(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use Initil U.S. Approvl: 2006 WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing informtion for complete boxed wrning. Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. (5.1) is not pproved for use in ptients with dementirelted psychosis. (5.1) -------------------------------- RECENT MAJOR CHANGES--------------------------------- Indictions nd Usge (1) 11/2014 Dosge nd Administrtion (2.2, 2.3) 11/2014 Dosge nd Administrtion (2.4) 06/2015 -------------------------------- INDICATIONS AND USAGE--------------------------------- is n typicl ntipsychotic indicted for Tretment of schizophreni. (1) Tretment of schizoffective disorder s monotherpy nd s n djunct to mood stbilizers or ntidepressnts. (1) -----------------------------DOSAGE AND ADMINISTRATION----------------------------- For intrmusculr injection only. (2.1) Ech injection must be dministered only by helth cre professionl. (2.1) For deltoid injection, use 1-inch 23G needle for ptients weighing less thn 90 kg or 1½-inch 22G needle for ptients weighing 90 kg or more. For glutel injection, use 1½-inch 22G needle regrdless of ptient weight. (2.1) Indiction Initition Dosing (deltoid) Dy 1 Dy 8 Monthly Mintennce Dose (deltoid or glutel) Revised: 06/2015 036554-150702 Mximum Monthly Dose Schizophreni (2.2) 234 mg 156 mg 39-234 mg b 234 mg Schizoffective disorder (2.2) 234 mg 156 mg 78-234 mg c 234 mg Administered 5 weeks fter the first injection. b The recommended mintennce dose for tretment of schizophreni is 117 mg. Some ptients my benefit from lower or higher mintennce doses within the dditionl vilble strengths (39 mg, 78 mg, 156 mg, nd 234 mg). c Adjust dose bsed on tolerbility nd/or efficcy using vilble strengths. The 39 mg strength ws not studied in the long-term schizoffective disorder study. For ptients nïve to orl pliperidone or orl or injectble risperidone, estblish tolerbility with orl pliperidone or orl risperidone prior to inititing tretment with. (2.2) Missed Doses: To mnge either missed second initition dose or missed monthly mintennce dose, refer to the Full Prescribing Informtion. (2.3) Moderte to severe renl impirment (cretinine clernce < 50 ml/min): is not recommended. (2.5) Mild renl impirment (cretinine clernce 50 ml/min to < 80 ml/min): Administer 156 mg on tretment dy 1 nd 117 mg one week lter, both dministered in the deltoid muscle. Follow with monthly injections of 78 mg in either the deltoid or glutel muscle. (2.5) --------------------------- DOSAGE FORMS AND STRENGTHS---------------------------- Extended-relese injectble suspension: 39 mg, 78 mg, 117 mg, 156 mg, or 234 mg (3) (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use ----------------------------------- CONTRAINDICATIONS------------------------------------ Known hypersensitivity to pliperidone, risperidone, or to ny excipients in the formultion (4) -----------------------------WARNINGS AND PRECAUTIONS------------------------------ Cerebrovsculr Adverse Rections, Including Stroke, in Elderly Ptients with Dementi-Relted Psychosis: Incresed incidence of cerebrovsculr dverse rections (e.g. stroke, trnsient ischemic ttck, including ftlities). is not pproved for use in ptients with dementi-relted psychosis (5.2) Neuroleptic Mlignnt Syndrome: Mnge with immedite discontinution of drug nd close monitoring (5.3) QT Prolongtion: Avoid use with drugs tht lso increse QT intervl nd in ptients with risk fctors for prolonged QT intervl (5.4) Trdive Dyskinesi: Discontinue drug if cliniclly pproprite (5.5) Metbolic Chnges: Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges tht my increse crdiovsculr/cerebrovsculr risk. These metbolic chnges include: Hyperglycemi nd Dibetes Mellitus: Monitor for symptoms of hyperglycemi including polydipsi, polyuri, polyphgi, nd wekness. Monitor glucose regulrly in ptients with dibetes or t risk for dibetes. (5.6) Dyslipidemi: Undesirble ltertions hve been observed. (5.6) Weight Gin: Significnt weight gin hs been reported. Monitor weight gin. (5.6) Orthosttic Hypotension nd Syncope: Use with cution in ptients with known crdiovsculr or cerebrovsculr disese nd ptients predisposed to hypotension (5.7) Leukopeni, Neutropeni, nd Agrnulocytosis: Monitor complete blood count in ptients with history of cliniclly significnt low white blood cell count (WBC) or drug-induced leukopeni/neutropeni. Consider discontinution if cliniclly significnt decline in WBC in the bsence of other custive fctors (5.8) Hyperprolctinemi: Prolctin elevtions occur nd persist during chronic dministrtion (5.9) Potentil for Cognitive nd Motor Impirment: Use cution when operting mchinery (5.10) Seizures: Use cutiously in ptients with history of seizures or with conditions tht lower the seizure threshold (5.11) ----------------------------------- ADVERSE REACTIONS------------------------------------ The most common dverse rections (incidence 5% nd occurring t lest twice s often s plcebo) were injection site rections, somnolence/sedtion, dizziness, kthisi, nd extrpyrmidl disorder. (6) To report SUSPECTED ADVERSE REACTIONS, contct Jnssen Phrmceuticls, Inc. t 1-800-JANSSEN (1-800-526-7736) or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch ----------------------------------- DRUG INTERACTIONS------------------------------------ Drugs tht my cuse orthosttic hypotension: An dditive effect my occur when co-dministered with. (7.1) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It my be necessry to increse the dose of when strong inducer of both CYP3A4 nd P-gp (e.g., crbmzepine, rifmpin, St John s wort) is co-dministered. Conversely, on discontinution of the strong inducer, it my be necessry to decrese the dose of. (7.2, 12.3) ----------------------------- USE IN SPECIFIC POPULATIONS------------------------------ Pregnncy: Bsed on niml dt, my cuse fetl hrm. (8.1) Nursing Mothers: Discontinue drug or nursing, tking into considertion the importnce of drug to the mother. (8.3) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling. Revised: 06/2015 1
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Administrtion Instructions 2.2 Schizophreni nd Schizoffective Disorder 2.3 Missed Doses 2.4 Use with Risperidone or with Orl Pliperidone 2.5 Dosge Adjustments 2.6 Switching from Other Antipsychotics 2.7 Instructions for Use 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Incresed Mortlity in Elderly Ptients with Dementi-Relted Psychosis 5.2 Cerebrovsculr Adverse Rections, Including Stroke, in Elderly Ptients with Dementi-Relted Psychosis 5.3 Neuroleptic Mlignnt Syndrome 5.4 QT Prolongtion 5.5 Trdive Dyskinesi 5.6 Metbolic Chnges 5.7 Orthosttic Hypotension nd Syncope 5.8 Leukopeni, Neutropeni, nd Agrnulocytosis 5.9 Hyperprolctinemi 5.10 Potentil for Cognitive nd Motor Impirment 5.11 Seizures 5.12 Dysphgi 5.13 Pripism 5.14 Disruption of Body Temperture Regultion 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 6.3 Adverse Rections Reported With Risperidone 7 DRUG INTERACTIONS 7.1 Potentil for to Affect Other Drugs 7.2 Potentil for Other Drugs to Affect 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lbor nd Delivery 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 8.8 Ptients with Prkinson s Disese or Lewy Body Dementi 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substnce 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Humn Experience 10.2 Mngement of Overdosge 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Schizophreni 14.2 Schizoffective Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION PATIENT INFORMATION * Sections or subsections omitted from the full prescribing informtion re not listed FULL PRESCRIBING INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth [see Wrnings nd Precutions (5.1)]. is not pproved for use in ptients with dementirelted psychosis [see Wrnings nd Precutions (5.1)]. 1 INDICATIONS AND USAGE (pliperidone plmitte) is indicted for the tretment of: Schizophreni [see Clinicl Studies 14.1]. Schizoffective disorder s monotherpy nd s n djunct to mood stbilizers or ntidepressnts [see Clinicl Studies 14.2]. 2 DOSAGE AND ADMINISTRATION 2.1 Administrtion Instructions Ech injection must be dministered only by helth cre professionl. Prenterl drug products should be inspected visully for foreign mtter nd discolortion prior to dministrtion, whenever product nd continer permit. is intended for intrmusculr use only. Do not dminister by ny other route. Avoid indvertent injection into blood vessel. Administer the dose in single injection; do not dminister the dose in divided injections. Inject slowly, deep into the muscle. The recommended needle size for dministrtion of into the deltoid muscle is determined by the ptient s weight: For ptients weighing less thn 90 kg, the 1-inch, 23 guge needle is recommended. For ptients weighing 90 kg or more, the 1½-inch, 22 guge needle is recommended. Deltoid injections should be lternted between the two deltoid muscles. The recommended needle size for dministrtion of into the glutel muscle is the 1½-inch, 22 guge needle regrdless of ptient weight. Administer into the upper-outer qudrnt of the glutel muscle. Glutel injections should be lternted between the two glutel muscles. 2.2 Schizophreni nd Schizoffective Disorder For ptients who hve never tken orl pliperidone or orl or injectble risperidone, it is recommended to estblish tolerbility with orl pliperidone or orl risperidone prior to inititing tretment with. The recommended dosing of for ech pproved indiction is displyed in Tble 1. The recommended initition of is with dose of 234 mg on tretment dy 1 nd 156 mg one week lter, both dministered in the deltoid muscle. Following the second initition dose, monthly mintennce doses cn be dministered in either the deltoid or glutel muscle. Tble 1. Recommended Dosing of for Adults with Schizophreni or Schizoffective Disorder Indiction Initition Dosing (deltoid) Dy 1 Dy 8 Monthly Mintennce Dose (deltoid or glutel) Mximum Monthly Dose Schizophreni 234 mg 156 mg 39-234 mg b 234 mg Schizoffective 234 mg 156 mg 78-234 mg disorder c 234 mg Administered 5 weeks fter the first injection. b The recommended mintennce dose for tretment of schizophreni is 117 mg. Some ptients my benefit from lower or higher mintennce doses within the dditionl vilble strengths (39 mg, 78 mg, 156 mg, nd 234 mg). c Adjust dose bsed on tolerbility nd/or efficcy using vilble strengths. The 39 mg strength ws not studied in the long-term schizoffective disorder study. Adjustment of the mintennce dose my be mde monthly. When mking dose djustments, the prolonged-relese chrcteristics of should be considered [see Clinicl Phrmcology (12.3)], s the full effect of the dose djustment my not be evident for severl months. 2.3 Missed Doses Avoiding Missed Doses It is recommended tht the second initition dose of be given one week fter the first dose. To void missed dose, ptients my be given the second dose 4 dys before or fter the one-week time point. Similrly, the third nd subsequent injections fter the initition regimen re recommended to be given monthly. To void missed monthly dose, ptients my be given the injection up to 7 dys before or fter the monthly time point. 2
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use Mngement of Missed Second Initition Dose If the trget dte for the second injection (one week ± 4 dys) is missed, the recommended reinitition depends on the length of time which hs elpsed since the ptient s first injection. In cse of missed second initition dose follow the dosing instructions provided in Tble 2. Tble 2. Mngement of Missed Second Initition Dose TIMING OF MISSED DOSING SECOND INITIATION DOSE Less thn 4 weeks since first injection 4 to 7 weeks since first injection More thn 7 weeks since first injection Administer the second initition dose of 156 mg in the deltoid muscle s soon s possible. 1. It is recommended to dminister third injection of 117 mg in either the deltoid or glutel muscle 5 weeks fter the first injection (regrdless of the timing of the second injection). 2. Therefter, resume regulr monthly dosing in either the deltoid or glutel muscle. Resume dosing with two injections of 156 mg in the following mnner: 1. Administer deltoid injection s soon s possible. 2. Administer second deltoid injection 1 week lter. 3. Therefter, resume regulr monthly dosing in either the deltoid or glutel muscle. Restrt dosing with recommended initition (see Section 2.2, Tble 1): 1. Administer 234 mg deltoid injection on Dy 1. 2. Administer 156 mg deltoid injection 1 week lter. 3. Therefter, resume regulr monthly dosing in either the deltoid or glutel muscle. Mngement of Missed Mintennce Dose In cse of missed mintennce dose follow the dosing instructions provided in Tble 3. Tble 3. Mngement of Missed Mintennce Dose TIMING OF MISSED DOSING MAINTENANCE DOSE 4 to 6 weeks since lst injection More thn 6 weeks to 6 months since lst injection More thn 6 months since lst injection Resume regulr monthly dosing s soon s possible t the ptient s previously stbilized dose, followed by injections t monthly intervls. Resume the sme dose the ptient ws previously stbilized on (unless the ptient ws stbilized on dose of 234 mg, then the first 2 injections should ech be 156 mg) in the following mnner: 1. Administer deltoid injection s soon s possible. 2. Administer second deltoid injection 1 week lter t the sme dose. 3. Therefter, resume dministering the previously stbilized dose in the deltoid or glutel muscle 1 month fter the second injection. Restrt dosing with recommended initition (see Section 2.2, Tble 1): 1. Administer 234 mg deltoid injection on Dy 1. 2. Administer 156 mg deltoid injection 1 week lter. 3. Therefter, resume dministering the previously stbilized dose in the deltoid or glutel muscle 1 month fter the second injection. 2.4 Use with Risperidone or with Orl Pliperidone Since pliperidone is the mjor ctive metbolite of risperidone, cution should be exercised when is codministered with risperidone or with orl pliperidone for extended periods of time. Sfety dt involving concomitnt use of with other ntipsychotics is limited. 2.5 Dosge Adjustments Renl Impirment hs not been systemticlly studied in ptients with renl impirment [see Clinicl Phrmcology (12.3)]. For ptients with mild renl impirment (cretinine clernce 50 ml/min to < 80 ml/min [Cockcroft-Gult Formul]), initite with dose of 156 mg on tretment dy 1 nd 117 mg one week lter. Administer both doses in the deltoid muscle. Therefter, follow with monthly injections of 78 mg in either the deltoid or glutel muscle [see Use in Specific Popultions (8.6) nd Clinicl Phrmcology (12.3)]. (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use is not recommended in ptients with moderte or severe renl impirment (cretinine clernce < 50 ml/min) [see Use in Specific Popultions (8.6) nd Clinicl Phrmcology (12.3)]. Codministrtion with Strong CYP3A4/P-glycoprotein (P-gp) Inducers It my be necessry to increse the dose of when strong inducer of both CYP3A4 nd P-gp (e.g., crbmzepine, rifmpin, St John s wort) is co-dministered. Conversely, on discontinution of the strong inducer, it my be necessry to decrese the dose of [see Drug Interctions (7.2) nd Clinicl Phrmcology (12.3)]. 2.6 Switching from Other Antipsychotics There re no systemticlly collected dt to specificlly ddress switching ptients with schizophreni or schizoffective disorder from other ntipsychotics to, or concerning concomitnt dministrtion with other ntipsychotics. 2.6.1 Switching from Orl Antipsychotics For ptients who hve never tken orl pliperidone or orl or injectble risperidone, tolerbility should be estblished with orl pliperidone or orl risperidone prior to inititing tretment with. Previous orl ntipsychotics cn be grdully discontinued t the time of initition of tretment with. Recommended initition of is with dose of 234 mg on tretment dy 1 nd 156 mg one week lter, both dministered in the deltoid muscle [see Dosge nd Administrtion (2.2)]. Ptients previously stbilized on different doses of INVEGA Extended-Relese tblets cn ttin similr pliperidone stedy-stte exposure during mintennce tretment with monthly doses s depicted in Tble 4. Tble 4. Doses of INVEGA nd needed to ttin similr stedy-stte pliperidone exposure during mintennce tretment Formultion INVEGA Extended-Relese Tblet Injection Dosing Frequency Once Dily Once every 4 weeks 12 234 Dose (mg) 6 117 3 39-78 2.6.2 Switching from Long-Acting Injectble Antipsychotics For ptients who hve never tken orl pliperidone or orl or injectble risperidone, tolerbility should be estblished with orl pliperidone or orl risperidone prior to inititing tretment with. When switching ptients currently t stedy-stte on long-cting injectble ntipsychotic, initite therpy in plce of the next scheduled injection. should then be continued t monthly intervls. The one-week initition dosing regimen s described in Section 2.2 is not required. See Tble 1 bove for recommended monthly mintennce dosing. Bsed on previous clinicl history of tolerbility nd/or efficcy, some ptients my benefit from lower or higher mintennce doses within the vilble strengths (39 mg, 78 mg, 117 mg, 156 mg, nd 234 mg). The 39 mg strength ws not studied in the long-term schizoffective disorder study. Monthly mintennce doses cn be dministered in either the deltoid or glutel muscle [see Dosge nd Administrtion (2.2)]. If is discontinued, its prolonged-relese chrcteristics must be considered. As recommended with other ntipsychotic medictions, the need for continuing existing extrpyrmidl symptoms (EPS) mediction should be re-evluted periodiclly. 2.7 Instructions for Use Ech injection must be dministered only by helth cre professionl. The kit contins prefilled syringe nd 2 sfety needles ( 1 ½-inch 22 guge needle nd 1-inch 23 guge needle) for intrmusculr injection. is for single use only. 3
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use. Shke the syringe vigorously for minimum of 10 seconds to ensure homogeneous suspension. (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use f. Bring the syringe with the ttched needle in upright position to de-erte. De-erte the syringe by moving the plunger rod crefully forwrd. b. Select the pproprite needle. For DELTOID injection: If the ptient weighs less thn 90 kg, use the 1-inch 23 guge needle (needle with blue colored hub). If the ptient weighs 90 kg or more, use the 1½-inch 22 guge needle (needle with gry colored hub). For GLUTEAL injection: Use the 1½-inch 22 guge needle (needle with gry colored hub) regrdless of ptient s weight. c. While holding the syringe upright, remove the rubber tip cp with n esy clockwise twisting motion. g. Inject the entire contents intrmusculrly slowly, deep into the selected deltoid or glutel muscle of the ptient. Do not dminister by ny other route. h. After the injection is complete, use either thumb or finger of one hnd (h1, h2) or flt surfce (h3) to ctivte the needle protection system. The needle protection system is fully ctivted when click is herd. Discrd the syringe with needle ppropritely. h1 h2 d. Peel the sfety needle pouch hlf wy open. Grsp the needle sheth using the plstic peel pouch. Attch the sfety needle to the luer connection of the syringe with n esy clockwise twisting motion. h3 e. Pull the needle sheth wy from the needle with stright pull. Do not twist the sheth s the needle my be loosened from the syringe. 3 DOSAGE FORMS AND STRENGTHS is vilble s white to off-white queous extendedrelese injectble suspension for intrmusculr injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, nd 234 mg pliperidone plmitte. 4 CONTRAINDICATIONS is contrindicted in ptients with known hypersensitivity to either pliperidone or risperidone, or to ny of the excipients in the formultion. Hypersensitivity rections, including nphylctic rections nd ngioedem, hve been observed in ptients treted with risperidone nd pliperidone. Pliperidone plmitte is converted to pliperidone, which is metbolite of risperidone. 5 WARNINGS AND PRECAUTIONS 5.1 Incresed Mortlity in Elderly Ptients with Dementi-Relted Psychosis Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. Anlyses of 17 plcebo-controlled trils (modl durtion of 10 weeks), lrgely in ptients tking typicl ntipsychotic drugs, reveled risk of deth in drug-treted ptients of between 1.6 to 1.7 times the risk of deth in plcebo-treted ptients. Over the course of typicl 10-week controlled tril, the rte of deth in drug-treted ptients ws bout 4.5%, compred to rte of bout 2.6% in the plcebo group. Although the cuses of deth were vried, most of the deths ppered to be either crdiovsculr (e.g., hert filure, sudden deth) or infectious (e.g., pneumoni) in nture. Observtionl studies suggest tht, similr to typicl ntipsychotic drugs, tretment with conventionl ntipsychotic drugs my increse mortlity. The extent to which the findings of incresed mortlity in observtionl studies my be ttributed to the ntipsychotic drug s opposed to some chrcteristic(s) of the ptients is not cler. (pliperidone plmitte) is not pproved for the tretment of ptients with dementi-relted psychosis [see Boxed Wrning]. 4
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use 5.2 Cerebrovsculr Adverse Rections, Including Stroke, in Elderly Ptients with Dementi-Relted Psychosis In plcebo-controlled trils with risperidone, ripiprzole, nd olnzpine in elderly subjects with dementi, there ws higher incidence of cerebrovsculr dverse rections (cerebrovsculr ccidents nd trnsient ischemic ttcks) including ftlities compred to plcebo-treted subjects. Orl pliperidone nd were not mrketed t the time these studies were performed nd re not pproved for the tretment of ptients with dementi-relted psychosis [see Boxed Wrning nd Wrnings nd Precutions (5.1)]. 5.3 Neuroleptic Mlignnt Syndrome A potentilly ftl symptom complex sometimes referred to s Neuroleptic Mlignnt Syndrome (NMS) hs been reported in ssocition with ntipsychotic drugs, including. Clinicl mnifesttions of NMS re hyperpyrexi, muscle rigidity, ltered mentl sttus, nd evidence of utonomic instbility (irregulr pulse or blood pressure, tchycrdi, diphoresis, nd crdic dysrhythmi). Additionl signs my include elevted cretine phosphokinse, myoglobinuri (rhbdomyolysis), nd cute renl filure. The dignostic evlution of ptients with this syndrome is complicted. In rriving t dignosis, it is importnt to identify cses in which the clinicl presenttion includes both serious medicl illness (e.g., pneumoni, systemic infection, etc.) nd untreted or indequtely treted extrpyrmidl signs nd symptoms (EPS). Other importnt considertions in the differentil dignosis include centrl nticholinergic toxicity, het stroke, drug fever, nd primry centrl nervous system pthology. The mngement of NMS should include: (1) immedite discontinution of ntipsychotic drugs nd other drugs not essentil to concurrent therpy; (2) intensive symptomtic tretment nd medicl monitoring; nd (3) tretment of ny concomitnt serious medicl problems for which specific tretments re vilble. There is no generl greement bout specific phrmcologicl tretment regimens for uncomplicted NMS. If ptient ppers to require ntipsychotic drug tretment fter recovery from NMS, reintroduction of drug therpy should be closely monitored, since recurrences of NMS hve been reported. 5.4 QT Prolongtion Pliperidone cuses modest increse in the corrected QT (QTc) intervl. The use of pliperidone should be voided in combintion with other drugs tht re known to prolong QTc including Clss 1A (e.g., quinidine, procinmide) or Clss III (e.g., miodrone, sotlol) ntirrhythmic medictions, ntipsychotic medictions (e.g., chlorpromzine, thioridzine), ntibiotics (e.g., gtifloxcin, moxifloxcin), or ny other clss of medictions known to prolong the QTc intervl. Pliperidone should lso be voided in ptients with congenitl long QT syndrome nd in ptients with history of crdic rrhythmis. Certin circumstnces my increse the risk of the occurrence of Torsdes de pointes nd/or sudden deth in ssocition with the use of drugs tht prolong the QTc intervl, including (1) brdycrdi; (2) hypoklemi or hypomgnesemi; (3) concomitnt use of other drugs tht prolong the QTc intervl; nd (4) presence of congenitl prolongtion of the QT intervl. The effects of orl pliperidone on the QT intervl were evluted in doubleblind, ctive-controlled (moxifloxcin 400 mg single dose), multicenter QT study in dults with schizophreni nd schizoffective disorder, nd in three plcebo- nd ctive-controlled 6-week, fixed-dose efficcy trils in dults with schizophreni. In the QT study (n=141), the 8 mg dose of immedite-relese orl pliperidone (n=50) showed men plcebo-subtrcted increse from bseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on dy 8 t 1.5 hours post-dose. The men stedystte pek plsm concentrtion for this 8 mg dose of pliperidone immedite relese (C mx ss = 113 ng/ml) ws more thn 2-fold the exposure observed with the mximum recommended 234 mg dose of dministered in the deltoid muscle (predicted medin C mx ss = 50 ng/ml). In this sme study, 4 mg dose of the immedite-relese orl formultion of pliperidone, for which C mx ss = 35 ng/ml, showed n incresed plcebo-subtrcted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on dy 2 t 1.5 hours post-dose. In the three fixed-dose efficcy studies of orl pliperidone extended relese in subjects with schizophreni, electrocrdiogrm (ECG) mesurements tken t vrious time points showed only one subject in the orl pliperidone 12 mg group hd chnge exceeding 60 msec t one time-point on Dy 6 (increse of 62 msec). In the four fixed-dose efficcy studies of in subjects with schizophreni nd in the long-term study in subjects with schizoffective disorder, no subject experienced chnge in QTcLD exceeding 60 msec nd no subject hd QTcLD vlue of > 500 msec t ny time point. In the mintennce study in subjects with schizophreni, no subject hd QTcLD chnge > 60 msec, nd one subject hd QTcLD vlue of 507 msec (Bzett s QT corrected intervl [QTcB] vlue of 483 msec); this ltter subject lso hd hert rte of 45 bets per minute. 5.5 Trdive Dyskinesi A syndrome of potentilly irreversible, involuntry, dyskinetic movements my develop in ptients treted with ntipsychotic drugs. Although the prevlence of the syndrome ppers to be highest mong the elderly, especilly elderly women, it is impossible (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use to predict which ptients will develop the syndrome. Whether ntipsychotic drug products differ in their potentil to cuse trdive dyskinesi is unknown. The risk of developing trdive dyskinesi nd the likelihood tht it will become irreversible pper to increse s the durtion of tretment nd the totl cumultive dose of ntipsychotic drugs dministered to the ptient increse, but the syndrome cn develop fter reltively brief tretment periods t low doses, lthough this is uncommon. There is no known tretment for estblished trdive dyskinesi, lthough the syndrome my remit, prtilly or completely, if ntipsychotic tretment is withdrwn. Antipsychotic tretment itself my suppress (or prtilly suppress) the signs nd symptoms of the syndrome nd my thus msk the underlying process. The effect of symptomtic suppression on the long-term course of the syndrome is unknown. Given these considertions, should be prescribed in mnner tht is most likely to minimize the occurrence of trdive dyskinesi. Chronic ntipsychotic tretment should generlly be reserved for ptients who suffer from chronic illness tht is known to respond to ntipsychotic drugs. In ptients who do require chronic tretment, the smllest dose nd the shortest durtion of tretment producing stisfctory clinicl response should be sought. The need for continued tretment should be ressessed periodiclly. If signs nd symptoms of trdive dyskinesi pper in ptient treted with, drug discontinution should be considered. However, some ptients my require tretment with despite the presence of the syndrome. 5.6 Metbolic Chnges Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges tht my increse crdiovsculr/cerebrovsculr risk. These metbolic chnges include hyperglycemi, dyslipidemi, nd body weight gin. While ll of the drugs in the clss hve been shown to produce some metbolic chnges, ech drug hs its own specific risk profile. Hyperglycemi nd Dibetes Mellitus Hyperglycemi nd dibetes mellitus, in some cses extreme nd ssocited with ketocidosis or hyperosmolr com or deth, hve been reported in ptients treted with ll typicl ntipsychotics. These cses were, for the most prt, seen in post-mrketing clinicl use nd epidemiologic studies, not in clinicl trils, nd there hve been few reports of hyperglycemi or dibetes in tril subjects treted with. Assessment of the reltionship between typicl ntipsychotic use nd glucose bnormlities is complicted by the possibility of n incresed bckground risk of dibetes mellitus in ptients with schizophreni nd the incresing incidence of dibetes mellitus in the generl popultion. Given these confounders, the reltionship between typicl ntipsychotic use nd hyperglycemi-relted dverse rections is not completely understood. However, epidemiologicl studies suggest n incresed risk of hyperglycemi-relted dverse rections in ptients treted with the typicl ntipsychotics. Becuse ws not mrketed t the time these studies were performed, it is not known if is ssocited with this risk. Ptients with n estblished dignosis of dibetes mellitus who re strted on typicl ntipsychotics should be monitored regulrly for worsening of glucose control. Ptients with risk fctors for dibetes mellitus (e.g., obesity, fmily history of dibetes) who re strting tretment with typicl ntipsychotics should undergo fsting blood glucose testing t the beginning of tretment nd periodiclly during tretment. Any ptient treted with typicl ntipsychotics should be monitored for symptoms of hyperglycemi including polydipsi, polyuri, polyphgi, nd wekness. Ptients who develop symptoms of hyperglycemi during tretment with typicl ntipsychotics should undergo fsting blood glucose testing. In some cses, hyperglycemi hs resolved when the typicl ntipsychotic ws discontinued; however, some ptients required continution of nti-dibetic tretment despite discontinution of the suspect drug. Pooled dt from the four plcebo-controlled (one 9-week nd three 13-week), fixed-dose studies in subjects with schizophreni re presented in Tble 5. Tble 5. Chnge in Fsting Glucose from Four Plcebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophreni Plcebo 39 mg 78 mg 156 mg 234/39 mg 234/156 mg 234/234 mg Men chnge from bseline (mg/dl) n=367 n=86 n=244 n=238 n=110 n=126 n=115 Serum Glucose Chnge from -1.3 1.3 3.5 0.1 3.4 1.8-0.2 bseline Proportion of Ptients with Shifts Serum Glucose Norml to High (<100 mg/dl to 126 mg/dl) 4.6% (11/241) 6.3% (4/64) 6.4% (11/173) 3.9% (6/154) 2.5% (2/79) 7.0% (6/86) 6.6% (5/76) Initil deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or glutel injection. Other dose groups (39 mg, 78 mg, nd 156 mg) re from studies involving only glutel injection. [See Clinicl Studies (14.1)]. 5
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use In long-term open-lbel phrmcokinetic nd sfety study in subjects with schizophreni in which the highest dose vilble (234 mg) ws evluted, ws ssocited with men chnge in glucose of -0.4 mg/dl t Week 29 (n=109) nd +6.8 mg/dl t Week 53 (n=100). During the initil 25-week open-lbel period of long-term study in subjects with schizoffective disorder, ws ssocited with men chnge in glucose of +5.3 mg/dl (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, ws ssocited with men chnge in glucose of +0.3 mg/dl (n=131) compred with men chnge of +4.0 mg/dl in the plcebo group (n=120). Dyslipidemi Undesirble ltertions in lipids hve been observed in ptients treted with typicl ntipsychotics. Pooled dt from the four plcebo-controlled (one 9-week nd three 13-week), fixed-dose studies in subjects with schizophreni re presented in Tble 6. Tble 6. Chnge in Fsting Lipids from Four Plcebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophreni Plcebo 39 mg 78 mg 156 mg 234/39 mg 234/156 mg 234/234 mg Men chnge from bseline (mg/dl) Cholesterol Chnge from bseline LDL Chnge from bseline HDL Chnge from bseline Triglycerides Chnge from bseline Cholesterol Norml to High (<200 mg/dl to 240 mg/dl) LDL Norml to High (<100 mg/dl to 160 mg/dl) HDL Norml to Low ( 40 mg/dl to <40 mg/dl) Triglycerides Norml to High (<150 mg/dl to 200 mg/dl) n=366-6.6 n=275-6.0 n=286 0.7 n=366-16.7 3.2% (7/222) 1.1% (1/95) 13.8% (28/203) 3.6% (8/221) n=89-6.4 n=80-4.8 n=89 2.1 n=89 7.6 2.0% (1/51) 0% (0/29) 14.8% (9/61) 6.1% (3/49) n=244-5.8 n=164-5.6 n=165 0.6 n=244-9.0 n=232-7.1 n=141-4.8 n=150 0.3 n=232-11.5 n=105-0.9 n=104 0.9 n=105 1.5 n=105-14.1 Proportion of Ptients with Shifts 2.0% (3/147) 0% (0/67) 9.6% (11/115) 9.2% (14/153) 2.1% (3/141) 0% (0/46) 14.2% (15/106) 7.2% (10/139) 0% (0/69) 0% (0/41) 12.7% (9/71) 1.3% (1/79) n=119-4.2 n=117-2.4 n=118 1.1 n=119-20.0 3.1% (2/65) 0% (0/37) 10.5% (8/76) 3.7% (3/82) n=120 9.4 n=108 5.2 n=115 0.0 n=120 11.9 7.1% (6/84) 0% (0/44) 16.0% (13/81) 10.7% (9/84) Initil deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or glutel injection. Other dose groups (39 mg, 78 mg, nd 156 mg) re from studies involving only glutel injection. [See Clinicl Studies (14.1)]. In long-term open-lbel phrmcokinetic nd sfety study in subjects with schizophreni in which the highest dose vilble (234 mg) ws evluted, the men chnges from bseline in lipid vlues re presented in Tble 7. Tble 7. Chnge in Fsting Lipids from Long-term Open-lbel Phrmcokinetic nd Sfety Study in Subjects with Schizophreni 234 mg Week 29 Week 53 Men chnge from bseline (mg/dl) Cholesterol n=112 n=100 Chnge from bseline -1.2 0.1 LDL n=107 n=89 Chnge from bseline -2.7-2.3 HDL n=112 n=98 Chnge from bseline -0.8-2.6 Triglycerides n=112 n=100 Chnge from bseline 16.2 37.4 (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use The men chnges from bseline in lipid vlues during the initil 25-week openlbel period nd t the endpoint of the subsequent 15-month double-blind period in long-term study in subjects with schizoffective disorder re presented in Tble 8. Tble 8. Chnge in Fsting Lipids from n Open-Lbel nd Double-Blind Periods of Long-Term Study in Subjects with Schizoffective Disorder Open-Lbel Period Double-Blind Period Plcebo Men chnge from bseline (mg/dl) Cholesterol n=198 n=119 n=132 Chnge from -3.9-4.2 2.3 bseline LDL n=198 n=117 n=130 Chnge from -2.7-2.8 5.9 bseline HDL n=198 n=119 n=131 Chnge from -2.7-0.9-0.7 bseline Triglycerides n=198 n=119 n=132 Chnge from bseline 7.0 2.5-12.3 Weight Gin Weight gin hs been observed with typicl ntipsychotic use. Clinicl monitoring of weight is recommended. Dt on men chnges in body weight nd the proportion of subjects meeting weight gin criterion of 7% of body weight from the four plcebo-controlled (one 9-week nd three 13-week), fixed-dose studies in subjects with schizophreni re presented in Tble 9. Tble 9. Men Chnge in Body Weight (kg) nd the Proportion of Subjects with 7% Gin in Body Weight from Four Plcebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophreni Plcebo 39 mg 78 mg 156 mg 234/39 mg 234/156 mg 234/234 mg n=451 n=116 n=280 n=267 n=137 n=144 n=145 Weight (kg) Chnge from bseline -0.4 0.4 0.8 1.4 0.4 0.7 1.4 Weight Gin 7% increse from bseline 3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1% Initil deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or glutel injection. Other dose groups (39 mg, 78 mg, nd 156 mg) re from studies involving only glutel injection. [See Clinicl Studies (14.1)]. In long-term open-lbel phrmcokinetic nd sfety study in which the highest dose vilble (234 mg) ws evluted, ws ssocited with men chnge in weight of +2.4 kg t Week 29 (n=134) nd +4.3 kg t Week 53 (n=113). During the initil 25-week open-lbel period of long-term study in subjects with schizoffective disorder, ws ssocited with men chnge in weight of +2.2 kg nd 18.4% of subjects hd n increse in body weight of 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, ws ssocited with men chnge in weight of -0.2 kg nd 13.0% of subjects hd n increse in body weight of 7% (n=161); the plcebo group hd men chnge in weight of -0.8 kg nd 6.0% of subjects hd n increse in body weight of 7% (n=168). 5.7 Orthosttic Hypotension nd Syncope Pliperidone cn induce orthosttic hypotension nd syncope in some ptients becuse of its lph-blocking ctivity. Syncope ws reported in < 1% (4/1293) of subjects treted with in the recommended dose rnge of 39 mg to 234 mg in the four fixed-dose, double-blind, plcebo-controlled trils compred with 0% (0/510) of subjects treted with plcebo. In the four fixeddose efficcy studies in subjects with schizophreni, orthosttic hypotension ws reported s n dverse event by < 1% (2/1293) of - treted subjects compred to 0% (0/510) with plcebo. Incidences of orthosttic hypotension nd syncope in the long-term studies in subjects with schizophreni nd schizoffective disorder were similr to those observed in the short-term studies. 6
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use should be used with cution in ptients with known crdiovsculr disese (e.g., hert filure, history of myocrdil infrction or ischemi, conduction bnormlities), cerebrovsculr disese, or conditions tht predispose the ptient to hypotension (e.g., dehydrtion, hypovolemi, nd tretment with ntihypertensive medictions). Monitoring of orthosttic vitl signs should be considered in ptients who re vulnerble to hypotension. 5.8 Leukopeni, Neutropeni, nd Agrnulocytosis In clinicl tril nd/or postmrketing experience, events of leukopeni/neutropeni hve been reported temporlly relted to ntipsychotic gents, including INVEGA, n orl form of pliperidone. Agrnulocytosis hs lso been reported. Possible risk fctors for leukopeni/neutropeni include pre-existing low white blood cell count (WBC) nd history of drug-induced leukopeni/neutropeni. Ptients with history of cliniclly significnt low WBC or drug-induced leukopeni/neutropeni should hve their complete blood count (CBC) monitored frequently during the first few months of therpy nd discontinution of should be considered t the first sign of cliniclly significnt decline in WBC in the bsence of other custive fctors. Ptients with cliniclly significnt neutropeni should be crefully monitored for fever or other symptoms or signs of infection nd treted promptly if such symptoms or signs occur. Ptients with severe neutropeni (bsolute neutrophil count <1000/mm 3 ) should discontinue nd hve their WBC followed until recovery. 5.9 Hyperprolctinemi Like other drugs tht ntgonize dopmine D 2 receptors, pliperidone elevtes prolctin levels nd the elevtion persists during chronic dministrtion. Pliperidone hs prolctin-elevting effect similr to tht seen with risperidone, drug tht is ssocited with higher levels of prolctin thn other ntipsychotic drugs. Hyperprolctinemi, regrdless of etiology, my suppress hypothlmic GnRH, resulting in reduced pituitry gondotrophin secretion. This, in turn, my inhibit reproductive function by impiring gondl steroidogenesis in both femle nd mle ptients. Glctorrhe, menorrhe, gynecomsti, nd impotence hve been reported in ptients receiving prolctin-elevting compounds. Long-stnding hyperprolctinemi when ssocited with hypogondism my led to decresed bone density in both femle nd mle subjects. Tissue culture experiments indicte tht pproximtely one-third of humn brest cncers re prolctin dependent in vitro, fctor of potentil importnce if the prescription of these drugs is considered in ptient with previously detected brest cncer. An increse in the incidence of pituitry glnd, mmmry glnd, nd pncretic islet cell neoplsi (mmmry denocrcinoms, pituitry nd pncretic denoms) ws observed in the risperidone crcinogenicity studies conducted in mice nd rts [see Nonclinicl Toxicology (13.1)]. Neither clinicl studies nor epidemiologic studies conducted to dte hve shown n ssocition between chronic dministrtion of this clss of drugs nd tumorigenesis in humns, but the vilble evidence is too limited to be conclusive. 5.10 Potentil for Cognitive nd Motor Impirment Somnolence, sedtion, nd dizziness were reported s dverse rections in subjects treted with [see Adverse Rections (6.1)]. Antipsychotics, including, hve the potentil to impir judgment, thinking, or motor skills. Ptients should be cutioned bout performing ctivities requiring mentl lertness, such s operting hzrdous mchinery or operting motor vehicle, until they re resonbly certin tht pliperidone therpy does not dversely ffect them. 5.11 Seizures In the four fixed-dose double-blind plcebo-controlled studies in subjects with schizophreni, <1% (1/1293) of subjects treted with in the recommended dose rnge of 39 mg to 234 mg experienced n dverse event of convulsion compred with <1% (1/510) of plcebo-treted subjects who experienced n dverse event of grnd ml convulsion. Like other ntipsychotic drugs, should be used cutiously in ptients with history of seizures or other conditions tht potentilly lower the seizure threshold. Conditions tht lower the seizure threshold my be more prevlent in ptients 65 yers or older. 5.12 Dysphgi Esophgel dysmotility nd spirtion hve been ssocited with ntipsychotic drug use. Aspirtion pneumoni is common cuse of morbidity nd mortlity in ptients with dvnced Alzheimer s dementi. nd other ntipsychotic drugs should be used cutiously in ptients t risk for spirtion pneumoni. 5.13 Pripism Drugs with lph-drenergic blocking effects hve been reported to induce pripism. Although no cses of pripism hve been reported in clinicl trils with, pripism hs been reported with orl pliperidone during postmrketing surveillnce. Severe pripism my require surgicl intervention. (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use 5.14 Disruption of Body Temperture Regultion Disruption of the body s bility to reduce core body temperture hs been ttributed to ntipsychotic gents. Approprite cre is dvised when prescribing to ptients who will be experiencing conditions which my contribute to n elevtion in core body temperture, e.g., exercising strenuously, exposure to extreme het, receiving concomitnt mediction with nticholinergic ctivity, or being subject to dehydrtion. 6 ADVERSE REACTIONS The following re discussed in more detil in other sections of the lbeling: Incresed mortlity in elderly ptients with dementi-relted psychosis [see Boxed Wrning nd Wrnings nd Precutions (5.1)] Cerebrovsculr dverse rections, including stroke, in elderly ptients with dementi-relted psychosis [see Wrnings nd Precutions (5.2)] Neuroleptic mlignnt syndrome [see Wrnings nd Precutions (5.3)] QT prolongtion [see Wrnings nd Precutions (5.4)] Trdive dyskinesi [see Wrnings nd Precutions (5.5)] Metbolic chnges [see Wrnings nd Precutions (5.6)] Orthosttic hypotension nd syncope [see Wrnings nd Precutions (5.7)] Leukopeni, neutropeni, nd grnulocytosis [see Wrnings nd Precutions (5.8)] Hyperprolctinemi [See Wrnings nd Precutions (5.9)] Potentil for cognitive nd motor impirment [see Wrnings nd Precutions (5.10)] Seizures [see Wrnings nd Precutions (5.11)] Dysphgi [see Wrnings nd Precutions (5.12)] Pripism [see Wrnings nd Precutions (5.13)] Disruption of body temperture regultion [see Wrnings nd Precutions (5.14)] The most common (t lest 5% in ny group) nd likely drugrelted (dverse events for which the drug rte is t lest twice the plcebo rte) dverse rections from the double-blind, plcebo-controlled trils in subjects with schizophreni were injection site rections, somnolence/sedtion, dizziness, kthisi, nd extrpyrmidl disorder. No occurrences of dverse events reched this threshold in the long-term double-blind, plcebo-controlled study in subjects with schizoffective disorder. The dt described in this section re derived from clinicl tril dtbse consisting of totl of 3817 subjects (pproximtely 1705 ptient-yers exposure) with schizophreni who received t lest one dose of in the recommended dose rnge of 39 mg to 234 mg nd totl of 510 subjects with schizophreni who received plcebo. Among the 3817 - treted subjects, 1293 received in four fixed-dose, doubleblind, plcebo-controlled trils (one 9-week nd three 13-week studies), 849 received in the mintennce tril (medin exposure 229 dys during the initil 33-week open-lbel phse of this study, of whom 205 continued to receive during the double-blind plcebo-controlled phse of this study [medin exposure 171 dys]), nd 1675 received in five non-plcebo controlled trils (three noninferiority ctive-comprtor trils, one long-term open-lbel phrmcokinetic nd sfety study, nd n injection site [deltoid-glutel] cross-over tril). One of the 13-week studies included 234 mg initition dose followed by tretment with either 39 mg, 156 mg, or 234 mg every 4 weeks. The sfety of ws lso evluted in long-term study in dult subjects with schizoffective disorder. A totl of 667 subjects received during the initil 25-week open-lbel period of this study (medin exposure 147 dys); 164 subjects continued to receive during the 15-month double-blind plcebo-controlled period of this study (medin exposure 446 dys). Adverse rections tht occurred more frequently in the thn the plcebo group ( 2% difference or more between groups) were weight incresed, nsophryngitis, hedche, hyperprolctinemi, nd pyrexi. 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in clinicl prctice. Commonly Reported Adverse Rections in Double-Blind, Plcebo-Controlled Clinicl Trils Tble 10 lists the dverse rections reported in 2% or more of - treted subjects nd t greter proportion thn in the plcebo group with schizophreni in the four fixed-dose, double-blind, plcebo-controlled trils. 7
(pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use Tble 10. Incidence of Adverse Rections in 2% of - Treted Subjects (nd greter thn Plcebo) with Schizophreni in Four Fixed-Dose, Double-Blind, Plcebo-Controlled Trils System Orgn Clss Adverse Event Totl percentge of subjects with dverse event Plcebo (N=510) 39 mg (N=130) 78 mg (N=302) 156 mg (N=312) 234/39 mg b (N=160) 234/156 mg b (N=165) 234/234 mg b (N=163) 70 75 68 69 63 60 63 Gstrointestinl disorders Abdominl 2 2 4 4 1 2 4 discomfort/ bdominl pin upper Dirrhe 2 0 3 2 1 2 2 Dry mouth 1 3 1 0 1 1 1 Nuse 3 4 4 3 2 2 2 Toothche 1 1 1 3 1 2 3 Vomiting 4 5 4 2 3 2 2 Generl disorders nd dministrtion site conditions Astheni 0 2 1 <1 0 1 1 Ftigue 1 1 2 2 1 2 1 Injection site rections 2 0 4 6 9 7 10 Infections nd infesttions Nsophryngitis 2 0 2 2 4 2 2 Upper 2 2 2 2 1 2 4 respirtory trct infection Urinry trct 1 0 1 <1 1 1 2 infection Investigtions Weight incresed 1 4 4 1 1 1 2 Musculoskeletl nd connective tissue disorders Bck pin 2 2 1 3 1 1 1 Musculoskeletl 1 1 <1 <1 1 1 2 stiffness Mylgi 1 2 1 <1 1 0 2 Pin in extremity 1 0 2 2 2 3 0 Nervous system disorders Akthisi 3 2 2 3 1 5 6 Dizziness 1 6 2 4 1 4 2 Extrpyrmidl 1 5 2 3 1 0 0 disorder Hedche 12 11 11 15 11 7 6 Somnolence/ 3 5 7 4 1 5 5 sedtion Psychitric disorders Agittion 7 10 5 9 8 5 4 Anxiety 7 8 5 3 5 6 6 Nightmre <1 2 0 0 0 0 0 Respirtory, thorcic nd medistinl disorders Cough 1 2 3 1 0 1 1 Vsculr disorders Hypertension 1 2 1 1 1 1 0 Percentges re rounded to whole numbers. Tble includes dverse events tht were reported in 2% or more of subjects in ny of the dose groups nd which occurred t greter incidence thn in the plcebo group. Plcebo group is pooled from ll studies nd included either deltoid or glutel injection depending on study design. b Initil deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or glutel injection. Other dose groups (39 mg, 78 mg, nd 156 mg) re from studies involving only glutel injection. [See Clinicl Studies (14.1)] Adverse events for which the incidence ws equl to or less thn plcebo re not listed in the tble, but included the following: dyspepsi, psychotic disorder, schizophreni, nd tremor. The following terms were combined: somnolence/sedtion, brest tenderness/brest pin, bdominl discomfort/ bdominl pin upper/stomch discomfort, nd tchycrdi/sinus tchycrdi/ hert rte incresed. All injection site rection-relted dverse events were collpsed nd re grouped under Injection site rections. (pliperidone plmitte) extended-relese injectble suspension, for intrmusculr use Other Adverse Rections Observed During the Clinicl Tril Evlution of The following list does not include rections: 1) lredy listed in previous tbles or elsewhere in lbeling, 2) for which drug cuse ws remote, 3) which were so generl s to be uninformtive, or 4) which were not considered to hve significnt clinicl implictions. Crdic disorders: trioventriculr block first degree, brdycrdi, bundle brnch block, plpittions, posturl orthosttic tchycrdi syndrome, tchycrdi Er nd lbyrinth disorders: vertigo Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gstrointestinl disorders: constiption, dyspepsi, fltulence, slivry hypersecretion Immune system disorders: hypersensitivity Investigtions: lnine minotrnsferse incresed, sprtte minotrnsferse incresed, electrocrdiogrm bnorml Metbolism nd nutrition disorders: decresed ppetite, hyperinsulinemi, incresed ppetite Musculoskeletl nd connective tissue disorders: rthrlgi, joint stiffness, muscle rigidity, muscle spsms, muscle tightness, muscle twitching, nuchl rigidity Nervous system disorders: brdykinesi, cerebrovsculr ccident, convulsion, dizziness posturl, drooling, dysrthri, dyskinesi, dystoni, hypertoni, lethrgy, oromndibulr dystoni, prkinsonism, psychomotor hyperctivity, syncope Psychitric disorders: insomni, restlessness Reproductive system nd brest disorders: menorrhe, brest dischrge, erectile dysfunction, glctorrhe, gynecomsti, menstrul disorder, menstrution delyed, menstrution irregulr, sexul dysfunction Respirtory, thorcic nd medistinl disorders: nsl congestion Skin nd subcutneous tissue disorders: drug eruption, pruritus, pruritus generlized, rsh, urticri Discontinutions Due to Adverse Events The percentge of subjects who discontinued due to dverse events in the four fixed-dose, double-blind, plcebo-controlled schizophreni trils were similr for - nd plcebo-treted subjects. The percentge of subjects who discontinued due to dverse events in the openlbel period of the long-term study in subjects with schizoffective disorder ws 7.5%. During the double-blind, plcebo-controlled period of tht study, the percentges of subjects who discontinued due to dverse events were 5.5% nd 1.8% in - nd plcebo-treted subjects, respectively. Dose-Relted Adverse Rections Bsed on the pooled dt from the four fixed-dose, double-blind, plcebocontrolled trils in subjects with schizophreni, mong the dverse rections tht occurred t 2% incidence in the subjects treted with, only kthisi incresed with dose. Hyperprolctinemi lso exhibited dose reltionship, but did not occur t 2% incidence in -treted subjects from the four fixed-dose studies. Demogrphic Differences An exmintion of popultion subgroups in the double-blind plcebo-controlled trils did not revel ny evidence of differences in sfety on the bsis of ge, gender, or rce lone; however, there were few subjects 65 yers of ge. Extrpyrmidl Symptoms (EPS) Pooled dt from the two double-blind, plcebo-controlled, 13-week, fixed-dose trils in dult subjects with schizophreni provided informtion regrding EPS. Severl methods were used to mesure EPS: (1) the Simpson-Angus globl score (men chnge from bseline or score t the end of tril) which brodly evlutes Prkinsonism, (2) the Brnes Akthisi Rting Scle globl clinicl rting score (men chnge from bseline or score t the end of tril) which evlutes kthisi, (3) use of nticholinergic medictions to tret EPS, (4) the Abnorml Involuntry Movement Scle scores (men chnge from bseline or scores t the end of tril) (Tble 11), nd (5) incidence of spontneous reports of EPS (Tble 12). 8