSTENNA(R) may result in an increase in serum prolactin levels, which may lead to reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.10)]. 8.4 Pediatric Use. Safety and effectiveness of INVEGA SUSTENNA(R) in patients 18 years of age have not been established.. Juvenile Animal StudiesIn study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, reversible impairment of performance in test of learning and memory was seen, in females only, with no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents.Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or mg/kg/day. Decreased bone length and density were seen with no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after 12-week drug-free recovery period.The long-term effects of INVEGA SUSTENNA(R) on growth and sexual maturation have not been fully evaluated in children and adolescents.. 8.5 Geriatric Use. Clinical studies of INVEGA SUSTENNA(R) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function [see Dosage and Administration (2.5)]. 8.6Renal Impairment. Use of INVEGA SUSTENNA(R) is not recommended in patients with moderate or severe renal impairment (creatinine clearance 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance >= 50 mL/min to 80 mL/min) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. INVEGA SUSTENNA(R) has not been studied in patients with hepatic impairment. Based on study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [Clinical Pharmacology (12.3)].. 8.8Patients with Parkinsons Disease or Lewy Body Dementia. Patients with Parkinsons Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA SUSTENNA(R). Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.