b'INVEGA SUSTENNA (paliperidone palmitate) INVEGA SUSTENNA (paliperidone palmitate)extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular useTable 5: Mean Change in Body Weight (kg) and the Proportion of SubjectsTissue culture experiments indicate that approximately one-third of human breastwith7% Gain in Body Weight from Four Placebo-Controlled, 9- tocancers are prolactin dependent in vitro, a factor of potential importance if the 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia prescription of these drugs is considered in a patient with previously detected INVEGASUSTENNA breast cancer. An increase in the incidence of pituitary gland, mammary gland, Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies n=451 n=116 n=280 n=267 n=137 n=144 n=145 conducted in mice and rats [see Nonclinical Toxicology (13.1) in Full Prescribing Weight (kg)Information]. Neither clinical studies nor epidemiologic studies conducted to Change from-0.4 0.4 0.8 1.4 0.4 0.7 1.4 date have shown an association between chronic administration of this class baseline of drugs and tumorigenesis in humans, but the available evidence is too limited Weight Gainto be conclusive. 7% increase3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1% Prolactin data from two long-term, double-blind, placebo-controlled studies from baseline with INVEGASUSTENNA are presented below; one study was in a population a I nitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg everyofpatientswithschizophrenia;thesecondstudywasinpatientswith 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, andschizoaffective disorder.156 mg) are from studies involving only gluteal injection. [see Clinical StudiesSchizophrenia(14.1) in Full Prescribing Information]. Inalong-termmaintenancetrialofINVEGASUSTENNAinschizophrenia In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGASUSTENNA was associatedpatients (Study PSY-3001), see Clinical Studies (14.1), elevations of prolactin with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg atto 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 Week 53 (n=113). noted in a higher percentage of the patients in the INVEGASUSTENNA group During the initial 25-week open-label period of a long-term study in subjectsthan those in the placebo group in males (51.9% vs. 29.0%) and in females withschizoaffectivedisorder,INVEGASUSTENNAwasassociatedwitha(50.5%vs.42.9%).Duringthedouble-blindphase,4females(4.2%)inthe mean change in weight of +2.2 kg and 18.4% of subjects had an increase in bodyINVEGASUSTENNA group experienced potentially prolactin-related adverse weight of7%(n=653). At the endpoint of the subsequent 15-month double-blindreactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), period of the study, INVEGASUSTENNA was associated with a mean changewhile 2 females (2.2%) in the placebo group experienced potentially prolactin-in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of7%related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% ofin the INVEGASUSTENNA group experienced erectile dysfunction and 1 male subjects had an increase in body weight of7% (n=168). (0.9%) in placebo group experienced gynecomastia.Orthostatic Hypotension and Syncope Prior to the double-blind phase (during the 33-week open-label phase of the long-Paliperidone can induce orthostatic hypotension and syncope in some patientsterm maintenance trial), the mean (SD) serum prolactin values at baseline were because of its alpha-adrenergic blocking activity. Syncope was reported in 1% (4/1293) of subjects treated with INVEGASUSTENNA in the recommended14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the dose range of 39 mg to 234 mgin the four fixed-dose, double-blind, placebo- end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL controlled trials compared with 0% (0/510) of subjects treated with placebo.in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label Inthefourfixed-doseefficacystudiesinsubjectswithschizophrenia,phases 49.2% of females and 47.7% of males experienced elevations of prolactin orthostatic hypotension was reported as an adverse event by 1% (2/1293) ofabove the reference range relative to baseline, and a higher proportion of INVEGASUSTENNA- treated subjects compared to 0% (0/510) with placebo.females experienced potentially prolactin-related adverse reactions compared Incidences of orthostatic hypotension and syncope in the long-term studies into males (5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially subjects with schizophrenia and schizoaffective disorder were similar to thoseprolactin-related adverse reaction in males were observed with a rate greater observed in the short-term studies. than 2%.INVEGASUSTENNA should be used with caution in patients with knownSchizoaffective Disordercardiovascular disease (e.g., heart failure, history of myocardial infarction orInalong-termmaintenancetrialofINVEGASUSTENNAinpatientswith ischemia, conduction abnormalities), cerebrovascular disease, or conditionsschizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations that predispose the patient to hypotension (e.g., dehydration, hypovolemia, andofprolactintoabovethereferencerange(13.13ng/mLinmalesand treatment with antihypertensive medications). Monitoring of orthostatic vital 26.72 ng/mL in females) relative to open-label baseline at any time during the signs should be considered in patients who are vulnerable to hypotension. 15-month double-blind phase were noted in a higher percentage of patients Falls in the INVEGA SUSTENNA group than those in the placebo group in males (55.6%vs.23.2%)andinfemales(44.3%vs.25.0%).Duringthe15-month Somnolence, postural hypotension, motor and sensory instability have beenreported with the use of antipsychotics, including INVEGASUSTENNA, whichdouble-blind phase, 11 females (13.9%) in the INVEGA SUSTENNAgroup may lead to falls and, consequently, fractures or other fall-related injuries. Forhad14potentiallyprolactin-relatedadversereactions(hyperprolactinemia patients,particularlytheelderly,withdiseases,conditions,ormedicationsN=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; that could exacerbate these effects, assess the risk of falls when initiatinggalactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially antipsychotic treatment and recurrently for patients on long-term antipsychoticprolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin therapy. increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the Leukopenia, Neutropenia, and Agranulocytosis INVEGASUSTENNA group experienced 6 potentially prolactin-related adverse In clinical trial and/or postmarketing experience, events of leukopenia andreactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction neutropenia have been reported temporally related to antipsychotic agents,N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of including INVEGASUSTENNA. Agranulocytosis has also been reported. blood prolactin increased.Possibleriskfactorsforleukopenia/neutropeniaincludepre-existinglowPrior to the 15-month double-blind phase (during the 25-week open-label phase white blood cell count (WBC)/absolute neutrophil count (ANC) and history ofof the long-term maintenance trial), the mean (SD) serum prolactin values at drug-induced leukopenia/neutropenia. In patients with a history of a clinicallybaseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform(N=302). At the end of the open-label phase, mean (SD) prolactin values were a complete blood count (CBC) frequently during the first few months of therapy.32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). In such patients, consider discontinuation of INVEGASUSTENNA at the firstDuring the open-label phase, 48.9% of females and 53.3% of males experienced sign of a clinically significant decline in WBC in the absence of other causativeelevations of prolactin above the reference range relative to baseline, and factors. ahigherproportionoffemalesexperiencedpotentiallyprolactin-related Monitorpatientswithclinicallysignificantneutropeniaforfeverorotheradverse reactions compared to males (10.0% vs. 9.0%). Amenorrhea (5.8%) symptoms or signs of infection and treat promptly if such symptoms or signsand galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile occur. Discontinue INVEGA SUSTENNA in patients with severe neutropeniadysfunction (2.5%) in males were observed with a rate greater than 2%.(absolute neutrophil count 1000/mm3) and follow their WBC until recovery. Potential for Cognitive and Motor ImpairmentHyperprolactinemia Somnolence,sedation,anddizzinesswerereportedasadversereactions Like other drugs that antagonize dopamine D 2receptors, paliperidone elevatesinsubjectstreatedwithINVEGA SUSTENNA[seeAdverseReactions]. prolactinlevelsandtheelevationpersistsduringchronicadministration.Antipsychotics, including INVEGASUSTENNA, have the potential to impair Paliperidone has a prolactin-elevating effect similar to that seen with risperidone,judgment,thinking,ormotorskills.Patientsshouldbecautionedabout a drug that is associated with higher levels of prolactin than other antipsychoticperforming activities requiring mental alertness, such as operating hazardous drugs. machinery or operating a motor vehicle, until they are reasonably certain that Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH,paliperidone therapy does not adversely affect them.resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibitSeizuresreproductive function by impairing gonadal steroidogenesis in both female andIn the four fixed-dose double-blind placebo-controlled studies in subjects with male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence haveschizophrenia, 1% (1/1293) of subjects treated with INVEGASUSTENNA in the beenreportedinpatientsreceivingprolactin-elevatingcompounds.Long- recommended dose range of 39 mg to 234 mg experienced an adverse event standing hyperprolactinemia when associated with hypogonadism may lead toof convulsion compared with 1% (1/510) of placebo-treated subjects who decreased bone density in both female and male subjects. experienced an adverse event of grand mal convulsion.'