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RISPERDAL®(risperidone)

HigHligHts of Prescribing information these highlights do not include all the information needed to use risPerDal® safely and effectively. see full prescribing information for risPerDal®.

risPerDal® (risperidone) tablets, for oral use risPerDal® (risperidone) oral solution risPerDal® m-tab® (risperidone) orally disintegrating tablets

initial U.s. approval: 1993

Warning: increaseD mortalitY in elDerlY Patients WitH

Dementia-relateD PsYcHosisSee full prescribing information for complete boxed warning.

• Elderlypatientswithdementia-relatedpsychosistreatedwithantipsychotic drugs are at an increased risk of death.

• RISPERDAL® isnotapprovedforuseinpatientswithdementia-relatedpsychosis. (5.1)

-------------------------------- inDications anD Usage ------------------------------- RISPERDAL® is an atypical antipsychotic indicated for:• Treatmentofschizophrenia(1.1)• As monotherapy or adjunctive therapy with lithium or valproate, for the

treatment of acute manic or mixed episodes associated with Bipolar IDisorder(1.2)

• Treatmentofirritabilityassociatedwithautisticdisorder(1.3)

-----------------------------Dosage anD aDministration ----------------------------• Recommendeddailydosage:

Initial Dose TargetDose EffectiveDoseRange

Schizophrenia:adults(2.1) 2mg 4to8mg 4to16mgSchizophrenia:adolescents(2.1) 0.5mg 3mg 1to6mgBipolarmania:Adults(2.2) 2to3mg 1to6mg 1to6mgBipolarmania:inchildrenandadolescents(2.2)

0.5mg 1to2.5mg 1to6mg

Irritabilityassociatedwithautisticdisorder(2.3)

0.25mg(Weight<20kg)

0.5mg(Weight≥20kg)

0.5mg(<20kg)

1mg(≥20kg)

0.5to3mg

• Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily atintervalsofatleastoneweek.(2.4)

• Oral Solution: Can be administered directly from calibrated pipette ormixedwithbeverage(water,coffee,orangejuice,orlow-fatmilk).(2.6)

• M-TAB Orally Disintegrating Tablets: Open the blister only when ready toadminister, and immediately place tablet under tongue. Can be swallowedwithorwithoutliquid.(2.7)

------------------------------Dosage forms anD strengtHs -------------------------• Tablets:0.25mg,0.5mg,1mg,2mg,3mg,and4mg(3)• Oralsolution:1mgpermL(3)• Orallydisintegratingtablets:0.5mg,1mg,2mg,3mg,and4mg(3)

-------------------------------------contrainDications ---------------------------------• KnownhypersensitivitytoRISPERDAL® (4)

----------------------------- Warnings anD PrecaUtions ----------------------------• Cerebrovascular events, including stroke, in elderly patients with dementia-

related psychosis: RISPERDAL® is not approved for use in patients withdementia-relatedpsychosis.(5.2)

• NeurolepticMalignantSyndrome:Managewith immediatediscontinuationof RISPERDAL®andclosemonitoring.(5.3)

• Tardivedyskinesia:ConsiderdiscontinuingRISPERDAL® ifclinicallyindicated.(5.4)

• MetabolicChanges:Atypical antipsychotic drugs havebeenassociatedwithmetabolic changes that may increase cardiovascular/ cerebrovascular risk.These metabolic changes include hyperglycemia, dyslipidemia, and weightgain.(5.5)o Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of

hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.Monitorglucose regularly inpatientswithdiabetesorat risk fordiabetes.(5.5)

o Dyslipidemia: Undesirable alterations have been observed in patientstreatedwithatypicalantipsychotics.(5.5)

o Weight Gain: Significant weight gain has been reported. Monitor weightgain.(5.5)

• Hyperprolactinemia: Prolactin elevations occur and persist during chronicadministration.(5.6)

• Orthostatic hypotension: For patients at risk, consider a lower starting doseandslowertitration.(5.7)

• Leukopenia, Neutropenia, and Agranulocytosis: Perform complete bloodcounts in patientswithahistoryof clinically significant lowwhitebloodcellcount (WBC). Consider discontinuing RISPERDAL® if a clinically significantdeclineinWBCoccursintheabsenceofothercausativefactors.(5.8)

• Potential for cognitive and motor impairment: Use caution when operatingmachinery.(5.9)

• Seizures: Use cautiously in patients with a history of seizures or withconditionsthatlowertheseizurethreshold.(5.10)

------------------------------------aDverse reactions-----------------------------------Themost common adverse reactions in clinical trials (>5%and twice placebo)were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety,blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort,dyspepsia,diarrhea,salivaryhypersecretion,constipation,drymouth, increasedappetite, increased weight, fatigue, rash, nasal congestion, upper respiratorytractinfection,nasopharyngitis,andpharyngolaryngealpain.(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

----------------------------------- DrUg interactions -----------------------------------• Carbamazepine and other enzyme inducers decrease plasmaconcentrations

ofrisperidone.IncreasetheRISPERDAL®doseuptodoublethepatient’susualdose.Titrateslowly.(7.1)

• Fluoxetine,paroxetine,andotherCYP2D6enzyme inhibitors increaseplasmaconcentrationsof risperidone.Reduce the initial dose.Donotexceedafinaldoseof8mgperdayofRISPERDAL®.(7.1)

------------------------------ Use in sPecific PoPUlations ----------------------------• Pregnancy:Basedonanimaldata,maycausefetalharm.(8.1)• NursingMothers: Discontinue drug or nursing, taking into consideration the

importanceofdrugtothemother.(8.3)

see 17 for Patient coUnseling information

revised: 04/2014

RISPERDAL® (risperidone)Revised:04/2014015036-140508

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fUll Prescribing information

Warning: increaseD mortalitY in elDerlY Patients WitH

Dementia-relateD PsYcHosisElderly patientswith dementia-related psychosis treatedwith antipsychoticdrugs are at an increased risk of death. risPerDal® (risperidone) is not approvedfor thetreatmentofpatientswithdementia-relatedpsychosis. [See Warnings and Precautions (5.1)]

1 inDications anD Usage1.1 schizophrenia RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia.Efficacy was established in 4 short-term trials in adults, 2 short-term trials inadolescents(ages13to17years),andonelong-termmaintenancetrialinadults[see Clinical Studies (14.1)].

1.2 bipolar maniaMonotherapy RISPERDAL® is indicated for the treatment of acute manic or mixed episodesassociatedwithBipolarIDisorder.Efficacywasestablishedin2short-termtrialsin adults and one short-term trial in children and adolescents (ages 10 to 17years)[see Clinical Studies (14.2)].AdjunctiveTherapy RISPERDAL® adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder.Efficacywasestablished inoneshort-term trial inadults [see Clinical Studies (14.3)].1.3 IrritabilityAssociatedwithAutisticDisorder RISPERDAL® is indicatedfor thetreatmentof irritabilityassociatedwithautisticdisorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy wasestablishedin3short-termtrialsinchildrenandadolescents(ages5to17years)[see Clinical Studies (14.4)].

fUll Prescribing information: contents*

Warning: increaseD mortalitY in elDerlY Patients WitH Dementia-relateD PsYcHosis1 inDications anD Usage 1.1 Schizophrenia 1.2 BipolarMania 1.3 IrritabilityAssociatedwithAutisticDisorder2 Dosage anD aDministration 2.1 Schizophrenia 2.2 BipolarMania 2.3 IrritabilityAssociatedwithAutisticDisorder –Pediatrics (Childrenand

Adolescents) 2.4 DosinginPatientswithSevereRenalorHepaticImpairment 2.5 DoseAdjustmentsforSpecificDrugInteractions 2.6 AdministrationofRISPERDAL®OralSolution 2.7 DirectionsforUseofRISPERDAL®M-TAB®OrallyDisintegratingTablets3 Dosage forms anD strengtHs4 contrainDications5 Warnings anD PrecaUtions 5.1 IncreasedMortalityinElderlyPatientswithDementia-RelatedPsychosis 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly

PatientswithDementia-RelatedPsychosis 5.3 NeurolepticMalignantSyndrome 5.4 TardiveDyskinesia 5.5 MetabolicChanges 5.6 Hyperprolactinemia 5.7 OrthostaticHypotension 5.8 Leukopenia,Neutropenia,andAgranulocytosis 5.9 PotentialforCognitiveandMotorImpairment 5.10 Seizures 5.11 Dysphagia 5.12 Priapism 5.13 BodyTemperatureRegulation 5.14 PatientswithPhenylketonuria6 aDverse reactions 6.1 ClinicalTrialsExperience 6.2 PostmarketingExperience7 DrUg interactions 7.1 Pharmacokinetic-relatedInteractions 7.2 Pharmacodynamic-relatedInteractions8 Use in sPecific PoPUlations 8.1 Pregnancy 8.2 LaborandDelivery 8.3 NursingMothers

8.4 PediatricUse 8.5 GeriatricUse 8.6 RenalImpairment 8.7 HepaticImpairment 8.8 PatientswithParkinson’sDiseaseorLewyBodyDementia9 DrUg abUse anD DePenDence 9.1 ControlledSubstance 9.2 Abuse 9.3 Dependence10 overDosage 10.1 HumanExperience 10.2 ManagementofOverdosage11 DescriPtion12 clinical PHarmacologY 12.1 MechanismofAction 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 nonclinical toXicologY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility 13.2 AnimalToxicology14 clinical stUDies 14.1 Schizophrenia 14.2 BipolarMania-Monotherapy 14.3 BipolarMania–AdjunctiveTherapywithLithiumorValproate 14.4 IrritabilityAssociatedwithAutisticDisorder16 HoW sUPPlieD/storage anD HanDling 16.1 HowSupplied 16.2 StorageandHandling17 Patient coUnseling information 17.1 OrthostaticHypotension 17.2 InterferencewithCognitiveandMotorPerformance 17.3 Pregnancy 17.4 Nursing 17.5 ConcomitantMedication 17.6 Alcohol 17.7 Phenylketonurics 17.8 MetabolicChanges 17.9 TardiveDyskinesia

*Sections or subsections omitted from the full prescribing information are notlisted

RISPERDAL® (risperidone) RISPERDAL® (risperidone)

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Sticky Note

neuroleptic malignant syndrome is closely related to TD. it is an extreme encephalitis like disorder caused by dopamine blockers that often leaves TD and cognitive dysfunction as a permanent effect

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2 Dosage anD aDministrationtable 1. recommended Daily Dosage by indication

initial Dose

titration (increments)

target Dose

effective Dose

rangeschizophrenia: adults (2.1)

2mg 1to2mg 4to8mg 4to16mg

schizophrenia: adolescents (2.2)

0.5mg 0.5to1mg 3mg 1to6mg

bipolar mania: adults (2.2)

2to3mg 1mg 1to6mg 1to6mg

bipolar mania: children and adolescents (2.2)

0.5mg 0.5to1mg 1to2.5mg 1to6mg

irritability in autistic disorder (2.3)

0.25mgCanincreaseto0.5mgbyDay4:(bodyweightlessthan20kg)

0.5mgCanincreaseto1mgbyDay4:(bodyweightgreaterthanorequalto20kg)

AfterDay4,atintervalsof >2weeks:0.25mg

(bodyweightlessthan20kg)

0.5mg(bodyweightgreaterthanorequalto20kg)

0.5mg:(body

weightlessthan20kg)

1mg:(bodyweight

greaterthanorequalto20kg)

0.5to3mg

Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5mgtwicedaily.Mayincreasetodosagesabove1.5mgtwicedailyatintervalsofoneweekorlonger.2.1 schizophreniaAdultsUsualInitialDose RISPERDAL®canbeadministeredonceortwicedaily. Initialdosing is2mgperday.May increasethedoseat intervalsof24hoursorgreater, in incrementsof 1to2 mgperday,astolerated,toarecommendeddoseof4to8mgperday.Insome patients, slower titration may be appropriate. Efficacy has beendemonstrated inarangeof4mgto16mgperday.However,dosesabove6mgper day for twice daily dosing were not demonstrated to be more efficaciousthan lower doses, were associated with more extrapyramidal symptoms andother adverse effects, and are generally not recommended. In a single studysupporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not beenevaluatedinclinicaltrials[see Clinical Studies (14.1)].AdolescentsThe initial dose is 0.5mgoncedaily, administeredasa single-dailydose in themorningorevening.Thedosemaybeadjustedatintervalsof24hoursorgreater,inincrementsof0.5mgor1 mgperday,astolerated,toarecommendeddoseof3mgperday.Althoughefficacyhasbeendemonstratedinstudiesofadolescentpatients with schizophrenia at doses between 1 mg to 6 mg per day, noadditional benefit was observed above 3 mg per day, and higher doses wereassociatedwithmoreadverseevents.Doseshigherthan6 mgperdayhavenotbeenstudied.Patientsexperiencingpersistentsomnolencemaybenefitfromadministeringhalfthedailydosetwicedaily.MaintenanceTherapyWhile it is unknown how long a patient with schizophrenia should remain on RISPERDAL®,theeffectivenessofRISPERDAL®2mgperdayto8mgperdayatdelayingrelapsewasdemonstratedina controlledtrialinadultpatientswhohadbeenclinicallystableforatleast4weeksandwerethenfollowedforaperiodof1to2years[see Clinical Studies (14.1)].Bothadultandadolescentpatientswhorespondacutely shouldgenerallybemaintainedon theireffectivedosebeyondtheacuteepisode.Patientsshouldbeperiodically reassessed todetermine theneedformaintenancetreatment.ReinitiationofTreatmentinPatientsPreviouslyDiscontinuedAlthough therearenodata tospecificallyaddress reinitiationof treatment, it isrecommendedthatafteranintervaloff RISPERDAL®,theinitialtitrationscheduleshouldbefollowed.SwitchingFromOtherAntipsychoticsThere are no systematically collected data to specifically address switchingschizophrenic patients from other antipsychotics to RISPERDAL®, or treatingpatientswithconcomitantantipsychotics.

2.2 bipolar maniaUsualDoseAdultsThe initial dose range is 2 mg to 3 mg per day. The dose may be adjusted atintervalsof24hoursorgreater,inincrementsof1mgperday.Theeffectivedoserange is1mg to6mgperday,asstudied in theshort-term,placebo-controlledtrials. Inthesetrials,short-term(3week)anti-manicefficacywasdemonstratedin a flexible dosage range of 1mg to 6mg per day [see Clinical Studies (14.2,14.3)].RISPERDAL®doseshigherthan6mgperdaywerenotstudied.PediatricsThe initial dose is 0.5mgoncedaily, administeredasa single-dailydose in themorningorevening.Thedosemaybeadjustedatintervalsof24hoursorgreater,inincrementsof0.5mgor1mgperday,astolerated,totherecommendedtargetdose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated instudies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, andhigher doses were associated with more adverse events. Doses higher than6 mgperdayhavenotbeenstudied.Patientsexperiencingpersistentsomnolencemaybenefitfromadministeringhalfthedailydosetwicedaily.MaintenanceTherapyThereisnobodyofevidenceavailablefromcontrolledtrialstoguideaclinicianinthelonger-termmanagementofapatientwhoimprovesduringtreatmentofanacute manic episode with RISPERDAL®. While it is generally agreed thatpharmacologicaltreatmentbeyondanacuteresponseinmaniaisdesirable,bothfor maintenance of the initial response and for prevention of new manicepisodes, there are no systematically obtained data to support the use of RISPERDAL®insuchlonger-termtreatment(i.e., beyond3weeks).Thephysicianwho elects to use RISPERDAL® for extended periods should periodicallyre-evaluatethelong-termrisksandbenefitsofthedrugfortheindividualpatient.2.3 IrritabilityAssociatedwithAutisticDisorder–Pediatrics(Childrenand

adolescents)Thedosageof RISPERDAL® shouldbe individualizedaccording to the responseand tolerability of the patient. The total daily dose of RISPERDAL® can beadministered once daily, or half the total daily dose can be administered twicedaily.Forpatientswithbodyweightlessthan20kg,initiatedosingat0.25mgperday.For patientswith bodyweight greater than or equal to 20 kg, initiate dosing at 0.5mgperday.Afteraminimumoffourdays,thedosemaybeincreasedtotherecommendeddoseof0.5mgperdayforpatientslessthan20kgand1.0mgperdayforpatientsgreaterthanorequalto20kg.Maintainthisdoseforaminimumof14 days.Inpatientsnotachievingsufficientclinicalresponse,thedosemaybeincreasedatintervalsof2weeksorgreater,inincrementsof0.25mgperdayforpatientslessthan20kg,orincrementsof0.5mgperdayforpatientsgreaterthanorequalto20kg.Theeffectivedoserangeis0.5mgto3mgperday.Nodosingdataareavailableforchildrenwhoweighlessthan15kg.Once sufficient clinical response has been achieved andmaintained, considergradually lowering the dose to achieve the optimal balance of efficacy andsafety. The physician who elects to use RISPERDAL® for extended periodsshould periodically re-evaluate the long-term risks and benefits of the drug fortheindividualpatient.Patientsexperiencingpersistentsomnolencemaybenefitfromaonce-dailydoseadministered at bedtime or administering half the daily dose twice daily, or areductionofthedose.2.4 DosinginPatientswithSevereRenalorHepaticImpairmentFor patients with severe renal impairment (CLcr < 30 mL/min) or hepaticimpairment(10-15pointsonChildPughSystem),theinitialstartingdoseis0.5mgtwice daily. The dose may be increased in increments of 0.5 mg or less,administered twice daily. For doses above 1.5 mg twice daily, increase inintervalsofoneweekorgreater[see Use in Specific Populations (8.6 and 8.7)].2.5 Dose adjustments for specific Drug interactionsWhen RISPERDAL® is co-administered with enzyme inducers (e.g.,carbamazepine),thedoseof RISPERDAL®shouldbeincreaseduptodoublethepatient’s usual dose. It may be necessary to decrease the RISPERDAL® dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of RISPERDAL® with other enzyme inducers (e.g., phenytoin, rifampin, andphenobarbital).Whenfluoxetineorparoxetineisco-administeredwithRISPERDAL®,thedoseof RISPERDAL®shouldbereduced.TheRISPERDAL®doseshouldnotexceed8mgper day in adults when co-administered with these drugs. When initiatingtherapy,RISPERDAL®shouldbetitratedslowly.Itmaybenecessarytoincreasethe RISPERDAL®dosewhenenzyme inhibitorssuchasfluoxetineorparoxetinearediscontinued[see Drug Interactions (7.1)].


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2.6 administration of risPerDal® oral solution RISPERDAL® Oral Solution can be administered directly from the calibratedpipette, or can bemixedwith a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the following beverages: water, coffee, orangejuice,andlow-fatmilk;itisNOTcompatiblewitheithercolaortea.2.7 Directions for Use of risPerDal® m-tab® orally Disintegrating tabletsTabletAccessing RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg RISPERDAL®M-TAB® OrallyDisintegrating Tablets 0.5mg, 1mg, and 2mg aresuppliedinblisterpacksof4tabletseach.Do not open the blister until ready to administer. For single tablet removal,separateoneof the fourblisterunitsby tearingapartat theperforations.Bendthecornerwhereindicated.Peelbackfoiltoexposethetablet.DONOTpushthetabletthroughthefoilbecausethiscoulddamagethetablet. RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL®M-TAB®OrallyDisintegratingTablets3mgand4mgaresuppliedinachild-resistantpouchcontainingablisterwith1tableteach.Thechild-resistantpouchshouldbetornopenatthenotchtoaccesstheblister.Donotopen theblisteruntil ready toadminister.Peelback foil fromtheside toexpose the tablet.DONOTpush the tablet through the foil, because this coulddamagethetablet.TabletAdministrationUsing dry hands, remove the tablet from the blister unit and immediately placethe entire RISPERDAL®M-TAB®OrallyDisintegratingTableton the tongue.The RISPERDAL® M-TAB® Orally Disintegrating Tablet should be consumedimmediately,as the tabletcannotbestoredonce removed from theblisterunit. RISPERDAL® M-TAB® Orally Disintegrating Tablets disintegrate in the mouthwithin seconds and can be swallowed subsequently with or without liquid.Patientsshouldnotattempttosplitortochewthetablet.3 Dosage forms anD strengtHs RISPERDAL®Tabletsareavailableinthefollowingstrengthsandcolors:0.25mg(darkyellow),0.5mg(red-brown),1mg(white),2mg(orange),3mg(yellow),and4 mg (green). All are capsule shaped, and imprinted with “JANSSEN” on onesideandeither“Ris0.25”,“Ris0.5”,“R1”,“R2”,“R3”,or“R4”ontheothersideaccordingtotheirrespectivestrengths. RISPERDAL®OralSolutionisavailableina1mg/mLstrength. RISPERDAL®M-TAB®OrallyDisintegratingTabletsareavailableinthefollowingstrengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral,square), 2mg (coral, square), 3 mg (coral, round), and 4mg (coral, round). All are biconvex and etched on one side with “R0.5”, “R1”, “R2”, “R3”, or “R4”accordingtotheirrespectivestrengths.4 contrainDications RISPERDAL® is contraindicated in patients with a known hypersensitivity to RISPERDAL®. Hypersensitivity reactions, including anaphylactic reactions andangioedema,havebeenobservedinpatientstreatedwithrisperidone.5 Warnings anD PrecaUtions5.1 IncreasedMortalityinElderlyPatientswithDementia-RelatedPsychosisElderly patients with dementia-related psychosis treated with antipsychoticdrugsareatanincreasedriskofdeath.Analysesof17placebo-controlledtrials(modal duration of 10 weeks), largely in patients taking atypical antipsychoticdrugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7times theriskofdeath inplacebo-treatedpatients.Over thecourseofa typical10-week controlled trial, the rate of death in drug-treated patients was about4.5%, compared to a rate of about 2.6% in the placebo group. Although thecauses of death were varied, most of the deaths appeared to be eithercardiovascular (e.g.,heart failure,suddendeath)or infectious (e.g.,pneumonia)in nature. Observational studies suggest that, similar to atypical antipsychoticdrugs, treatmentwith conventional antipsychotic drugsmay increasemortality.Theextent towhich thefindingsof increasedmortality inobservationalstudiesmaybeattributedtotheantipsychoticdrugasopposedtosomecharacteristic(s)ofthepatientsisnotclear. Intwoof fourplacebo-controlledtrials inelderlypatientswithdementia-relatedpsychosis,a higherincidenceofmortalitywasobservedinpatientstreatedwithfurosemide plus RISPERDAL® when compared to patients treated with RISPERDAL®aloneorwithplaceboplusfurosemide.Nopathologicalmechanismhasbeenidentifiedtoexplainthisfinding,andnoconsistentpatternforcauseofdeathwasobserved. RISPERDAL®(risperidone)isnotapprovedforthetreatmentofdementia-relatedpsychosis [see Boxed Warning].

5.2 cerebrovascular adverse reactions, including stroke, in elderly Patients withDementia-RelatedPsychosis

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack),including fatalities,were reported in patients (meanage 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidenceof cerebrovascular adverse events in patients treated with risperidonecomparedtopatientstreatedwithplacebo.RISPERDAL® isnotapprovedforthetreatmentof patientswithdementia-relatedpsychosis.[see Boxed Warning and Warnings and Precautions (5.1)] 5.3 neuroleptic malignant syndromeAntipsychotic drugs including RISPERDAL® can cause a potentially fatalsymptom complex referred to as Neuroleptic Malignant Syndrome (NMS).Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, alteredmental status, and autonomic instability (irregular pulse or blood pressure,tachycardia,diaphoresis,andcardiacdysrhythmia).Additionalsignsmayincludeelevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, andacuterenalfailure.The diagnostic evaluation of patients with this syndrome is complicated. Inarriving at a diagnosis, it is important to identify cases in which the clinicalpresentation includes both serious medical illness (e.g., pneumonia, systemicinfection, etc.) and untreated or inadequately treated extrapyramidal signs andsymptoms (EPS). Other important considerations in the differential diagnosisinclude central anticholinergic toxicity, heat stroke, drug fever, and primarycentralnervoussystempathology.The management of NMS should include: (1) immediate discontinuation ofantipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment ofanyconcomitantseriousmedicalproblems forwhichspecific treatmentsareavailable. There is no general agreement about specific pharmacologicaltreatmentregimensforuncomplicatedNMS.Ifapatient requiresantipsychoticdrug treatmentafter recovery fromNMS, thepotential reintroduction of drug therapy should be carefully considered. Thepatient should be carefully monitored, since recurrences of NMS have beenreported.5.4 tardive DyskinesiaA syndrome of potentially irreversible, involuntary, dyskinetic movements maydevelop in patients treated with antipsychotic drugs. The risk of developingtardivedyskinesiaandthelikelihoodthatitwillbecomeirreversiblearebelievedto increase as the duration of treatment and the total cumulative dose ofantipsychoticdrugsadministeredtothepatientincrease.However,thesyndromecan develop, although much less commonly, after relatively brief treatmentperiodsatlowdoses.There is no known treatment for established cases of tardive dyskinesia,although the syndrome may remit, partially or completely, if antipsychotictreatment iswithdrawn.Antipsychotic treatment, itself, however,may suppress(orpartiallysuppress)thesignsandsymptomsofthesyndromeandtherebymaypossiblymask theunderlyingprocess.Theeffect thatsymptomaticsuppressionhasuponthelong-termcourseof thesyndromeisunknown.Given these considerations, prescribe RISPERDAL® in a manner that is mostlikely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotictreatment should generally be reserved for patientswho suffer from a chronicillness that: (1) is known to respond to antipsychotic drugs, and (2) for whomalternative, equally effective, but potentially less harmful treatments are notavailable or appropriate. In patients who do require chronic treatment, thesmallest dose and the shortest duration of treatment producing a satisfactoryclinicalresponseshouldbesought.Theneedforcontinuedtreatmentshouldbereassessedperiodically.If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, consider drug discontinuation. However, some patients mayrequiretreatmentwithRISPERDAL®despitethepresenceofthesyndrome.5.5 metabolic changesAtypicalantipsychoticdrugshavebeenassociatedwithmetabolicchangesthatmay increase cardiovascular/cerebrovascular risk. These metabolic changesinclude hyperglycemia, dyslipidemia, and body weight gain. While all of thedrugs in theclasshavebeenshowntoproducesomemetabolicchanges,eachdrughasitsownspecificriskprofile.HyperglycemiaandDiabetesMellitusHyperglycemia and diabetes mellitus, in some cases extreme and associatedwith ketoacidosis or hyperosmolar coma or death, have been reported inpatientstreatedwithatypicalantipsychoticsincludingRISPERDAL®.Assessmentoftherelationshipbetweenatypicalantipsychoticuseandglucoseabnormalities


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is complicated by the possibility of an increased background risk of diabetesmellitus inpatientswithschizophreniaandthe increasing incidenceofdiabetesmellitus in the general population. Given these confounders, the relationshipbetweenatypicalantipsychoticuseandhyperglycemia-relatedadverseeventsisnot completely understood. However, epidemiological studies suggest anincreased risk of treatment-emergent hyperglycemia-related adverse events inpatients treated with the atypical antipsychotics. Precise risk estimates forhyperglycemia-related adverse events in patients treated with atypicalantipsychoticsarenotavailable.Patientswith an established diagnosis of diabetesmellituswho are started onatypical antipsychotics, including RISPERDAL®, should be monitored regularlyforworseningofglucosecontrol.Patientswithriskfactorsfordiabetesmellitus(e.g.,obesity,familyhistoryof diabetes)whoarestartingtreatmentwithatypicalantipsychotics, including RISPERDAL®, should undergo fasting blood glucosetesting at the beginning of treatment and periodically during treatment. Anypatient treated with atypical antipsychotics, including RISPERDAL®, should bemonitored for symptoms of hyperglycemia including polydipsia, polyuria,polyphagia, and weakness. Patients who develop symptoms of hyperglycemiaduring treatment with atypical antipsychotics, including RISPERDAL®, shouldundergo fasting blood glucose testing. In some cases, hyperglycemia hasresolved when the atypical antipsychotic, including RISPERDAL®, wasdiscontinued; however, some patients required continuation of anti-diabetictreatmentdespitediscontinuationofRISPERDAL®.Pooled data from three double-blind, placebo-controlled schizophrenia studiesand four double-blind, placebo-controlled bipolar monotherapy studies arepresentedinTable2.

table 2. change in random glucose from seven Placebo-controlled, 3- to 8-Week, Fixed-orFlexible-DoseStudiesinAdultSubjectswithSchizophreniaorbipolar mania

RISPERDAL®

Placebo 1-8mg/day >8-16mg/daymean change from baseline (mg/dl)

n=555 n=748 n=164SerumGlucose -1.4 0.8 0.6

ProportionofpatientswithshiftsSerumGlucose (<140mg/dLto≥200mg/dL)

0.6% (3/525)

0.4% (3/702)

0% (0/158)

In longer-term, controlled and uncontrolled studies, RISPERDAL® wasassociatedwithameanchangeinglucoseof+2.8mg/dLatWeek24(n=151)and+4.1mg/dLatWeek48(n=50).Datafromtheplacebo-controlled3-to6-weekstudyinchildrenandadolescentswith schizophrenia (13-17 years of age), bipolarmania (10-17 years of age), orautisticdisorder(5to17yearsofage)arepresentedinTable3.

table 3. change in fasting glucose from three Placebo-controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia(13-17 years of age), bipolar mania (10-17 years of age), or autistic Disorder (5 to 17 years of age)

RISPERDAL®

Placebo 0.5-6mg/daymean change from baseline (mg/dl)

n=76 n=135SerumGlucose -1.3 2.6

ProportionofpatientswithshiftsSerumGlucose (<100mg/dLto≥126mg/dL)

0% (0/64)

0.8% (1/120)

Inlonger-term,uncontrolled,open-labelextensionpediatricstudies,RISPERDAL® wasassociatedwithameanchangeinfastingglucoseof+5.2mg/dLatWeek24(n=119).

DyslipidemiaUndesirable alterations in lipids have been observed in patients treated withatypicalantipsychotics.Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dosestudies in adult subjectswith schizophrenia or bipolar mania are presented inTable4.

table 4. change in random lipids from seven Placebo-controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects withschizophrenia or bipolar mania

RISPERDAL®

Placebo 1-8mg/day >8-16mg/daymean change from baseline (mg/dl)

cholesterol n=559 n=742 n=156Changefrombaseline 0.6 6.9 1.8triglycerides n=183 n=307 n=123Changefrombaseline -17.4 -4.9 -8.3

Proportion of patients With shiftscholesterol (<200mg/dLto≥240mg/dL)

2.7% (10/368)

4.3% (22/516)

6.3% (6/96)

triglycerides (<500mg/dLto≥500mg/dL)

1.1% (2/180)

2.7% (8/301)

2.5% (3/121)

In longer-term, controlled and uncontrolled studies, RISPERDAL® wasassociatedwith amean change in (a) non-fasting cholesterol of +4.4mg/dL atWeek 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fastingtriglyceridesof+19.9mg/dLatWeek24(n=52).Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies inchildrenandadolescentswithschizophrenia(13-17yearsofage),bipolarmania(10-17 years of age), or autistic disorder (5-17 years of age) are presented inTable5.table 5. change in fasting lipids from three Placebo-controlled, 3- to 6-Week,

Fixed-Dose Studies in Children and Adolescents with Schizophrenia(13-17 Years of age), bipolar mania (10-17 Years of age), or autistic Disorder (5 to 17 Years of age)

RISPERDAL®

Placebo 0.5-6mg/daymean change from baseline (mg/dl)

cholesterol n=74 n=133Changefrombaseline 0.3 -0.3lDl n=22 n=22Changefrombaseline 3.7 0.5HDl n=22 n=22Changefrombaseline 1.6 -1.9triglycerides n=77 n=138Changefrombaseline -9.0 -2.6

Proportionofpatientswithshiftscholesterol (<170mg/dLto≥200mg/dL)

2.4% (1/42)

3.8% (3/80)

lDl (<110mg/dLto≥130mg/dL)

0% (0/16)

0% (0/16)

HDl (≥40mg/dLto<40mg/dL)

0% (0/19)

10% (2/20)

triglycerides (<150mg/dLto≥200mg/dL)

1.5% (1/65)

7.1% (8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL® was associatedwith amean change in (a) fasting cholesterol of+2.1mg/dLatWeek24(n=114);(b)fastingLDLof-0.2mg/dLatWeek24(n=103);(c)fastingHDLof+0.4mg/dLatWeek24(n=103);and(d)fastingtriglyceridesof+6.8mg/dLatWeek24(n=120).

WeightGainWeight gain has been observed with atypical antipsychotic use. Clinicalmonitoringofweightisrecommended.Dataonmeanchangesinbodyweightandtheproportionofsubjectsmeetingaweightgaincriterionof7%orgreaterofbodyweightfrom7placebo-controlled,3-to8-week,fixed-orflexible-dosestudiesinadultsubjectswithschizophreniaorbipolarmaniaarepresentedinTable6.

Table6.MeanChangeinBodyWeight(kg)andtheProportionofSubjectswith≥7% gain in body Weight from seven Placebo-controlled, 3- to 8-Week, fixed- or flexible-Dose studies in adult subjects With schizophrenia or bipolar mania

RISPERDAL®

Placebo (n=597)

1-8mg/day (n=769)

>8-16mg/day (n=158)

Weight (kg)Changefrombaseline -0.3 0.7 2.2Weight gain≥7%increasefrombaseline 2.9% 8.7% 20.9%


6

In longer-term, controlled and uncontrolled studies, RISPERDAL® wasassociated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3kgatWeek48(n=203).Data onmean changes in bodyweight and the proportion of subjectsmeetingthe criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to8-week, fixed-dose studies in children and adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), autistic disorder (5-17 years of age), or other psychiatric disorders (5-17 years of age) arepresentedinTable7.

table 7. mean change in body Weight (kg) and the Proportion of subjects With ≥7% gain in body Weight from nine Placebo-controlled, 3- to 8-Week, fixed-Dose studies in children and adolescents With schizophrenia (13-17 Years of age), bipolar mania (10-17 Years of age), autistic Disorder (5 to 17 Years of age) or other Psychiatric Disorders (5-17 Years of age)

Placebo (n=375)

risPerDal® 0.5-6 mg/day (n=448)

Weight (kg)Changefrombaseline 0.6 2.0Weight gain≥7%increasefrombaseline 6.9% 32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL®wasassociatedwithameanchange inweightof+5.5kgatWeek24(n=748)and+8.0kgatWeek48(n=242).In a long-term, open-label extension study in adolescent patients withschizophrenia,weight increasewas reportedasa treatment-emergent adverseevent in14%ofpatients. In103adolescentpatientswithschizophrenia,ameanincreaseof 9.0 kgwasobservedafter 8monthsof RISPERDAL® treatment.Themajority of that increasewas observedwithin the first 6 months. The averagepercentiles at baseline and 8months, respectively,were 56 and 72 forweight,55 and58forheight,and51and71forbodymassindex.In long-term,open-label trials (studies inpatientswithautisticdisorderorotherpsychiatricdisorders),ameanincreaseof7.5kgafter12monthsofRISPERDAL® treatment was observed, which was higher than the expected normal weightgain (approximately3 to3.5kgperyearadjusted forage,basedonCenters forDisease Control and Prevention normative data). The majority of that increaseoccurred within the first 6 months of exposure to RISPERDAL®. The averagepercentilesatbaselineand12months, respectively,were49and60 forweight,48and53forheight,and50and62forbodymassindex.Inone3-week,placebo-controlledtrial inchildrenandadolescentpatientswithacutemanic ormixed episodes of bipolar I disorder, increases in bodyweightwere higher in the RISPERDAL® groups than the placebo group, but not doserelated(1.90kgintheRISPERDAL®0.5-2.5 mggroup,1.44kgintheRISPERDAL® 3-6 mggroup,and0.65kgintheplacebogroup).Asimilartrendwasobservedinthemeanchangefrombaselineinbodymassindex.When treating pediatric patients with RISPERDAL® for any indication, weightgainshouldbeassessedagainstthatexpectedwithnormalgrowth.5.6 HyperprolactinemiaAs with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevatesprolactinlevelsandtheelevationpersistsduringchronicadministration. RISPERDAL® is associated with higher levels of prolactin elevation than otherantipsychoticagents.Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reducedpituitarygonadotropinsecretion.This,inturn,mayinhibitreproductivefunctionbyimpairinggonadalsteroidogenesisinbothfemaleandmalepatients. Galactorrhea,amenorrhea, gynecomastia, and impotence have been reported in patientsreceivingprolactin-elevatingcompounds.Long-standinghyperprolactinemiawhenassociated with hypogonadism may lead to decreased bone density in bothfemaleandmalesubjects.Tissuecultureexperimentsindicatethatapproximatelyone-thirdofhumanbreastcancers are prolactin dependent in vitro, a factorofpotential importance if theprescriptionofthesedrugsiscontemplatedinapatientwithpreviouslydetectedbreast cancer. An increase in pituitary gland, mammary gland, and pancreaticislet cell neoplasia (mammary adenocarcinomas, pituitary and pancreaticadenomas)wasobservedintherisperidonecarcinogenicitystudiesconductedinmice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies norepidemiologic studies conducted to date have shown an association betweenchronic administration of this class of drugs and tumorigenesis in humans; theavailableevidenceisconsideredtoolimitedtobeconclusiveatthistime.5.7 orthostatic Hypotension RISPERDAL® may induce orthostatic hypotension associated with dizziness,tachycardia, and in some patients, syncope, especially during the initial dose-titrationperiod,probably reflecting itsalpha-adrenergicantagonisticproperties.Syncope was reported in 0.2% (6/2607) of RISPERDAL®-treated patients inPhase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic

hypotensionand syncopemaybeminimizedby limiting the initial dose to 2mgtotal (either once daily or 1mg twice daily) in normal adults and 0.5mg twicedaily in the elderly and patientswith renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)]. Monitoring of orthostatic vital signs should beconsidered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be used withparticular caution in patients with known cardiovascular disease (history ofmyocardial infarction or ischemia, heart failure, or conduction abnormalities),cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significanthypotension has been observed with concomitant use of RISPERDAL® and antihypertensivemedication.5.8 leukopenia, neutropenia, and agranulocytosisClass Effect: In clinical trial and/or postmarketing experience, events ofleukopenia/neutropenia have been reported temporally related to antipsychoticagents,includingRISPERDAL®.Agranulocytosishasalsobeenreported.Possible risk factors for leukopenia/neutropenia include pre-existing lowwhiteblood cell count (WBC) and history of drug-induced leukopenia/neutropenia.Patients with a history of a clinically significant low WBC or a drug-inducedleukopenia/neutropeniashouldhavetheircompletebloodcount(CBC)monitoredfrequently during the first few months of therapy and discontinuation of RISPERDAL® should be considered at the first sign of a clinically significantdeclineinWBCintheabsenceofothercausativefactors.Patientswithclinicallysignificantneutropeniashouldbecarefullymonitoredforfever or other symptoms or signs of infection and treated promptly if suchsymptomsorsignsoccur.Patientswithsevereneutropenia(absoluteneutrophilcount<1000/mm3)shoulddiscontinueRISPERDAL®andhavetheirWBCfolloweduntilrecovery.5.9 Potential for cognitive and motor impairmentSomnolence was a commonly reported adverse reaction associated with RISPERDAL® treatment, especially when ascertained by direct questioning ofpatients. This adverse reaction is dose-related, and in a study utilizing achecklist todetectadverseevents,41% of thehigh-dosepatients (RISPERDAL® 16mg/day) reported somnolence compared to 16% of placebo patients. Directquestioning is more sensitive for detecting adverse events than spontaneousreporting, bywhich 8% of RISPERDAL® 16mg/day patients and 1% of placebopatients reported somnolence as an adverse reaction. Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients should becautioned about operating hazardous machinery, including automobiles, untilthey are reasonably certain that RISPERDAL® therapy does not affect themadversely.5.10 seizuresDuring premarketing testing in adult patients with schizophrenia, seizuresoccurred in 0.3% (9/2607) of RISPERDAL®-treated patients, two in associationwith hyponatremia. RISPERDAL® should be used cautiously in patients with ahistoryofseizures.5.11 DysphagiaEsophageal dysmotility andaspirationhavebeenassociatedwithantipsychoticdruguse.Aspirationpneumoniaisacommoncauseofmorbidityandmortalityinpatients with advanced Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in patients at risk for aspirationpneumonia.[see Boxed Warning and Warnings and Precautions (5.1)]5.12 PriapismPriapismhasbeenreportedduringpostmarketingsurveillance.Severepriapismmayrequiresurgicalintervention.5.13 body temperature regulationDisruption of body temperature regulation has been attributed to antipsychoticagents. Both hyperthermia and hypothermia have been reported in associationwithoralRISPERDAL®use.Cautionisadvisedwhenprescribingforpatientswhowillbeexposedtotemperatureextremes.5.14 PatientswithPhenylketonuriaInform patients that RISPERDAL® M-TAB® Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.84 mgphenylalanine; each 3 mg RISPERDAL® M-TAB® Orally Disintegrating Tabletcontains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-TAB® OrallyDisintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mgphenylalanine.6 aDverse reactionsThefollowingarediscussedinmoredetailinothersectionsofthelabeling:• Increasedmortality in elderly patientswith dementia-related psychosis [see

Boxed Warning and Warnings and Precautions (5.1)]• Cerebrovascular adverse events, including stroke, in elderly patients with

dementia-relatedpsychosis[see Warnings and Precautions (5.2)]


7

• Neurolepticmalignantsyndrome[see Warnings and Precautions (5.3)]• Tardivedyskinesia[see Warnings and Precautions (5.4)]• Metabolic Changes (Hyperglycemia and diabetesmellitus, Dyslipidemia, and

WeightGain)[see Warnings and Precautions (5.5)]• Hyperprolactinemia[see Warnings and Precautions (5.6)]• Orthostatichypotension[see Warnings and Precautions (5.7)]• Leukopenia,neutropenia,andagranulocytosis[see Warnings and Precautions

(5.8)]• Potential forcognitiveandmotor impairment [see Warnings and Precautions

(5.9)]• Seizures[see Warnings and Precautions (5.10)]• Dysphagia[see Warnings and Precautions (5.11)]• Priapism[see Warnings and Precautions (5.12)]• Disruption of body temperature regulation [see Warnings and Precautions

(5.13)]• PatientswithPhenylketonuria[see Warnings and Precautions (5.14)].Themost common adverse reactions in clinical trials (>5%and twice placebo)were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety,blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort,dyspepsia,diarrhea,salivaryhypersecretion,constipation,drymouth, increasedappetite, increased weight, fatigue, rash, nasal congestion, upper respiratorytractinfection,nasopharyngitis,andpharyngolaryngealpain.Themostcommonadversereactions thatwereassociatedwithdiscontinuationfrom clinical trials (causing discontinuation in >1% of adults and/or >2% ofpediatrics) were nausea, somnolence, sedation, vomiting, dizziness, andakathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6.1)].The data described in this section are derived from a clinical trial databaseconsistingof9803adultandpediatricpatientsexposedtooneormoredosesof RISPERDAL®forthetreatmentofschizophrenia,bipolarmania,autisticdisorder,andotherpsychiatricdisordersinpediatricsandelderlypatientswithdementia.Of these 9803 patients, 2687 were patients who received RISPERDAL® whileparticipating in double-blind, placebo-controlled trials. The conditions andduration of treatment with RISPERDAL® varied greatly and included (inoverlapping categories) double-blind, fixed- and flexible-dose, placebo- oractive-controlled studies and open-label phases of studies, inpatients andoutpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years)exposures. Safety was assessed by collecting adverse events and performingphysicalexaminations,vitalsigns,bodyweights,laboratoryanalyses,andECGs.6.1 clinical trials experienceBecauseclinical trials areconductedunderwidely varyingconditions, adversereaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in theclinical trials of anotherdrugandmaynot reflect theratesobservedinclinicalpractice.Commonly-Observed Adverse Reactions in Double-Blind, Placebo-ControlledClinicalTrials–SchizophreniaAdult Patients with SchizophreniaTable 8 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult patients with schizophrenia in three 4- to 8-week, double-blind,placebo-controlledtrials.

table 8. adverse reactions in ≥2% of risPerDal®-treated adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-controlled trials

Percentage of Patients reporting reaction

risPerDal®

system/organ classAdverseReaction

2-8 mg per day (n=366)

>8-16 mg per day (n=198)

Placebo (n=225)

cardiac DisordersTachycardia 1 3 0eye DisordersVisionblurred 3 1 1gastrointestinal DisordersNausea 9 4 4Constipation 8 9 6 Dyspepsia 8 6 5Drymouth 4 0 1Abdominaldiscomfort 3 1 1Salivaryhypersecretion 2 1 <1 Diarrhea 2 1 1general DisordersFatigue 3 1 0Chestpain 2 2 1 Asthenia 2 1 <1

table 8. adverse reactions in ≥2% of risPerDal®-treated adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-controlled trials (continued)


risPerDal®



>8-16 mg per day (n=198)

Placebo (n=225)

infections and infestationsNasopharyngitis 3 4 3Upperrespiratorytractinfection 2 3 1Sinusitis 1 2 1Urinarytractinfection 1 3 0investigationsBloodcreatinephosphokinase increased

1 2 <1

Heartrateincreased <1 2 0musculoskeletal and connective tissue DisordersBackpain 4 1 1Arthralgia 2 3 <1Paininextremity 2 1 1nervous system DisordersParkinsonism* 14 17 8Akathisia* 10 10 3 Sedation 10 5 2Dizziness 7 4 2Dystonia* 3 4 2Tremor* 2 3 1Dizzinesspostural 2 0 0Psychiatric DisordersInsomnia 32 25 27Anxiety 16 11 11respiratory, thoracic and mediastinal DisordersNasalcongestion 4 6 2 Dyspnea 1 2 0Epistaxis <1 2 0skin and subcutaneous tissue Disorders Rash 1 4 1Dryskin 1 3 0vascular DisordersOrthostatichypotension 2 1 0* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness,parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, maskedfacies,musclerigidity,andParkinson’sdisease.Akathisiaincludesakathisiaandrestlessness.Dystoniaincludesdystonia,musclespasms,musclecontractionsinvoluntary, muscle contracture, oculogyration, tongue paralysis. Tremorincludestremorandparkinsonianresttremor.

Pediatric Patients with SchizophreniaTable 9 lists the adverse reactions reported in 5% or more of RISPERDAL®-treatedpediatricpatientswithschizophreniaina6-weekdouble-blind,placebo-controlledtrial.

table 9. adverse reactions in ≥5% of risPerDal®-treated Pediatric Patients (andgreaterthanplacebo)withSchizophreniainaDouble-BlindTrial

Percentage of Patients reporting reaction risPerDal®




Placebo (n=54)

gastrointestinal DisordersSalivaryhypersecretion 0 10 2nervous system Disorders Sedation 24 12 4Parkinsonism* 16 28 11Tremor 11 10 6Akathisia* 9 10 4Dizziness 7 14 2Dystonia* 2 6 0Psychiatric DisordersAnxiety 7 6 0* Parkinsonismincludesextrapyramidaldisorder,musclerigidity,musculoskeletalstiffness, and hypokinesia. Akathisia includes akathisia and restlessness.Dystoniaincludesdystoniaandoculogyration.


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Commonly-Observed Adverse Reactions in Double-Blind, Placebo-ControlledClinicalTrials–BipolarManiaAdult Patients with Bipolar ManiaTable 10 lists the adverse reactions reported in 2% or more of RISPERDAL®-treatedadultpatientswithbipolarmania in four3-week,double-blind,placebo-controlledmonotherapytrials.

table 10. adverse reactions in ≥2% of risPerDal®-treated adult Patients (and greater than placebo)withBipolarMania inDouble-Blind, Placebo-controlled monotherapy trials



risPerDal®


Placebo (n=424)

eye DisordersVisionblurred 2 1gastrointestinal DisordersNausea 5 2 Diarrhea 3 2Salivaryhypersecretion 3 1Stomachdiscomfort 2 <1general DisordersFatigue 2 1nervous system DisordersParkinsonism* 25 9 Sedation 11 4Akathisia* 9 3Tremor* 6 3Dizziness 6 5Dystonia* 5 1Lethargy 2 1*Parkinsonism includesextrapyramidal disorder, parkinsonism,musculoskeletalstiffness,hypokinesia,musclerigidity,muscletightness,bradykinesia,cogwheelrigidity.Akathisia includesakathisia and restlessness. Tremor includes tremorand parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms,oculogyration,torticollis.

Table 11 lists the adverse reactions reported in 2% or more of RISPERDAL®-treatedadult patientswithbipolarmania in two3-week, double-blind, placebo-controlledadjuvanttherapytrials.

table 11. adverse reactions in ≥2% of risPerDal®-treated adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-controlled adjunctive therapy trials

Percentage of Patients reporting reaction system/organ class

risPerDal® + mood stabilizer

Placebo + mood stabilizer

AdverseReaction (n=127) (n=126)cardiac Disorders Palpitations 2 0gastrointestinal Disorders Dyspepsia 9 8Nausea 6 4 Diarrhea 6 4Salivaryhypersecretion 2 0general DisordersChestpain 2 1infections and infestationsUrinarytractinfection 2 1nervous system DisordersParkinsonism* 14 4 Sedation 9 4Akathisia* 8 0Dizziness 7 2Tremor 6 2Lethargy 2 1Psychiatric DisordersAnxiety 3 2respiratory, thoracic and mediastinal DisordersPharyngolaryngealpain 5 2Cough 2 0* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.Akathisiaincludeshyperkinesiaandakathisia.

Pediatric Patients with Bipolar ManiaTable 12 lists the adverse reactions reported in 5% or more of RISPERDAL®-treatedpediatricpatientswithbipolarmania ina3-weekdouble-blind,placebo-controlledtrial.

table 12. adverse reactions in ≥5% of risPerDal®-treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind,Placebo-controlled trials

Percentage of Patients reporting reaction risPerDal ®


0.5-2.5 mg per day (n=50)


Placebo (n=58)

eye DisordersVisionblurred 4 7 0gastrointestinal DisordersAbdominalpainupper 16 13 5Nausea 16 13 7Vomiting 10 10 5 Diarrhea 8 7 2 Dyspepsia 10 3 2Stomachdiscomfort 6 0 2general DisordersFatigue 18 30 3metabolism and nutrition Disorders Increased appetite 4 7 2nervous system Disorders Sedation 42 56 19Dizziness 16 13 5Parkinsonism* 6 12 3Dystonia* 6 5 0Akathisia* 0 8 2Psychiatric DisordersAnxiety 0 8 3respiratory, thoracic and mediastinal DisordersPharyngolaryngealpain 10 3 5skin and subcutaneous tissue Disorders Rash 0 7 2*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,bradykinesia,andnuchalrigidity.Dystoniaincludesdystonia, laryngospasm,andmusclespasms.Akathisiaincludesrestlessnessandakathisia.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-ControlledClinicalTrials-AutisticDisorderTable 13 lists the adverse reactions reported in 5% or more of RISPERDAL®-treatedpediatricpatients treatedfor irritabilityassociatedwithautisticdisorderin two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind,placebo-controlledstudy.

table 13. adverse reactions in ≥5% of risPerDal®-treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated withautistic Disorder in Double-blind, Placebo-controlled trials


system/organ class risPerDal®

0.5-4.0 mg/day Placebo adverse reaction (n=107) (n=115)gastrointestinal DisordersVomiting 20 17Constipation 17 6Drymouth 10 4Nausea 8 5Salivaryhypersecretion 7 1general Disorders and administration site conditionsFatigue 31 9Pyrexia 16 13Thirst 7 4infections and infestationsNasopharyngitis 19 9 Rhinitis 9 7Upperrespiratorytractinfection 8 3investigationsWeightincreased 8 2metabolism and nutrition Disorders Increased appetite 44 15


9

table 13. adverse reactions in ≥5% of risPerDal®-treated Pediatric Patients (and greater than placebo) treated for irritability associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials(continued)


system/organ class risPerDal®

0.5-4.0 mg/day Placebo adverse reaction (n=107) (n=115)nervous system Disorders Sedation 63 15Drooling 12 4Headache 12 10 Tremor 8 1Dizziness 8 2Parkinsonism* 8 1renal and Urinary DisordersEnuresis 16 10respiratory, thoracic and mediastinal DisordersCough 17 12 Rhinorrhea 12 10Nasalcongestion 10 4skin and subcutaneous tissue Disorders Rash 8 5*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,musclerigidity,cogwheelrigidity,andmuscletightness.

Other Adverse Reactions Observed During the Clinical Trial Evaluation ofRisperidoneThe following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL® in adultsandpediatricpatients.BloodandLymphaticSystemDisorders:anemia,granulocytopenia,neutropeniaCardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular blockfirstdegree,bundlebranchblockleft,bundlebranchblockright,atrioventricularblockEarandLabyrinthDisorders:earpain,tinnitusEndocrineDisorders:hyperprolactinemiaEyeDisorders:ocularhyperemia,eyedischarge,conjunctivitis,eyerolling,eyelidedema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased,photophobia,glaucoma,visualacuityreducedGastrointestinalDisorders:dysphagia,fecaloma,fecalincontinence,gastritis, lipswelling,cheilitis,aptyalismGeneral Disorders: edema peripheral, thirst, gait disturbance, influenza-likeillness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort,face edema, discomfort, generalized edema, drug withdrawal syndrome,peripheralcoldness,feelingabnormalImmuneSystemDisorders:drughypersensitivityInfections and Infestations: pneumonia, influenza, ear infection, viral infection,pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis,cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia,respiratorytractinfection,tracheobronchitis,otitismediachronicInvestigations: body temperature increased, blood prolactin increased, alanineaminotransferase increased, electrocardiogram abnormal, eosinophil countincreased, white blood cell count decreased, blood glucose increased,hemoglobin decreased, hematocrit decreased, body temperature decreased,bloodpressuredecreased,transaminasesincreasedMetabolismandNutritionDisorders:decreasedappetite,polydipsia,anorexiaMusculoskeletal andConnectiveTissueDisorders: joint stiffness, joint swelling,musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscularweakness,rhabdomyolysisNervous System Disorders: balance disorder, disturbance in attention,dysarthria,unresponsivetostimuli,depressedlevelofconsciousness,movementdisorder, transient ischemic attack, coordination abnormal, cerebrovascularaccident, speech disorder, syncope, loss of consciousness, hypoesthesia,tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder,neurolepticmalignantsyndrome,diabeticcoma,headtitubationPsychiatric Disorders: agitation, blunted affect, confusional state, middleinsomnia, nervousness, sleep disorder, listlessness, libido decreased, andanorgasmia

RenalandUrinaryDisorders:enuresis,dysuria,pollakiuria,urinaryincontinenceReproductiveSystemandBreastDisorders:menstruationirregular,amenorrhea,gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectiledysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction,breastenlargementRespiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumoniaaspiration, sinus congestion, dysphonia, productive cough, pulmonarycongestion, respiratory tract congestion, rales, respiratory disorder,hyperventilation,nasaledemaSkin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skinlesion,pruritus,skindisorder,rasherythematous,rashpapular,rashgeneralized,rashmaculopapular,acne,hyperkeratosis,seborrheicdermatitisVascularDisorders:hypotension,flushingAdditionalAdverseReactionsReportedwithRISPERDAL®CONSTA®

The following is a list of additional adverse reactions that have been reportedduring the premarketing evaluation of RISPERDAL® CONSTA®, regardless offrequencyofoccurrence:CardiacDisorders:bradycardiaEarandLabyrinthDisorders:vertigoEyeDisorders:blepharospasmGastrointestinalDisorders:toothache,tonguespasmGeneralDisordersandAdministrationSiteConditions:painInfections and Infestations: lower respiratory tract infection, infection,gastroenteritis,subcutaneousabscessInjuryandPoisoning:fallInvestigations: weight decreased, gamma-glutamyltransferase increased,hepaticenzymeincreasedMusculoskeletal,ConnectiveTissue,andBoneDisorders:buttockpainNervousSystemDisorders:convulsion,paresthesiaPsychiatric Disorders: depressionSkinandSubcutaneousTissueDisorders:eczemaVascularDisorders:hypertension

DiscontinuationsDuetoAdverseReactionsSchizophrenia - AdultsApproximately 7% (39/564) of RISPERDAL®-treated patients in double-blind,placebo-controlled trials discontinued treatment due to an adverse reaction,comparedwith4%(10/225)whowerereceivingplacebo.Theadversereactionsassociatedwithdiscontinuationin2ormoreRISPERDAL®-treatedpatientswere:

table 14. adverse reactions associated With Discontinuation in 2 or more risPerDal®-treated adult Patients in schizophrenia trials

risPerDal®

adverse reaction

2-8 mg/day (n=366)

>8-16 mg/day (n=198)

Placebo (n=225)

Dizziness 1.4% 1.0% 0%Nausea 1.4% 0% 0%Vomiting 0.8% 0% 0%Parkinsonism 0.8% 0% 0%Somnolence 0.8% 0% 0%Dystonia 0.5% 0% 0%Agitation 0.5% 0% 0%Abdominalpain 0.5% 0% 0%Orthostatichypotension 0.3% 0.5% 0%Akathisia 0.3% 2.0% 0%

Discontinuationforextrapyramidalsymptoms(includingParkinsonism,akathisia,dystonia,and tardivedyskinesia)was1% inplacebo-treatedpatients,and3.4%in active control-treated patients in a double-blind, placebo- and active-controlledtrial.Schizophrenia - PediatricsApproximately 7% (7/106), of RISPERDAL®-treated patients discontinuedtreatmentduetoanadversereaction inadouble-blind,placebo-controlledtrial,compared with 4% (2/54) placebo-treated patients. The adverse reactionsassociated with discontinuation for at least one RISPERDAL®-treated patientweredizziness(2%),somnolence(1%),sedation(1%),lethargy(1%),anxiety(1%),balancedisorder(1%),hypotension(1%),andpalpitation(1%).


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Bipolar Mania - AdultsIn double-blind, placebo-controlled trials with RISPERDAL® as monotherapy,approximately 6% (25/448) of RISPERDAL®-treated patients discontinuedtreatmentduetoanadverseevent,comparedwithapproximately5%(19/424)ofplacebo-treatedpatients.Theadversereactionsassociatedwithdiscontinuationin RISPERDAL®-treatedpatientswere:

table 15. adverse reactions associated With Discontinuation in 2 or more risPerDal®-treated adult Patients in bipolar mania clinical trials

adverse reaction

risPerDal® 1-6 mg/day

(n=448)

Placebo (n=424)

Parkinsonism 0.4% 0%Lethargy 0.2% 0%Dizziness 0.2% 0%Alanineaminotransferaseincreased

0.2% 0.2%

Aspartateaminotransferaseincreased

0.2% 0.2%

Bipolar Mania - PediatricsIn a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treatedpatients discontinued due to an adverse reaction, compared with 7% (4/58) ofplacebo-treatedpatients.Theadversereactionsassociatedwithdiscontinuationin more than one RISPERDAL®-treated pediatric patient were nausea (3%),somnolence(2%),sedation(2%),andvomiting(2%).Autistic Disorder - PediatricsIn the two 8-week, placebo-controlled trials in pediatric patients treated forirritability associatedwith autistic disorder (n = 156), one RISPERDAL®-treatedpatient discontinued due to an adverse reaction (Parkinsonism), and oneplacebo-treatedpatientdiscontinuedduetoanadverseevent.DoseDependencyofAdverseReactionsinClinicalTrialsExtrapyramidal SymptomsDatafromtwofixed-dosetrialsinadultswithschizophreniaprovidedevidenceofdose-relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.Two methods were used to measure extrapyramidal symptoms (EPS) in an8-week trial comparing 4 fixeddosesof RISPERDAL® (2, 6, 10, and 16mg/day),including (1) a Parkinsonism score (mean change from baseline) from theExtrapyramidal Symptom Rating Scale, and (2) incidence of spontaneouscomplaintsofEPS:

table 16.Dose groups Placebo risPerDal®

2 mg risPerDal®

6 mg risPerDal®

10 mg risPerDal®

16 mgParkinsonism 1.2 0.9 1.8 2.4 2.6EPS Incidence 13% 17% 21% 21% 35%

Similar methods were used to measure extrapyramidal symptoms (EPS) in an8-weektrialcomparing5fixeddosesofRISPERDAL®(1,4,8,12,and16mg/day):

table 17.Dose groups risPerDal®

1 mg risPerDal®

4 mg risPerDal®

8 mg risPerDal®

12 mg risPerDal®

16 mgParkinsonism 0.6 1.7 2.4 2.9 4.1EPS Incidence 7% 12% 17% 18% 20%

DystoniaClass Effect:Symptomsofdystonia,prolongedabnormalcontractionsofmusclegroups, may occur in susceptible individuals during the first few days oftreatment. Dystonic symptoms include: spasm of the neckmuscles, sometimesprogressing to tightnessof the throat, swallowingdifficulty, difficultybreathing,and/orprotrusionofthetongue.Whilethesesymptomscanoccurat lowdoses,they occurmore frequently andwith greater severitywith high potency andathigher doses of first generation antipsychotic drugs. An elevated risk of acutedystoniaisobservedinmalesandyoungeragegroups.Other Adverse ReactionsAdverse event data elicited by a checklist for side effects from a large studycomparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) wereexplored for dose-relatedness of adverse events. A Cochran-Armitage Test fortrend in thesedata revealed a positive trend (p<0.05) for the followingadversereactions:somnolence,visionabnormal,dizziness,palpitations,weightincrease,erectiledysfunction,ejaculationdisorder,sexualfunctionabnormal,fatigue,andskindiscoloration.ChangesinBodyWeightWeight gain was observed in short-term, controlled trials and longer-termuncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use in Specific Populations (8.4)].

ChangesinECGParametersBetween-group comparisons for pooled placebo-controlled trials in adultsrevealednostatisticallysignificantdifferencesbetweenrisperidoneandplaceboin mean changes from baseline in ECG parameters, including QT, QTc, and PRintervals, and heart rate. When all RISPERDAL® doses were pooled fromrandomizedcontrolledtrialsinseveralindications,therewasameanincreaseinheart rateof1beatperminutecompared tonochange forplacebopatients. Inshort-termschizophrenia trials, higherdosesof risperidone (8-16mg/day)wereassociated with a higher mean increase in heart rate compared to placebo (4-6beatsperminute).Inpooledplacebo-controlledacutemaniatrialsinadults,there were small decreases in mean heart rate, similar among all treatmentgroups.In the two placebo-controlled trials in children and adolescents with autisticdisorder (aged 5 - 16 years) mean changes in heart rate were an increase of 8.4beatsperminute in the RISPERDAL®groupsand6.5beatsperminute in theplacebogroup.TherewerenoothernotableECGchanges.Inaplacebo-controlledacutemaniatrialinchildrenandadolescents(aged10–17years), therewerenosignificantchanges inECGparameters,other than theeffect of RISPERDAL®totransientlyincreasepulserate(<6beatsperminute).Intwo controlled schizophrenia trials in adolescents (aged 13 – 17 years), therewere no clinically meaningful changes in ECG parameters including correctedQTintervalsbetweentreatmentgroupsorwithintreatmentgroupsovertime.6.2 Postmarketing experienceThefollowingadversereactionshavebeenidentifiedduringpostapprovaluseofrisperidone.Becausethesereactionsarereportedvoluntarily fromapopulationofuncertainsize,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablish a causal relationship to drug exposure. These adverse reactionsinclude: alopecia, anaphylactic reaction, angioedema, atrial fibrillation,cardiopulmonary arrest, diabetic ketoacidosis in patients with impaired glucosemetabolism,dysgeusia,hypoglycemia,hypothermia, ileus, inappropriateantidiuretic hormone secretion, intestinal obstruction, jaundice, mania,pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QTprolongation, sleep apnea syndrome, sudden death, thrombocytopenia,thromboticthrombocytopenicpurpura,urinaryretention,andwaterintoxication.7 DrUg interactions7.1 Pharmacokinetic-related interactionsThe dose of RISPERDAL® should be adjusted when used in combination withCYP2D6enzymeinhibitors(e.g.,fluoxetine,andparoxetine)andenzymeinducers(e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5)].Doseadjustment is not recommended for RISPERDAL® when co-administered withranitidine,cimetidine,amitriptyline,orerythromycin[see Table 18].table 18 summary of effect of coadministered Drugs on exposure to active

moiety ( risperidone + 9-Hydroxy-risperidone) in Healthy subjects or PatientswithSchizophrenia

CoadministeredDrug DosingSchedule Effect on ActiveMoiety(Risperidone +9-Hydroxy-Risperidone (Ratio*)

Risperidone Dose Recommendation

CoadministeredDrug

Risperidone AUC Cmax

Enzyme(CYP2D6)InhibitorsFluoxetine 20mg/day 2or3mg

twicedaily1.4 1.5 Re-evaluate

dosing.Donotexceed8 mg/day

Paroxetine 10mg/day 4mg/day 1.3 - Re-evaluatedosing.Donotexceed8 mg/day

20mg/day 4mg/day 1.6 -40mg/day 4mg/day 1.8 -

Enzyme(CYP3A/PgPinducers)InducersCarbamazepine 573±168mg/day 3mgtwice

daily0.51 0.55 Titratedose

upwards.Donotexceedtwicethepatient’susualdose

Enzyme(CYP3A)InhibitorsRanitidine 150mgtwice

daily1mgsingledose

1.2 1.4 Doseadjustmentnot needed

Cimetidine 400mgtwicedaily

1mgsingledose


Erythromycin 500mgfourtimesdaily

1mgsingledose


OtherDrugsAmitriptyline 50mgtwice

daily3mgtwicedaily


*Changerelativetoreference


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EffectofRisperidoneonotherdrugsLithiumRepeated oral doses of RISPERDAL® (3 mg twice daily) did not affect theexposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Doseadjustmentforlithiumisnotrecommended.ValproateRepeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However,therewas a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERDAL®. Dose adjustment for valproate isnotrecommended.Digoxin RISPERDAL®(0.25mgtwicedaily)didnotshowaclinicallyrelevanteffectonthepharmacokineticsofdigoxin.Doseadjustmentfordigoxinisnotrecommended.

7.2 Pharmacodynamic-related interactionsCentrally-ActingDrugsandAlcoholGiven the primary CNS effects of risperidone, caution should be used when RISPERDAL® is taken in combination with other centrally-acting drugs andalcohol.DrugswithHypotensiveEffectsBecauseofitspotentialforinducinghypotension,RISPERDAL®mayenhancethehypotensiveeffectsofothertherapeuticagentswiththispotential.LevodopaandDopamineAgonists RISPERDAL®mayantagonizetheeffectsoflevodopaanddopamineagonists.ClozapineChronic administration of clozapine with RISPERDAL® may decrease theclearanceofrisperidone.

8 Use in sPecific PoPUlations8.1 PregnancyPregnancyCategoryCRisk SummaryAdequateandwellcontrolledstudieswithRISPERDALhavenotbeenconductedin pregnant women. Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester of pregnancy are at risk forextrapyramidal and/or withdrawal symptoms following delivery. There was noincrease in the incidence of malformations in embryo-fetal studies in rats andrabbitsat0.4–6 timesMHRD. Increasedpupmortalitywasnotedatalldoses inperi-postnatal studies in rats. RISPERDAL® should be used during pregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.Clinical ConsiderationsFetal/NeonatalAdverseReactionsMonitor neonates exhibiting extrapyramidal or withdrawal symptoms. Someneonates recover within hours or days without specific treatment; others mayrequireprolongedhospitalization.DataHumanDataTherehavebeenreportsofagitation,hypertonia,hypotonia,tremor,somnolence,respiratory distress, and feeding disorder in neonates following in uteroexposure to antipsychotics in the third trimester. These complications havevariedinseverity;whileinsomecasessymptomshavebeenself-limited,inothercases neonates have required intensive care unit support and prolongedhospitalization.Therewasonereportofacaseofagenesisof thecorpuscallosuminan infantexposedtorisperidone in utero.ThecausalrelationshiptoRISPERDAL® therapy isunknown.AnimalDataTheteratogenicpotentialofrisperidonewasstudiedinthreeSegmentIIstudiesinSprague-DawleyandWistarrats(0.63-10mg/kgor0.4to6timesthemaximumrecommendedhumandose[MRHD]onamg/m2bodysurfaceareabasis)andinoneSegmentIIstudyinNewZealandrabbits(0.31-5 mg/kgor0.4to6timestheMRHDonamg/m2 bodysurfaceareabasis).Therewerenoteratogeniceffectsin offspring of rats or rabbits given 0.4 to 6 times theMRHD on amg/m2 bodysurfaceareabasis. In threereproductivestudies inrats (twoSegment IIIandamultigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times theMRHD on a mg/m2bodysurfaceareabasis.It isnotknownwhetherthesedeathswereduetoadirecteffectonthefetusesorpupsortoeffectsonthedams.Therewasnono-effectdosefor increasedratpupmortality. InoneSegmentIIIstudy, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or1.5 times theMRHD on a mg/m2body surface area basis. In a cross-fosteringstudy in Wistar rats, toxic effects on the fetus or pups were observed, asevidenced by a decrease in the number of live pups and an increase in thenumberofdeadpupsatbirth(Day0),andadecrease inbirthweight inpupsof

drug-treateddams.Inaddition,therewasanincreaseindeathsbyDay1amongpups of drug-treated dams, regardless of whether or not the pups werecross-fostered. Risperidone also appeared to impair maternal behavior in thatpupbodyweightgainandsurvival(fromDay1to4oflactation)werereducedinpups born to control but reared by drug-treated dams. These effects were allnotedattheonedoseofrisperidonetested,i.e.,5mg/kgor3 timestheMRHDonamg/m2 bodysurfaceareabasis.Placentaltransferofrisperidoneoccursinratpups.8.2 labor and DeliveryTheeffectofRISPERDAL®onlaboranddeliveryinhumansisunknown.8.3 nursing mothersRisperidone and 9-hydroxyrisperidone are present in human breast milk.Because of the potential for serious adverse reactions in nursing infants fromrisperidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseApprovedPediatricIndicationsSchizophreniaTheefficacyandsafetyof RISPERDAL® in the treatmentofschizophreniaweredemonstrated in 417 adolescents, aged 13 – 17 years, in two short-term (6 and 8weeks, respectively)double-blindcontrolled trials [see Indications and Usage (1.1),Adverse Reactions (6.1),and Clinical Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-labelextensionstudyin284oftheseadolescentpatientswithschizophrenia.Safety and effectiveness of RISPERDAL® in children less than 13 years of agewithschizophreniahavenotbeenestablished.Bipolar I DisorderThe efficacy and safety of RISPERDAL® in the short-term treatment of acutemanicormixedepisodesassociatedwithBipolar IDisorder in169childrenandadolescentpatients,aged10–17years,weredemonstratedinonedouble-blind,placebo-controlled, 3-week trial [see Indications and Usage (1.2), Adverse Reactions (6.1),and Clinical Studies (14.2)].Safety and effectiveness of RISPERDAL® in children less than 10 years of agewithbipolardisorderhavenotbeenestablished.Autistic DisorderTheefficacyandsafetyofRISPERDAL®inthetreatmentofirritabilityassociatedwith autistic disorder were established in two 8-week, double-blind, placebo-controlledtrialsin156 childrenandadolescentpatients,aged5to16years[see Indications and Usage (1.3), Adverse Reactions (6.1) and Clinical Studies (14.4)].Additionalsafetyinformationwasalsoassessedinalong-termstudyinpatientswith autistic disorder, or in short- and long-term studies in more than 1200pediatric patients with psychiatric disorders other than autistic disorder,schizophrenia, or bipolarmaniawhowere of similar age andweight, andwhoreceived similar dosages of RISPERDAL® as patients treated for irritabilityassociatedwithautisticdisorder.A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled,fixed-dosestudy toevaluate theefficacyandsafetyofa lower thanrecommendeddoseof risperidone insubjects5 to17yearsofagewithautisticdisorderandassociatedirritability,andrelatedbehavioralsymptoms.Thereweretwoweight-based,fixeddosesofrisperidone(high-doseandlow-dose).Thehighdosewas1.25mgperdayforpatientsweighing20to<45kg,anditwas1.75mgper day for patientsweighing> 45 kg. The lowdosewas 0.125mgper day forpatients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day forpatients weighing > 45 kg. The study demonstrated the efficacy of high-doserisperidone,butitdidnotdemonstrateefficacyforlow-doserisperidone.AdverseReactionsinPediatricPatientsTardive DyskinesiaIn clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved ondiscontinuation of RISPERDAL® treatment [see also Warnings and Precautions (5.4)].Weight GainWeight gain has been observed in children and adolescents during treatmentwith RISPERDAL®. Clinical monitoring of weight is recommended duringtreatment.Data derive from short-term placebo-controlled trials and longer-termuncontrolledstudiesinpediatricpatients(ages5to17years)withschizophrenia,bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-termtrials(3to8weeks),themeanweightgainforRISPERDAL®-treatedpatientswas 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials,approximately33%oftheRISPERDAL®grouphadweightgain>7%,comparedto7% in the placebo group. In longer-term, uncontrolled, open-label pediatricstudies, themeanweightgainwas5.5kgatWeek24and8 kgatWeek48 [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].


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This is grossly misleading. The trials lasting a few weeks were much too short to cause tardive dyskinesia except in rare cases

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SomnolenceSomnolence was frequently observed in placebo-controlled clinical trials ofpediatric patientswith autistic disorder.Most casesweremild or moderate inseverity. These events were most often of early onset with peak incidenceoccurringduring thefirst twoweeksof treatment, and transientwithamedianduration of 16 days. Somnolence was the most commonly observed adversereaction in the clinical trial of bipolar disorder in children and adolescents, aswell as in the schizophrenia trials in adolescents. As was seen in the autisticdisorder trials, these adverse reactions were most often of early onset andtransientinduration [see Adverse Reactions (6.1 and 6.2)].Patientsexperiencingpersistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1,2.2,and 2.3)].Hyperprolactinemia RISPERDAL® has been shown to elevate prolactin levels in children andadolescentsaswellasinadults[see Warnings and Precautions (5.6)].Indouble-blind, placebo-controlled studies of up to 8 weeks duration in children andadolescents (aged 5 to 17 years)with autistic disorder or psychiatric disordersotherthanautisticdisorder,schizophrenia,orbipolarmania,49%ofpatientswhoreceivedRISPERDAL®hadelevatedprolactinlevelscomparedto2%ofpatientswho received placebo. Similarly, in placebo-controlled trials in children andadolescents(aged10to17years)withbipolardisorder,oradolescents(aged13to 17 years)with schizophrenia, 82–87%ofpatientswho received RISPERDAL® had elevated levels of prolactin compared to 3-7% of patients on placebo.Increasesweredose-dependentandgenerallygreater infemalesthan inmalesacrossindications.Inclinical trials in1885childrenandadolescents,galactorrheawas reported in0.8%ofRISPERDAL®-treatedpatientsandgynecomastiawasreportedin2.3%of RISPERDAL®-treatedpatients.GrowthandSexualMaturationThelong-termeffectsofRISPERDAL®ongrowthandsexualmaturationhavenotbeenfullyevaluatedinchildrenandadolescents.JuvenileAnimalStudiesJuveniledogsweretreatedfor40weekswithoralrisperidonedosesof0.31,1.25,or5mg/kg/day.Decreasedbonelengthanddensitywereseen,withano-effectdose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidoneplusitsactivemetabolitepaliperidone(9-hydroxy-risperidone)whichwere similar to those in children and adolescents receiving the maximumrecommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexualmaturationwasseenatalldoses inbothmalesand females.Theaboveeffects showed little or no reversibility in females after a 12 week drug-freerecoveryperiod.Inastudyinwhichjuvenileratsweretreatedwithoralrisperidonefromdays12to 50 of age, a reversible impairment of performance in a test of learning andmemorywasseen,infemalesonly,withano-effectdoseof0.63mg/kg/day.Thisdose produced plasma levels (AUC) of risperidone plus paliperidone about halfthose observed in humans at the MRHD. No other consistent effects onneurobehavioral or reproductive development were seen up to the highesttestable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) ofrisperidonepluspaliperidonewhichwereabout twothirdsof thoseobserved inhumansattheMRHD.8.5 geriatric UseClinicalstudiesofRISPERDAL®inthetreatmentofschizophreniadidnotincludesufficientnumbersofpatientsaged 65andovertodeterminewhetherornottheyresponddifferentlythanyoungerpatients.Otherreportedclinicalexperiencehasnot identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient,reflecting a decreased pharmacokinetic clearance in the elderly, as well as agreater frequency of decreased hepatic, renal, or cardiac function, and ofconcomitantdiseaseorotherdrugtherapy[see Clinical Pharmacology (12.3) and Dosage and Administration (2.4, 2.5)]. While elderly patients exhibit a greatertendency toorthostatichypotension, its risk in theelderlymaybeminimizedbylimiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)].Monitoringoforthostaticvital signsshouldbeconsideredinpatientsforwhomthisisofconcern.Thisdrugissubstantiallyexcretedbythekidneys,andtheriskoftoxicreactionsto this drug may be greater in patients with impaired renal function. Becauseelderlypatientsaremorelikelytohavedecreasedrenalfunction,careshouldbetaken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)].8.6 renal impairmentIn patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease,clearanceofthesumofrisperidoneanditsactivemetabolitedecreasedby60%,compared to younghealthy subjects. RISPERDAL® doses should be reduced inpatientswithrenaldisease[see Dosage and Administration (2.4)].

8.7 Hepatic impairmentWhile the pharmacokinetics of risperidone in subjects with liver diseasewerecomparable to those in young healthy subjects, the mean free fraction ofrisperidone in plasma was increased by about 35% because of the diminishedconcentrationof bothalbuminanda1-acidglycoprotein.RISPERDAL®dosesshouldbereducedinpatientswithliverdisease[see Dosage and Administration (2.4)].8.8 PatientswithParkinson’sDiseaseorLewyBodyDementiaPatientswithParkinson’sDiseaseorDementiawithLewyBodiescanexperienceincreased sensitivity to RISPERDAL®. Manifestations can include confusion,obtundation, postural instability with frequent falls, extrapyramidal symptoms,andclinicalfeaturesconsistentwithneurolepticmalignantsyndrome.

9 DrUg abUse anD DePenDence9.1 controlled substance RISPERDAL®(risperidone)isnotacontrolledsubstance.9.2 abuse RISPERDAL® has not been systematically studied in animals or humans for itspotential forabuse.While theclinical trialsdidnot revealany tendency foranydrug-seeking behavior, these observations were not systematic and it is notpossible topredicton thebasisof this limitedexperiencetheextent towhichaCNS-active drug will be misused, diverted, and/or abused once marketed.Consequently,patientsshouldbeevaluatedcarefullyforahistoryofdrugabuse,andsuchpatientsshouldbeobservedclosely for signsof RISPERDAL®misuseor abuse (e.g., development of tolerance, increases in dose, drug-seekingbehavior).9.3 Dependence RISPERDAL® has not been systematically studied in animals or humans for itspotentialfortoleranceorphysicaldependence.

10 overDosage10.1 Human experiencePremarketing experience included eight reports of acute RISPERDAL® overdosagewithestimateddosesrangingfrom20to300mgandnofatalities.Ingeneral, reported signs and symptoms were those resulting from anexaggerationof thedrug’sknownpharmacologicaleffects, i.e.,drowsinessandsedation,tachycardiaandhypotension,andextrapyramidalsymptoms.Onecase,involvinganestimatedoverdoseof 240mg,wasassociatedwithhyponatremia,hypokalemia, prolonged QT, and widened QRS. Another case, involving anestimatedoverdoseof36mg,wasassociatedwithaseizure.Postmarketing experience includes reports of acute RISPERDAL® overdosage,withestimateddosesof up to 360mg. Ingeneral, themost frequently reportedsigns and symptoms are those resulting from an exaggeration of the drug’sknown pharmacological effects, i.e., drowsiness, sedation, tachycardia,hypotension, and extrapyramidal symptoms. Other adverse reactions reportedsince market introduction related to RISPERDAL® overdose include prolongedQT interval and convulsions. Torsade de pointes has been reported inassociationwithcombinedoverdoseofRISPERDAL®andparoxetine.10.2 management of overdosageFor the most up to date information on the management of RISPERDAL® overdosage, contact a certified poison control center (1-800-222-1222 orwww.poison.org). Provide supportive care including close medical supervision andmonitoring. Treatment should consist of general measures employed in themanagement of overdosage with any drug. Consider the possibility of multipledrug overdosage. Ensure an adequate airway, oxygenation, and ventilation.Monitor cardiac rhythm and vital signs. Use supportive and symptomaticmeasures.ThereisnospecificantidotetoRISPERDAL®.11 DescriPtion RISPERDAL® contains risperidone, an atypical antipsychotic belonging to thechemical class of benzisoxazole derivatives. The chemical designation is3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.ItsmolecularformulaisC23H27FN4O2 and itsmolecularweightis410.49.Thestructuralformulais:

Risperidoneisawhitetoslightlybeigepowder.Itispracticallyinsolubleinwater,freelysolubleinmethylenechloride,andsolubleinmethanoland0.1NHCl.


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RISPERDAL® Tablets are for oral administration and available in 0.25mg (darkyellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the following inactiveingredients:colloidalsilicondioxide,hypromellose,lactose,magnesiumstearate,microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch(corn).The0.25mg,0.5mg,2mg,3mg,and4mg tabletsalsocontain talcandtitaniumdioxide.The0.25 mgtabletscontainyellowironoxide;the0.5mgtabletscontain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 AluminumLake; the 3 mg and 4 mg tablets contain D&C YellowNo. 10; the 4 mg tabletscontainFD&CBlueNo.2 AluminumLake. RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® OralSolution contains the following inactive ingredients: tartaric acid, benzoic acid,sodiumhydroxide,andpurifiedwater. RISPERDAL®M-TAB®OrallyDisintegratingTabletsareavailable in0.5mg (lightcoral), 1 mg (lightcoral), 2mg (coral), 3mg (coral), and4mg (coral) strengths. RISPERDAL®M-TAB®OrallyDisintegratingTabletscontainthefollowinginactiveingredients:Amberlite® resin, gelatin,mannitol, glycine, simethicone,carbomer,sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition,the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tabletscontainxanthangum.12 clinical PHarmacologY12.1 mechanism of actionThe mechanism of action of RISPERDAL®, in schizophrenia, is unknown.However, it has been proposed that the drug’s therapeutic activity inschizophreniacouldbemediatedthrougha combinationofdopamineType2(D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from RISPERDAL® results from the combined concentrations of risperidone and itsmajor metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] mayexplainsomeoftheothereffectsofRISPERDAL®.

12.2 Pharmacodynamics RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2),a1 and a2 adrenergic, and H1 histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, butwith lower potency. RISPERDAL® has low tomoderateaffinity (Kiof 47 to253nM) for theserotonin5HT1C, 5HT1D, and5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, andnoaffinity (when testedat concentrations>10-5M)forcholinergicmuscarinicorb1 and b2adrenergicreceptors.12.3 PharmacokineticsAbsorptionRisperidone iswell absorbed. The absolute oral bioavailability of risperidone is70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is94% (CV=10%)whencomparedtoasolution.PharmacokineticstudiesshowedthatRISPERDAL®M-TAB®OrallyDisintegratingTabletsandRISPERDAL®OralSolutionarebioequivalenttoRISPERDAL®Tablets.Plasmaconcentrationsof risperidone, itsmajormetabolite, 9-hydroxyrisperidone,and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosingrangeof1to16mgdaily(0.5to8mgtwicedaily).Followingoraladministrationofsolution or tablet, mean peak plasma concentrations of risperidone occurred atabout 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about3 hoursinextensivemetabolizers,and17hoursinpoormetabolizers.Steady-stateconcentrationsof risperidonearereached in1day inextensivemetabolizersandwould be expected to reach steady-state in about 5 days in poor metabolizers.Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days(measuredinextensivemetabolizers).Food EffectFooddoesnotaffecteithertherateorextentofabsorptionofrisperidone.Thus, RISPERDAL®canbegivenwithorwithoutmeals.DistributionRisperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. Inplasma, risperidone is bound to albumin anda1-acid glycoprotein. The plasmaprotein binding of risperidone is 90%, and that of its major metabolite,9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidonedisplaceseachotherfromplasmabindingsites.Hightherapeuticconcentrationsof sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinicalsignificance.MetabolismRisperidone isextensivelymetabolized in the liver.Themainmetabolicpathwayis through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme,CYP 2D6. A minor metabolic pathway is through N-dealkylation. The mainmetabolite, 9-hydroxyrisperidone, has similar pharmacological activity asrisperidone. Consequently, the clinical effect of the drug results from thecombinedconcentrationsofrisperidoneplus9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible formetabolism of many neuroleptics, antidepressants, antiarrhythmics, and otherdrugs.CYP2D6issubjecttogeneticpolymorphism(about6%-8%ofCaucasians,and a very low percentage of Asians, have little or no activity and are “poormetabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convertrisperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6metabolizersconvertitmuchmoreslowly.Althoughextensivemetabolizershavelower risperidone and higher 9-hydroxyrisperidone concentrations than poormetabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidonecombined, after single and multiple doses, are similar in extensive and poormetabolizers.Risperidone could be subject to two kinds of drug-drug interactions. First,inhibitors of CYP 2D6 interfere with conversion of risperidone to9-hydroxyrisperidone [see Drug Interactions (7)]. This occurs with quinidine,giving essentially all recipients a risperidone pharmacokinetic profile typical ofpoormetabolizers.Thetherapeuticbenefitsandadverseeffectsofrisperidoneinpatients receiving quinidine have not been evaluated, but observations in amodest number (n@70) of poormetabolizers given RISPERDAL® do not suggestimportant differences between poor and extensive metabolizers. Second,co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin,rifampin, and phenobarbital) with RISPERDAL® may cause a decrease in thecombined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7)]. Itwouldalsobepossible forrisperidoneto interferewithmetabolism of other drugs metabolized by CYP 2D6. Relatively weak bindingof risperidonetotheenzymesuggeststhisisunlikely[see Drug Interactions (7)].In vitro studies indicate that risperidone is a relatively weak inhibitor ofCYP 2D6. Therefore, RISPERDAL® is not expected to substantially inhibit theclearance of drugs that are metabolized by this enzymatic pathway. In druginteraction studies, RISPERDAL® did not significantly affect the pharmaco-kineticsofdonepezilandgalantamine,whicharemetabolizedbyCYP2D6.In vitro studies demonstrated that drugs metabolized by other CYP isozymes,including 1A1, 1A2, 2C9, 2C19, and 3A4, are onlyweak inhibitors of risperidonemetabolism.ExcretionRisperidone and its metabolites are eliminated via the urine and, to a muchlesserextent,viathefeces.Asillustratedbyamassbalancestudyofasingle1mgoraldoseof 14C-risperidoneadministeredassolution to threehealthymalevolunteers, total recoveryof radioactivity at 1 weekwas 84%, including 70% intheurineand14% inthefeces.The apparent half-life of risperidone was 3 hours (CV=30%) in extensivemetabolizersand20 hours(CV=40%)inpoormetabolizers.Theapparenthalf-lifeof 9-hydroxyrisperidonewasabout21hours(CV=20%)inextensivemetabolizersand 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics ofrisperidoneand9-hydroxyrisperidonecombined,aftersingleandmultipledoses,were similar in extensive and poor metabolizers, with an overall meaneliminationhalf-lifeofabout20hours.Drug-DrugInteractionStudies[See Drug Interactions (7)].SpecificPopulationsRenal and Hepatic Impairment[See Use in Specific Populations (8.6 and 8.7)].ElderlyIn healthy elderly subjects, renal clearance of both risperidone and9-hydroxyrisperidonewasdecreased,andeliminationhalf-liveswereprolongedcompared to younghealthy subjects.Dosing should bemodifiedaccordingly inthe elderly patients [see Use in Specific Populations (8.5)].PediatricThepharmacokineticsof risperidoneand9-hydroxyrisperidone inchildrenweresimilartothoseinadultsaftercorrectingforthedifferenceinbodyweight.Race and Gender EffectsNo specific pharmacokinetic study was conducted to investigate race andgender effects, but a population pharmacokinetic analysis did not identifyimportant differences in the disposition of risperidone due to gender (whethercorrectedforbodyweightornot)orrace.13 nonclinical toXicologY13.1 carcinogenesis, mutagenesis, impairment of fertilityCarcinogenesisCarcinogenicity studieswere conducted in Swiss albinomice andWistar rats.Risperidonewasadministered inthedietatdosesof0.63mg/kg,2.5mg/kg,and10 mg/kg for 18 months to mice and for 25 months to rats. These doses areequivalent to approximately 2, 9, and 38 times the maximum recommendedhumandose(MRHD)forschizophreniaof16 mg/dayonamg/kgbasisor0.2, 0.75,and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 bodysurfacebasis.A maximumtolerateddosewasnotachievedinmale


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14

mice.Therewerestatisticallysignificant increases inpituitaryglandadenomas,endocrine pancreas adenomas, and mammary gland adenocarcinomas. Thetable below summarizes the multiples of the human dose on a mg/m2 (mg/kg)basisatwhichthesetumorsoccurred.

multiples of maximum Human Dose in mg/m2

(mg/kg)tumor type species sex Lowest

effect level

Highest no-effect

levelPituitaryadenomas mouse female 0.75(9.4) 0.2(2.4)Endocrine pancreas adenomas

rat male 1.5(9.4) 0.4(2.4)

Mammaryglandadenocarcinomas

mouse female 0.2(2.4) none

rat female 0.4(2.4) nonerat male 6.0(37.5) 1.5(9.4)

Mammaryglandneoplasm,Total

rat male 1.5(9.4) 0.4(2.4)

Antipsychotic drugshavebeen shown to chronically elevate prolactin levels inrodents. Serum prolactin levels were not measured during the risperidonecarcinogenicity studies; however, measurements during subchronic toxicitystudiesshowedthatrisperidoneelevatedserumprolactinlevels5-6foldinmiceand ratsat thesamedosesused in thecarcinogenicity studies.An increase inmammary, pituitary, and endocrine pancreas neoplasms has been found inrodents after chronic administration of other antipsychotic drugs and isconsidered to be prolactin-mediated. The relevance for human risk of thefindings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6)].MutagenesisNoevidenceofmutagenicorclastogenicpotential forrisperidonewasfound inthe Ames gene mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in vivo micronucleus test in mice, the sex-linkedrecessive lethal test inDrosophila,or thechromosomalaberrationtest inhumanlymphocytesorChinesehamsterovarycells.ImpairmentofFertilityRisperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, inWistarratsinthreereproductivestudies(twoSegmentIandamultigenerationalstudy)atdoses0.1 to3 times themaximumrecommendedhumandose(MRHD)onamg/m2 bodysurfaceareabasis.Theeffectappearedtobeinfemales,sinceimpairedmatingbehaviorwasnotnoted in theSegment Istudy inwhichmalesonly were treated. In a subchronic study in Beagle dogs in which risperidonewas administered orally at doses of 0.31 to 5 mg/kg, sperm motility andconcentrationwere decreased at doses 0.6 to 10 times theMRHDon amg/m2 body surface area basis. Dose-related decreases were also noted in serumtestosterone at the same doses. Serum testosterone and sperm parameterspartially recovered, but remained decreased after treatmentwas discontinued.A no-effectdosecouldnotbedeterminedineitherratordog.13.2 animal toxicologyJuveniledogsweretreatedfor40weekswithoralrisperidonedosesof0.31,1.25,or 5 mg/kg/day. Decreased bone length and density were observed with ano-effect dose of 0.31 mg/kg/day. This dose produced plasma AUC levels ofrisperidoneplusitsactivemetabolitepaliperidone(9-hydroxy-risperidone)whichwere similar to those in children and adolescents receiving the maximumrecommended human dose (MRHD) of 6mg/day. In addition, a delay in sexualmaturationwasseenatalldoses inbothmalesandfemales.Theaboveeffectsshowed little or no reversibility in females after a 12 week drug-free recoveryperiod.Inastudyinwhichjuvenileratsweretreatedwithoralrisperidonefromdays12to 50 of age, a reversible impairment of performance in a test of learning andmemorywasobserved in femalesonlywithano-effectdoseof0.63mg/kg/day.This dose produced plasma AUC levels of risperidone plus paliperidone abouthalf those observed in humans at the MRHD. No other consistent effects onneurobehavioral or reproductive development were seen up to the highesttestable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels ofrisperidonepluspaliperidonewhichwereabout twothirdsof thoseobserved inhumansattheMRHD.

14 clinical stUDies14.1 schizophreniaAdultsShort-Term EfficacyTheefficacyof RISPERDAL® in the treatmentof schizophreniawasestablishedinfourshort-term(4-to8-week)controlledtrialsofpsychoticinpatientswhometDSM-III-Rcriteriaforschizophrenia.

Severalinstrumentswereusedforassessingpsychiatricsignsandsymptomsinthese studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate theeffects of drug treatment in schizophrenia. The BPRS psychosis cluster(conceptualdisorganization,hallucinatorybehavior,suspiciousness,andunusualthoughtcontent)isconsideredaparticularlyusefulsubsetforassessingactivelypsychotic schizophrenic patients. A second traditional assessment, the ClinicalGlobal Impression (CGI), reflects the impression of a skilled observer, fullyfamiliarwiththemanifestationsofschizophrenia,abouttheoverallclinicalstateof the patient. In addition, the Positive andNegative Syndrome Scale (PANSS)andtheScaleforAssessingNegativeSymptoms(SANS)wereemployed.Theresultsofthetrialsfollow:(1) In a 6-week, placebo-controlled trial (n=160) involving titration of

RISPERDAL® indosesup to10 mg/day (twice-dailyschedule), RISPERDAL® was generally superior to placebo on the BPRS total score, on the BPRSpsychosiscluster,andmarginallysuperiortoplaceboontheSANS.

(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed dosesof RISPERDAL® (2 mg/day,6 mg/day,10mg/day,and16mg/day,ona twice-dailyschedule),all4 RISPERDAL®groupsweregenerallysuperiortoplaceboontheBPRStotalscore,BPRSpsychosiscluster,andCGIseverityscore;the3 highest RISPERDAL® dose groupswere generally superior to placebo onthePANSSnegativesubscale.Themostconsistentlypositive responsesonall measures were seen for the 6 mg dose group, and there was nosuggestionofincreasedbenefitfromlargerdoses.

(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed dosesof RISPERDAL® (1 mg/day,4 mg/day,8mg/day,12mg/day,and16mg/day,ona twice-daily schedule), the four highest RISPERDAL® dose groups weregenerallysuperiortothe1mgRISPERDAL®dosegrouponBPRStotalscore,BPRS psychosis cluster, and CGI severity score. None of the dose groupsweresuperiortothe1mggrouponthePANSSnegativesubscale.Themostconsistentlypositiveresponseswereseenforthe4mgdosegroup.

(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving2 fixed doses of RISPERDAL® (4 and 8 mg/day on a once-daily schedule),both RISPERDAL® dose groups were generally superior to placebo onseveralPANSSmeasures,includingaresponsemeasure(>20%reductioninPANSS total score), PANSS total score, and the BPRS psychosis cluster(derivedfromPANSS).Theresultsweregenerallystrongerforthe8mgthanforthe4mgdosegroup.

Long-Term EfficacyIn a longer-term trial, 365 adult outpatients predominantly meeting DSM-IVcriteriaforschizophreniaandwhohadbeenclinicallystableforatleast4weeksonanantipsychoticmedicationwererandomizedtoRISPERDAL®(2-8mg/day)orto an active comparator, for 1 to 2 years of observation for relapse. Patientsreceiving RISPERDAL® experienced a significantly longer time to relapse overthistimeperiodcomparedtothosereceivingtheactivecomparator.PediatricsThe efficacy of RISPERDAL® in the treatment of schizophrenia in adolescentsaged13–17yearswasdemonstratedintwoshort-term(6and8weeks),double-blind controlled trials. All patients met DSM-IV diagnostic criteria forschizophreniaandwereexperiencinganacuteepisodeattimeofenrollment.Inthe first trial (study #1), patients were randomized into one of three treatmentgroups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg), RISPERDAL®4-6mg/day(n=51,meanmodaldose=5.3mg),orplacebo(n = 54).In the second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day (n = 132, mean modal dose = 0.5 mg) orRISPERDAL®1.5–6mg/day(n=125,meanmodaldose=4mg).Inallcases,studymedicationwasinitiatedat0.5mg/day(withtheexceptionofthe0.15-0.6mg/daygroup in study #2, where the initial dose was 0.05 mg/day) and titrated to thetarget dosage range by approximately Day 7. Subsequently, dosage wasincreasedtothemaximumtolerateddosewithinthetargetdoserangebyDay14.Theprimaryefficacyvariable inallstudieswasthemeanchangefrombaselineintotalPANSSscore.Resultsof thestudiesdemonstratedefficacyof RISPERDAL® inalldosegroupsfrom1-6 mg/daycompared toplacebo,asmeasuredbysignificant reductionoftotal PANSS score. The efficacy on the primary parameter in the 1-3 mg/daygroupwas comparable to the 4-6 mg/day group in study #1, and similar to theefficacy demonstrated in the 1.5–6 mg/day group in study #2. In study #2, theefficacyinthe1.5-6mg/daygroupwasstatisticallysignificantlygreaterthanthatin the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not reveal anytrendtowardsgreaterefficacy.14.2 bipolar mania - monotherapyAdultsTheefficacyof RISPERDAL® inthetreatmentofacutemanicormixedepisodeswasestablished in twoshort-term(3-week)placebo-controlled trials inpatientswho met the DSM-IV criteria for Bipolar I Disorder with manic or mixedepisodes.Thesetrialsincludedpatientswithorwithoutpsychoticfeatures.


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Theprimaryratinginstrumentusedforassessingmanicsymptomsinthesetrialswas the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scaletraditionally used to assess the degree of manic symptomatology (irritability,disruptive/aggressivebehavior,sleep,elevatedmood,speech,increasedactivity,sexual interest, language/thought disorder, thought content, appearance, andinsight) in a range from 0 (no manic features) to 60 (maximum score). Theprimary outcome in these trials was change from baseline in the YMRS totalscore.Theresultsofthetrialsfollow:(1) Inone3-weekplacebo-controlledtrial(n=246),limitedtopatientswithmanic

episodes, which involved a dose range of RISPERDAL® 1-6 mg/day, oncedaily,startingat3mg/day(meanmodaldosewas4.1mg/day), RISPERDAL® wassuperiortoplacebointhereductionofYMRStotalscore.

(2) In another 3-week placebo-controlled trial (n=286), which involved a doserangeof1-6 mg/day,oncedaily,startingat3mg/day(meanmodaldosewas5.6 mg/day),RISPERDAL®wassuperiortoplacebointhereductionof YMRStotalscore.

PediatricsTheefficacyofRISPERDAL®inthetreatmentofmaniainchildrenoradolescentswithBipolarIdisorderwasdemonstratedina3-week,randomized,double-blind,placebo-controlled,multicentertrialincludingpatientsranginginagesfrom10to17yearswhowereexperiencingamanicormixedepisodeofbipolarIdisorder.Patients were randomized into one of three treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg), RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, studymedicationwasinitiatedat0.5mg/dayandtitratedtothetargetdosagerangebyDay7,withfurtherincreasesindosagetothemaximumtolerateddosewithinthetargeteddoserangebyDay10.Theprimaryratinginstrumentusedforassessingefficacy in this study was the mean change from baseline in the total YMRSscore.Resultsofthisstudydemonstratedefficacyof RISPERDAL® inbothdosegroupscompared with placebo, as measured by significant reduction of total YMRSscore.Theefficacyontheprimaryparameterinthe3-6mg/daydosegroupwascomparabletothe0.5-2.5mg/daydosegroup.Doseshigherthan2.5mg/daydidnotrevealanytrendtowardsgreaterefficacy.14.3 BipolarMania–AdjunctiveTherapywithLithiumorValproateThe efficacy of RISPERDAL® with concomitant lithium or valproate in thetreatment of acutemanic ormixed episodeswas established in one controlledtrialinadultpatientswhomettheDSM-IVcriteriaforBipolarIDisorder.Thistrialincludedpatientswithorwithoutpsychoticfeaturesandwithorwithoutarapid-cyclingcourse.(1) Inthis3-weekplacebo-controlledcombinationtrial,148in-oroutpatientson

lithium or valproate therapy with inadequately controlled manic or mixedsymptomswere randomized to receive RISPERDAL®, placebo, or an activecomparator, in combination with their original therapy. RISPERDAL®, ina dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in atherapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL,respectively)was superior to lithium or valproate alone in the reduction ofYMRStotalscore.

(2) In a second 3-week placebo-controlled combination trial, 142 in- oroutpatientsonlithium,valproate,orcarbamazepinetherapywithinadequatelycontrolled manic or mixed symptoms were randomized to receive RISPERDAL® or placebo, in combination with their original therapy. RISPERDAL®,inadoserangeof1-6 mg/day,oncedaily,startingat2 mg/day(mean modal dose of 3.7 mg/day), combined with lithium, valproate, orcarbamazepine (in therapeutic rangesof 0.6 mEq/L to 1.4mEq/L for lithium,50mcg/mLto125mcg/mLforvalproate,or4-12mcg/mLforcarbamazepine,respectively)wasnotsuperiortolithium,valproate,orcarbamazepinealonein the reductionof YMRS total score.Apossibleexplanation for the failure ofthistrialwasinductionofrisperidoneand9-hydroxyrisperidoneclearanceby carbamazepine, leading to subtherapeutic levels of risperidone and9-hydroxyrisperidone.

14.4 IrritabilityAssociatedwithAutisticDisorderShort-TermEfficacyThe efficacy of RISPERDAL® in the treatment of irritability associated withautistic disorder was established in two 8-week, placebo-controlled trials inchildrenandadolescents (aged5 to 16 years)whomet theDSM-IVcriteria forautistic disorder. Over 90% of these subjects were under 12 years of age andmostweighedover20kg(16-104.3kg).Efficacy was evaluated using two assessment scales: the Aberrant BehaviorChecklist (ABC)and theClinicalGlobal Impression -Change (CGI-C) scale. Theprimary outcome measure in both trials was the change from baseline toendpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscalemeasured the emotional and behavioral symptoms of autism, includingaggression towards others, deliberate self-injuriousness, temper tantrums, andquicklychangingmoods.TheCGI-C ratingatendpointwasaco-primaryoutcomemeasureinoneofthestudies.

Theresultsofthesetrialsareasfollows:(1) In one of the 8-week, placebo-controlled trials, children and adolescents

withautisticdisorder(n=101),aged5to16years,receivedtwicedailydosesof placebo or RISPERDAL® 0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25mg/day or 0.5 mg/day depending on baselineweight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response(meanmodaldoseof1.9 mg/day,equivalent to0.06 mg/kg/day),significantlyimproved scores on theABC-I subscale and on the CGI-C scale comparedwithplacebo.

(2) Intheother8-week,placebo-controlledtrialinchildrenwithautisticdisorder(n=55),aged5 to12 years,RISPERDAL®0.02to0.06mg/kg/daygivenonceortwicedaily,startingat0.01 mg/kg/dayandtitratedtoclinicalresponse(meanmodal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantlyimprovedscoresontheABC-Isubscalecomparedwithplacebo.

A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled,fixed-dosestudy toevaluate theefficacyandsafetyofa lower thanrecommendeddoseof risperidone in subjects (N=96) 5 to 17 years of agewithautistic disorder (defined by DSM-IV criteria) and associated irritability andrelatedbehavioralsymptoms.Approximately77%ofpatientswereyoungerthan12 years of age (mean age = 9), and 88% were male. Most patients (73%)weighed less than 45 kg (meanweight = 40 kg).Approximately 90%of patientswereantipsychotic-naïvebeforeenteringthestudy.Therewere twoweight-based, fixed doses of risperidone (high-dose and low-dose). The high dosewas 1.25mgper day for patientsweighing 20 to < 45 kg,and it was 1.75 mg per day for patients weighing > 45 kg. The low dose was 0.125mgperdayforpatientsweighing20to< 45kg,anditwas0.175mgperdayfor patients weighing > 45 kg. The dose was administered once daily in themorning,orintheeveningifsedationoccurred.The primary efficacy endpointwas themean change in the Aberrant BehaviorChecklist–Irritabilitysubscale(ABC-I)scorefrombaselinetotheendofWeek6.The studydemonstrated theefficacyof high-dose risperidone, asmeasuredbythemean change in ABC-I score. It did not demonstrate efficacy for low-doserisperidone. The mean baseline ABC-I scores were 29 in the placebo group (n=35),27 intherisperidonelow-dosegroup(n=30),and28intherisperidonehigh-dosegroup(n=31).ThemeanchangesinABC-Iscoreswere-3.5,-7.4,and-12.4 in theplacebo, low-dose,andhigh-dosegrouprespectively.Theresults inthe high-dose groupwere statistically significant (p< 0.001) but not in the low-dosegroup(p=0.164).Long-TermEfficacyFollowingcompletionof thefirst8-weekdouble-blindstudy,63 patientsenteredan open-label study extension where they were treated with RISPERDAL® for 4or6months (dependingonwhether they received RISPERDAL®orplacebo inthe double-blind study). During this open-label treatment period, patientsweremaintainedonameanmodaldoseof RISPERDAL®of1.8-2.1mg/day(equivalentto0.05-0.07 mg/kg/day).Patientswhomaintainedtheirpositiveresponseto RISPERDAL® (responsewasdefined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of‘much improved’ or ‘very much improved’) during the 4-6 month open-labeltreatment phase for about 140 days, on average, were randomized to receive RISPERDAL® orplaceboduringan8-week,double-blindwithdrawalstudy (n=39of the 63 patients). A pre-planned interim analysis of data from patients whocompleted the withdrawal study (n=32), undertaken by an independent DataSafety Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of astatistically significant effect on relapse prevention. Relapse was defined as≥ 25% worsening on the most recent assessment of the ABC-I subscale (inrelationtobaselineoftherandomizedwithdrawalphase).16 HoW sUPPlieD/storage anD HanDling16.1 HowSupplied RISPERDAL®(risperidone)Tablets RISPERDAL® (risperidone) Tablets are imprinted “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to theirrespectivestrengths.0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04,bottles of 500 NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC50458-301-01.0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06,bottles of 500 NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC50458-302-01.1mgwhite,capsule-shapedtablets:bottlesof60NDC50458-300-06,bottlesof500NDC50458-300-50,andhospitalunitdoseblisterpacksof100NDC50458-300-01.2mgorange,capsule-shapedtablets:bottlesof60NDC50458-320-06,bottlesof500NDC50458-320-50,andhospitalunitdoseblisterpacksof100NDC50458-320-01.3mgyellow,capsule-shapedtablets:bottlesof60NDC50458-330-06,bottlesof500NDC50458-330-50,andhospitalunitdoseblisterpacksof100NDC50458-330-01.4mggreen,capsule-shapedtablets:bottlesof60NDC50458-350-06andhospitalunitdoseblisterpacksof100NDC50458-350-01.


16

RISPERDAL®(risperidone)OralSolution RISPERDAL® (risperidone)1mg/mLOralSolution(NDC50458-305-03)issuppliedin 30 mL bottles with a calibrated (in milligrams and milliliters) pipette. Theminimumcalibratedvolumeis0.25 mL,whilethemaximumcalibratedvolumeis3 mL.

RISPERDAL®M-TAB®(risperidone)OrallyDisintegratingTablets RISPERDAL®M-TAB® (risperidone) Orally Disintegrating Tablets are etched onone side with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respectivestrengths. RISPERDAL®M-TAB®OrallyDisintegratingTablets0.5mg,1mg,and 2 mg are packaged in blister packs of 4 (2 X 2) tablets. Orally DisintegratingTablets 3 mg and 4 mg are packaged in a child-resistant pouch containing ablisterwith1tablet.0.5mglightcoral,round,biconvextablets:7blisterpackages(4tabletseach)perbox, NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC50458-395-30.1 mg lightcoral,square,biconvextablets:7blisterpackages(4tabletseach)perbox,NDC 50458-315-28,andlong-termcareblisterpackagingof30tabletsNDC50458-315-30.2mgcoral,square,biconvextablets:7blisterpackages(4tabletseach)perbox,NDC 50458-325-28.3mgcoral,round,biconvextablets:28blistersperbox,NDC50458-335-28.4mgcoral,round,biconvextablets:28blistersperbox,NDC50458-355-28.16.2 storage and Handling RISPERDAL® Tablets should be stored at controlled room temperature15°-25°C (59°-77°F).Protectfromlightandmoisture. RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled roomtemperature15°-25°C(59°-77°F).Protectfromlightandfreezing. RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored atcontrolledroomtemperature15°-25°C(59°-77°F).Keepoutofreachofchildren.

17 Patient coUnseling informationPhysicians are advised to discuss the following issueswith patients forwhomtheyprescribeRISPERDAL®andtheircaregivers:17.1 orthostatic HypotensionAdvise patients and caregivers about the risk of orthostatic hypotension,especially during the period of initial dose titration [see Warnings and Precautions (5.7)].17.2 InterferencewithCognitiveandMotorPerformanceInform patients and caregivers that RISPERDAL® has the potential to impairjudgment, thinking, or motor skills. Advise caution about operating hazardousmachinery, including automobiles, until patients are reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and Precautions (5.9)].17.3 PregnancyAdvise patients and caregivers to notify their physician if the patient becomespregnant or intends to become pregnant during therapy [see Use in Specific Populations (8.1)].17.4 nursingInform patients and caregivers that risperidone and its active metabolite arepresent inhumanbreastmilk; there isapotential forseriousadverse reactionsfrom RISPERDAL® innursing infants.Advisepatients that thedecisionwhetherto discontinue nursing or to discontinue the RISPERDAL® should take intoaccount the importance of the drug to the patient [see Use in Specific Populations (8.3)].17.5 concomitant medicationAdvisepatientsandcaregiverstoinformtheirphysiciansifthepatientistaking,orplans to take,anyprescriptionorover-the-counterdrugs,becausethere isapotential for interactions [see Drug Interactions (7)].17.6 alcoholAdvisepatientstoavoidalcoholwhiletakingRISPERDAL® [see Drug Interactions (7.2)].17.7 PhenylketonuricsInformpatientswithPhenylketonuriaandcaregivers that RISPERDAL®M-TAB® Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is acomponentofaspartame.Each4mgRISPERDAL®M-TAB®OrallyDisintegratingTablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.42 mgphenylalanine; each 1 mg RISPERDAL® M-TAB® Orally Disintegrating Tabletcontains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14mg phenylalanine [see Warnings and Precautions (5.14)].

17.8 metabolic changesInform patients and caregivers that treatment with RISPERDAL® can beassociatedwith hyperglycemia and diabetesmellitus, dyslipidemia, andweightgain[see Warnings and Precautions (5.5)].17.9 tardive DyskinesiaInform patients and caregivers about the risk of tardive dyskinesia [see Warnings and Precautions (5.4)].

RISPERDAL®TabletsActiveingredientismadeinIrelandFinishedproductismanufacturedby:JanssenOrtho,LLCGurabo,PuertoRico00778 RISPERDAL®OralSolutionFinishedproductismanufacturedby:JanssenPharmaceuticaNVBeerse,Belgium

RISPERDAL®M-TAB®OrallyDisintegratingTabletsActiveingredientismadeinIrelandFinishedproductismanufacturedby:JanssenOrtho,LLCGurabo,PuertoRico00778

RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and RISPERDAL®OralSolutionaremanufacturedfor:JanssenPharmaceuticals,Inc.Titusville,NJ08560

RevisedApril2014©JanssenPharmaceuticals,Inc.2007

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