dosing & administration - mental illness treatment .... resume regular monthly dosing in either...

INDICATION INVEGA® SUSTENNA® (paliperidone palmitate) is indicated for the treatment of:

• Schizophrenia.• Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants.IMPORTANT SAFETY INFORMATION FOR INVEGA® SUSTENNA® (paliperidone palmitate)

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.See full Prescribing Information for complete Boxed Warning

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

• INVEGA® SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis.

Please see Important Safety Information, including Boxed Warning, starting on page 9. Please see enclosed full Prescribing Information.

REAL LIFE. REAL RESULTS.

Dosing & Administration

Recommended dosing for INVEGA® SUSTENNA® (paliperidone palmitate) when initiating or switching from oral antipsychotics

1

InITIATIng oR SwITchIng FRom oRAL AnTIpSychoTIcS


INITIATION DOSING WINDOW

1st initiation dose(Deltoid muscle)

2nd initiation dose(Deltoid muscle)

-4 Days +4 Days

mg mg

NO ORAL SUPPLEMENTATION NEEDED.

DAY 1 DAY 8

MAINTENANCE DOSING WINDOW

-7 Days +7 Days

-mg


1st maintenance dose (Deltoid or gluteal muscle)

-7 Days +7 Days

mg mgmgmg mg

mg

SCHIZOPHRENIA

SCHIZOAFFECTIVE DISORDER

mgmgmg mg

DAY36

1st maintenance dose (Deltoid or gluteal muscle)

DAY36

NOTE: Establish tolerability with oral paliperidone or oral risperidone before starting InVEgA® SUSTEnnA®.

Initiation doses must be given in the deltoid muscle

monthly maintenance doses may be administered in either the deltoid or gluteal muscle

Each injection must be administered only by a healthcare professional

Initiating or switching from oral antipsychotics

2

DoSIng InFoRmATIon whEn SwITchIng FRom oRAL AnTIpSychoTIcS

INITIATION

Both starting doses must be given in the deltoid muscle

no oral supplementation is needed

Establish tolerability with oral paliperidone or oral risperidone before starting InVEgA® SUSTEnnA® (paliperidone palmitate)

paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the formulation

mAINTENANcE

monthly maintenance dose should be administered 5 weeks after the first injection (regardless of the timing of the second injection)

Utilizing the maintenance dosing window to help avoid missed doses should be considered the exception rather than the rule

Schizophrenia: The recommended maintenance dose for the treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg)

Schizoaffective Disorder: Adjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not studied in the schizoaffective disorder trial. For the 164 subjects who were randomized to InVEgA® SUSTEnnA®, the dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%), and 234 mg (38.4%). There is no recommended maintenance dose for the treatment of schizoaffective disorder

Initiation maintenance

must be administered only by a healthcare provider.* 117 mg is the recommended maintenance dose for schizophrenia. no recommended maintenance dose for schizoaffective disorder.

whEn STARTIng A pATIEnT, InITIATIon AnD mAInTEnAncE ScRIpTS ShoULD BE wRITTEn AT ThE SAmE TImE AS FoLLowS:

3

SwITchIng FRom AnoThER Long-AcTIng InJEcTABLE AnTIpSychoTIc

Recommended dosing for INVEGA® SUSTENNA® (paliperidone palmitate) when switching from another long-acting injectable antipsychotic



-7 Days +7 Days

-mg

mg mgmgmg mg

2nd maintenance dose

*The 39 mg strength was not studied in patients with schizoa�ective disorder.

*

*

(Deltoid or gluteal muscle)

DAY28 1st maintenance dose

AT TIME OF NEXT SCHEDULED INJECTION

(Deltoid or gluteal muscle)

DAY AVAILABLE DOSES1

-mg

INITIATE INVEGA® SUSTENNA® THERAPY IN PLACE OF THE NEXT SCHEDULED INJECTION.INVEGA® SUSTENNA® SHOULD THEN BE CONTINUED AT MONTHLY INTERVALS.

NOTE: For patients who have never taken oral paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone before starting INVEGA® SUSTENNA®.

When switching patients from another long-acting injectable antipsychotic, the 2 initiation doses are not required.

*

For Schizophrenia: The recommended monthly dose is 117 mgFor Schizoa�ective Disorder: There is no recommended monthly dose

For Schizophrenia: The recommended monthly dose is 117 mgFor Schizoa�ective Disorder: There is no recommended monthly dose

Switching from long-acting injectable antipsychotics

4

DoSIng InFoRmATIon whEn SwITchIng FRom AnoThER Long-AcTIng InJEcTABLE AnTIpSychoTIc

when switching from another long-acting injectable antipsychotic, administer InVEgA® SUSTEnnA® (paliperidone palmitate) in place of the next injection

mAINTENANcE DOSINg

For Schizophrenia: The recommended monthly dose is 117 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths: 39 mg, 78 mg, 156 mg, and 234 mg

For Schizoaffective Disorder: There is no recommended maintenance dose. The 39 mg strength was not studied in schizoaffective disorder. For the 164 subjects who were randomized to InVEgA® SUSTEnnA®, the dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%), and 234 mg (38.4%)

Adjustment of the maintenance dose may be made monthly

Utilizing the maintenance dosing window to help avoid missed doses should be considered the exception rather than the rule

whEn SwITchIng, ThE FIRST pREScRIpTIon FoR A mAInTEnAncE DoSE ShoULD BE wRITTEn AS FoLLowS:

must be administered only by a healthcare provider.* 117 mg is the recommended maintenance dose for schizophrenia. no recommended maintenance dose for schizoaffective disorder.

What to do when the second initiation dose is missed

5

ADDRESSIng mISSED InITIATIon DoSES


Administer the second initiation dose of 156 mg in the deltoid muscle as soon as possible. 1. It is recommended to administer a third injection of 117 mg in either the deltoid or gluteal

muscle 5 weeks after the first injection (regardless of the timing of the second injection).

2. Resume regular monthly dosing in either the deltoid or gluteal muscle.

Resume dosing with 2 injections of 156 mg. 1. Administer a deltoid injection as soon as possible.

2. Administer a second deltoid injection 1 week later.


Restart dosing with recommended initiation plan. 1. Administer a 234 mg deltoid injection on Day 1.

2. Administer a 156 mg deltoid injection 1 week later.


<4 weeksfrom first injection

4-7 weeksfrom first injection

>7 weeksfrom first injection

TImINg OF mISSED SEcOND INITIATION DOSE AcTION STEpS

missed doses

What to do when a maintenance dose is missed

6

ADDRESSIng mISSED mAInTEnAncE DoSES

Resume regular monthly dosing as soon as possible at patient’s previously stabilized dose, followed by injections at monthly intervals.

Continue dosing at patient’s previously stabilized dose.* 1. Administer a deltoid injection as soon as possible.2. Administer a second deltoid injection 1 week later at same dose.3. Resume administering previously stabilized dose in the deltoid or gluteal muscle 1 month

after the second injection.

*If patient was stabilized on 234 mg, the first 2 injections should be 156 mg.

4-6 weeks late

AcTION STEpS

>6 weeks to 6 months late

>6 months lateRestart dosing with recommended initiation plan. 1. Administer a 234 mg deltoid injection on Day 1.2. Administer a 156 mg deltoid injection 1 week later.3. Resume administering previously stabilized dose in the deltoid or gluteal muscle 1 month

after second injection.

TImINg OF mISSED mAINTENANcE DOSE


What to consider for specific patient populations

DoSIng conSIDERATIonS

coADmInISTRATIon wITh STRong cyp3A4/p-gLycopRoTEIn (p-gp) InDUcERS

It may be necessary to increase the dose of InVEgA® SUSTEnnA® when a strong inducer of both cyp3A4 and p-glycoprotein (eg, carbamazepine, rifampin, St. John’s wort) is coadministered. conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of InVEgA® SUSTEnnA®

pREgnAncy/nURSIng

Adequate and well-controlled studies with InVEgA® SUSTEnnA® have not been conducted in pregnant women. neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery

InVEgA® SUSTEnnA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

hEpATIc ImpAIRmEnT

InVEgA® SUSTEnnA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dosage adjustment is required in patients with mild or moderate hepatic impairment. paliperidone has not been studied in patients with severe hepatic impairment

7

REnAL ImpAIRmEnT

InVEgA® SUSTEnnA® (paliperidone palmitate) has not been systematically studied in patients with renal impairment

The dose of InVEgA® SUSTEnnA® should be reduced in patients with mild renal impairment as it has not been systematically studied in patients with renal impairment— For patients with mild renal impairment (creatinine clearance ≥50 mL/min to <80 mL/min), the recommended

initiation doses of InVEgA® SUSTEnnA® are 156 mg on treatment Day 1 and 117 mg 1 week later. Administer both doses in the deltoid muscle

— Follow with monthly injections of 78 mg in either the deltoid or gluteal muscle InVEgA® SUSTEnnA® is not recommended in patients with moderate or severe renal impairment

(creatinine clearance <50 mL/min)


Administration & dosing considerations

noTES

ADmInISTRATIon InFoRmATIon

8

INVEGA® SUSTENNA® is water-soluble.

Store at room temperature. No need for refrigeration.

Select appropriate needle size depending on patient’s weight and injection location. Shake the prefilled syringe for 10 seconds before administering.

Each injection must be administered only by a healthcare professional

InVEgA® SUSTEnnA® (paliperidone palmitate) is intended for intramuscular use only

Avoid inadvertent injection into a blood vessel

Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the muscle

paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the formulation

9




• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.• INVEGA® SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis.

Contraindications: Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the formulation.

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone, aripiprazole, and olanzapine. The incidence of cerebrovascular adverse reactions was significantly higher than with placebo. INVEGA® SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly female patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension and Syncope: INVEGA® SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. INVEGA® SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including paliperidone. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of INVEGA® SUSTENNA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue INVEGA® SUSTENNA® and have their WBC followed until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA® SUSTENNA® elevates prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA® SUSTENNA®. INVEGA® SUSTENNA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA® SUSTENNA® does not adversely affect them.

Seizures: INVEGA® SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Administration: For intramuscular injection only by a healthcare professional. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA® SUSTENNA® when a strong inducer of both CYP3A4 and P-gp (e.g. carbamazepine, rifampin, St. John’s wort) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA® SUSTENNA®.

Pregnancy/Nursing: Patients should be advised to notify their physician if they become pregnant/intend to become pregnant or intend to nurse during treatment with INVEGA® SUSTENNA®.

Commonly Observed Adverse Reactions for INVEGA® SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5% and twice placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. No adverse events occurred at a rate of ≥5% and twice placebo during the long-term double-blind, placebo-controlled study in patients with schizoaffective disorder. The following adverse reactions occurred more frequently (a ≥2% difference vs. placebo) in the long-term study in patients with schizoaffective disorder: weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.

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© Janssen pharmaceuticals, Inc. 2014 December 2014 022287-140930

REAL LIFE. REAL RESULTS.




• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

• INVEGA® SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis.


INVEGA® SUSTENNA®

(paliperidone palmitate) extended-release injectable suspension, for intramuscular use

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use INVEGA® SUSTENNA® safely and effectively. See full prescribing information for INVEGA® SUSTENNA®.INVEGA® SUSTENNA® (paliperidone palmitate) extended-release injectable suspension, for intramuscular useInitial U.S. Approval: 2006

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.• Elderlypatientswithdementia-relatedpsychosistreatedwithantipsychotic

drugs are at an increased risk of death. (5.1)• INVEGA® SUSTENNA® isnotapproved foruse inpatientswithdementia-

related psychosis. (5.1)

-------------------------------- RECENT MAJOR CHANGES --------------------------------Indications and Usage (1) 11/2014Dosage and Administration (2.2, 2.3) 11/2014

-------------------------------- INDICATIONS AND USAGE --------------------------------INVEGA® SUSTENNA® is an atypical antipsychotic indicated for• Treatmentofschizophrenia.(1)• Treatment of schizoaffective disorder as monotherapy and as an adjunct to

moodstabilizersorantidepressants.(1)

-----------------------------DOSAGE AND ADMINISTRATION-----------------------------• Forintramuscularinjectiononly.(2.1)• Eachinjectionmustbeadministeredonlybyahealthcareprofessional.(2.1)• Fordeltoidinjection,use1-inch23Gneedleforpatientsweighinglessthan90kg

or1½-inch22Gneedleforpatientsweighing90kgormore.Forglutealinjection,use1½-inch22Gneedleregardlessofpatientweight.(2.1)

IndicationInitiation Dosing

(deltoid)Monthly

Maintenance Dosea (deltoid or gluteal)

Maximum Monthly Dose

Day 1 Day 8

Schizophrenia(2.2) 234 mg 156 mg 39-234mgb 234 mg

Schizoaffectivedisorder (2.2) 234 mg 156 mg 78-234 mgc 234 mg

aAdministered5weeksafterthefirstinjection.bTherecommendedmaintenancedosefortreatmentofschizophreniais117mg.Somepatientsmaybenefitfromlowerorhighermaintenancedoseswithintheadditionalavailablestrengths(39mg,78mg,156mg,and234mg).

cAdjustdosebasedontolerabilityand/orefficacyusingavailablestrengths.The39mgstrengthwasnotstudiedinthelong-termschizoaffectivedisorderstudy.

• Forpatientsnaïvetooralpaliperidoneororalorinjectablerisperidone,establishtolerabilitywithoralpaliperidoneororalrisperidonepriortoinitiatingtreatmentwithINVEGA® SUSTENNA®. (2.2)

• MissedDoses:Tomanageeitheramissedsecondinitiationdoseoramissedmonthlymaintenancedose,refertotheFullPrescribingInformation.(2.3)

• Moderate to severe renal impairment (creatinine clearance < 50 mL/min):INVEGA® SUSTENNA® is not recommended. (2.5)

• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min):Administer 156 mg on treatment day 1 and 117 mg one week later, bothadministeredinthedeltoidmuscle.Followwithmonthlyinjectionsof78mgineither the deltoid or gluteal muscle. (2.5)

--------------------------- DOSAGE FORMS AND STRENGTHS ---------------------------Extended-releaseinjectablesuspension:39mg,78mg,117mg,156mg,or234mg(3)

----------------------------------- CONTRAINDICATIONS -----------------------------------Known hypersensitivity to paliperidone, risperidone, or to any excipients in theformulation (4)

-----------------------------WARNINGS AND PRECAUTIONS -----------------------------• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients

with Dementia-Related Psychosis: Increased incidence of cerebrovascularadversereactions (e.g.stroke, transient ischemicattack, including fatalities).INVEGA® SUSTENNA® is not approved for use in patients with dementia-related psychosis (5.2)

• Neuroleptic Malignant Syndrome:Managewith immediatediscontinuationofdrug and close monitoring (5.3)

• QT Prolongation: Avoid usewith drugs that also increaseQT interval and inpatientswithriskfactorsforprolongedQTinterval(5.4)

• Tardive Dyskinesia: Discontinue drug if clinically appropriate (5.5)• Metabolic Changes:Atypical antipsychoticdrugshavebeenassociatedwith

metabolic changes that may increase cardiovascular/cerebrovascular risk.Thesemetabolicchangesinclude:

° Hyperglycemia and Diabetes Mellitus: Monitor for symptoms ofhyperglycemia including polydipsia, polyuria, polyphagia, and weakness.Monitorglucoseregularly inpatientswithdiabetesorat risk fordiabetes.(5.6)

° Dyslipidemia:Undesirablealterationshavebeenobserved.(5.6) ° Weight Gain:Significantweightgainhasbeenreported.Monitorweightgain.

(5.6)• Orthostatic Hypotension and Syncope: Use with caution in patients with

knowncardiovascularorcerebrovasculardiseaseandpatientspredisposedtohypotension (5.7)

• Leukopenia, Neutropenia, and Agranulocytosis:Monitorcompletebloodcountinpatientswithahistoryofaclinicallysignificantlowwhitebloodcellcount(WBC)oradrug-inducedleukopenia/neutropenia.ConsiderdiscontinuationifclinicallysignificantdeclineinWBCintheabsenceofothercausativefactors(5.8)

• Hyperprolactinemia: Prolactin elevations occur and persist during chronicadministration(5.9)

• Potential for Cognitive and Motor Impairment: Use caution when operatingmachinery (5.10)

• Seizures:Usecautiouslyinpatientswithahistoryofseizuresorwithconditionsthatlowertheseizurethreshold(5.11)

----------------------------------- ADVERSE REACTIONS -----------------------------------Themostcommonadversereactions(incidence≥5%andoccurringatleasttwiceasoftenasplacebo)wereinjectionsitereactions,somnolence/sedation,dizziness,akathisia,andextrapyramidaldisorder.(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 -----------------------------------• Drugs thatmaycauseorthostatichypotension:Anadditiveeffectmayoccur

whenco-administeredwithINVEGA® SUSTENNA®. (7.1)• StrongCYP3A4/P-glycoprotein(P-gp)inducers:Itmaybenecessarytoincrease

the dose of INVEGA® SUSTENNA® when a strong inducer of both CYP3A4and P-gp (e.g., carbamazepine, rifampin, St John’swort) is co-administered.Conversely, ondiscontinuationof the strong inducer, itmaybenecessary todecrease the dose of INVEGA® SUSTENNA®. (7.2, 12.3)

----------------------------- USE IN SPECIFIC POPULATIONS -----------------------------• Pregnancy:Basedonanimaldata,maycausefetalharm.(8.1)• NursingMothers: Discontinue drug or nursing, taking into consideration the

importance of drug to the mother. (8.3)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2014

INVEGA® SUSTENNA® (paliperidone palmitate) extended-release injectable suspension, for intramuscular use

1

Revised:11/2014024972-141209

FULL PRESCRIBING INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

• Elderlypatientswithdementia-relatedpsychosistreatedwithantipsychoticdrugs are at an increased risk of death [see Warnings and Precautions (5.1)].

• INVEGA® SUSTENNA® isnotapproved foruse inpatientswithdementia-related psychosis [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGEINVEGA® SUSTENNA®(paliperidonepalmitate)isindicatedforthetreatmentof:• Schizophrenia[see Clinical Studies 14.1].• Schizoaffectivedisorderasmonotherapyandasanadjuncttomoodstabilizers

or antidepressants [see Clinical Studies 14.2].

2 DOSAGE AND ADMINISTRATION2.1 Administration InstructionsEach injection must be administered only by a health care professional.Parenteral drug products should be inspected visually for foreign matter anddiscolorationpriortoadministration,wheneverproductandcontainerpermit.INVEGA® SUSTENNA® is intended for intramuscular use only. Do not administer byanyotherroute.Avoidinadvertentinjectionintoabloodvessel.Administerthedoseinasingleinjection;donotadministerthedoseindividedinjections.Injectslowly,deepintothemuscle.The recommendedneedlesize foradministrationof INVEGA® SUSTENNA® into thedeltoidmuscleisdeterminedbythepatient’sweight:• Forpatientsweighinglessthan90kg,the1-inch,23gaugeneedleisrecommended.• Forpatientsweighing90kgormore,the1½-inch,22gaugeneedleisrecommended.Deltoidinjectionsshouldbealternatedbetweenthetwodeltoidmuscles.The recommendedneedlesize foradministrationof INVEGA® SUSTENNA® into theglutealmuscleisthe1½-inch,22gaugeneedleregardlessofpatientweight.Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections shouldbealternatedbetweenthetwoglutealmuscles.

2.2 Schizophrenia and Schizoaffective DisorderFor patients who have never taken oral paliperidone or oral or injectablerisperidone, it is recommended toestablish tolerabilitywithoralpaliperidoneororalrisperidonepriortoinitiatingtreatmentwithINVEGA® SUSTENNA®.The recommended dosing of INVEGA® SUSTENNA®foreachapprovedindicationis displayed in Table 1. The recommended initiation of INVEGA® SUSTENNA® iswith a dose of 234mg on treatment day 1 and 156mg oneweek later, bothadministeredinthedeltoidmuscle.Followingthesecondinitiationdose,monthlymaintenance doses can be administered in either the deltoid or gluteal muscle.Table 1. Recommended Dosing of INVEGA® SUSTENNA® for Adults with

Schizophrenia or Schizoaffective Disorder

IndicationInitiation Dosing

(deltoid)Monthly

Maintenance Dosea (deltoid or gluteal)

Maximum Monthly Dose

Day 1 Day 8

Schizophrenia 234 mg 156 mg 39-234mgb 234 mg

Schizoaffectivedisorder 234 mg 156 mg 78-234 mgc 234 mg

aAdministered5weeksafterthefirstinjection.bTherecommendedmaintenancedosefortreatmentofschizophreniais117mg.Somepatientsmaybenefitfromlowerorhighermaintenancedoseswithintheadditionalavailablestrengths(39mg,78mg,156mg,and234mg).

cAdjustdosebasedontolerabilityand/orefficacyusingavailablestrengths.The39mgstrengthwasnotstudiedinthelong-termschizoaffectivedisorderstudy.

Adjustmentof themaintenancedosemaybemademonthly.Whenmakingdoseadjustments, the prolonged-release characteristics of INVEGA® SUSTENNA® should be considered [see Clinical Pharmacology (12.3)], as the full effect of the doseadjustmentmaynotbeevidentforseveralmonths.2.3 Missed DosesAvoidingMissedDosesIt is recommended that the second initiation dose of INVEGA® SUSTENNA® be givenoneweekafterthefirstdose.Toavoidamisseddose,patientsmaybegiventheseconddose4daysbeforeoraftertheone-weektimepoint.Similarly,thethirdand subsequent injections after the initiation regimen are recommended to be givenmonthly.Toavoidamissedmonthlydose,patientsmaybegiventheinjectionup to 7 days before or after the monthly time point.

2



FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 Administration Instructions 2.2 SchizophreniaandSchizoaffectiveDisorder 2.3 MissedDoses 2.4 UsewithOralPaliperidoneorwithRisperidone 2.5 Dosage Adjustments 2.6 SwitchingfromOtherAntipsychotics 2.7 Instructions for Use3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 IncreasedMortalityinElderlyPatientswithDementia-RelatedPsychosis 5.2 CerebrovascularAdverseReactions,IncludingStroke,inElderly

PatientswithDementia-RelatedPsychosis 5.3 NeurolepticMalignantSyndrome 5.4 QTProlongation 5.5 TardiveDyskinesia 5.6 MetabolicChanges 5.7 OrthostaticHypotensionandSyncope 5.8 Leukopenia,Neutropenia,andAgranulocytosis 5.9 Hyperprolactinemia 5.10 PotentialforCognitiveandMotorImpairment 5.11 Seizures 5.12 Dysphagia 5.13 Priapism 5.14 DisruptionofBodyTemperatureRegulation6 ADVERSE REACTIONS 6.1 ClinicalTrialsExperience 6.2 PostmarketingExperience 6.3 AdverseReactionsReportedWithRisperidone

7 DRUG INTERACTIONS 7.1 PotentialforINVEGA® SUSTENNA®toAffectOtherDrugs 7.2 PotentialforOtherDrugstoAffectINVEGA® SUSTENNA®

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 LaborandDelivery 8.3 NursingMothers 8.4 PediatricUse 8.5 Geriatric Use 8.6 Renal Impairment 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,ImpairmentofFertility14 CLINICAL STUDIES 14.1 Schizophrenia 14.2 SchizoaffectiveDisorder16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATIONPATIENT INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed

Management of a Missed Second Initiation DoseIf the target date for the second INVEGA® SUSTENNA® injection (one week ± 4 days) is missed, the recommended reinitiation depends on the length of time whichhaselapsedsincethepatient’sfirstinjection.IncaseofamissedsecondinitiationdosefollowthedosinginstructionsprovidedinTable2.Table 2. Management of a Missed Second Initiation Dose

TIMING OF MISSED SECOND INITIATION DOSE

DOSING

Lessthan4weekssincefirst injection

Administer the second initiation dose of 156 mg in the deltoid muscle as soon as possible.1. It is recommended to administer a third injection

of 117 mg in either the deltoid or gluteal muscle 5weeksafterthefirstinjection(regardlessofthetiming of the second injection).

2. Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.

4to7weekssince first injection

Resumedosingwithtwoinjectionsof156mginthefollowingmanner:1. Administer a deltoid injection as soon as possible.2. Administeraseconddeltoidinjection1weeklater.3. Thereafter, resume regular monthly dosing in

either the deltoid or gluteal muscle.Morethan7weekssincefirst injection

Restartdosingwithrecommendedinitiation(see Section 2.2, Table 1):1. Administer a 234 mg deltoid injection on Day 1.2. Administera156mgdeltoidinjection1weeklater.3. Thereafter, resume regular monthly dosing in

either the deltoid or gluteal muscle.

Management of a Missed Maintenance DoseIncaseofamissedmaintenancedosefollowthedosinginstructionsprovidedinTable 3.Table 3. Management of a Missed Maintenance Dose

TIMING OF MISSED MAINTENANCE DOSE

DOSING

4to6weekssince last injection

Resume regular monthly dosing as soon as possible at the patient’s previously stabilized dose,followedbyinjectionsatmonthlyintervals.

Morethan6weeksto6months since last injection

Resumethesamedosethepatientwaspreviouslystabilizedon(unlessthepatientwasstabilizedona dose of 234 mg, then the first 2 injections should eachbe156mg)inthefollowingmanner:1. Administer a deltoid injection as soon as possible.2. Administer a second deltoid injection 1 week

later at the same dose.3. Thereafter,resumeadministeringthepreviously

stabilizeddoseinthedeltoidorglutealmuscle1month after the second injection.

More than 6 months since last injection

Restartdosingwithrecommendedinitiation(see Section 2.2, Table 1):1. Administer a 234 mg deltoid injection on Day 1.2. Administera156mgdeltoidinjection1weeklater.3. Thereafter,resumeadministeringthepreviously

stabilizeddoseinthedeltoidorglutealmuscle1month after the second injection.

2.4 UsewithOralPaliperidoneorwithRisperidoneConcomitant use of INVEGA® SUSTENNA® with oral paliperidone or oral orinjectable risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additivepaliperidone exposure if any of these medications are coadministered withINVEGA® SUSTENNA®.2.5 Dosage AdjustmentsRenal ImpairmentINVEGA® SUSTENNA® has not been systematically studied in patients withrenal impairment [see Clinical Pharmacology (12.3)].Forpatientswithmildrenalimpairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-GaultFormula]), initiate INVEGA® SUSTENNA® with a dose of 156 mg on treatmentday1and117mgoneweek later.Administerbothdoses in thedeltoidmuscle.Thereafter,followwithmonthlyinjectionsof78mgineitherthedeltoidorglutealmuscle [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

INVEGA® SUSTENNA® is not recommended in patients with moderate orsevererenalimpairment(creatinineclearance<50mL/min)[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].CoadministrationwithStrongCYP3A4/P-glycoprotein(P-gp)InducersIt may be necessary to increase the dose of INVEGA® SUSTENNA®whenastronginducerofbothCYP3A4andP-gp(e.g.,carbamazepine,rifampin,StJohn’swort)isco-administered.Conversely,ondiscontinuationofthestronginducer,itmaybenecessary to decrease the dose of INVEGA® SUSTENNA® [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].2.6 SwitchingfromOtherAntipsychoticsThere are no systematically collected data to specifically address switchingpatientswithschizophreniaorschizoaffectivedisorderfromotherantipsychoticsto INVEGA® SUSTENNA®, or concerningconcomitantadministrationwithotherantipsychotics.2.6.1SwitchingfromOralAntipsychoticsFor patients who have never taken oral paliperidone or oral or injectablerisperidone, tolerability should be established with oral paliperidone or oralrisperidonepriortoinitiatingtreatmentwithINVEGA® SUSTENNA®.Previous oral antipsychotics can be discontinued at the time of initiation of treatment with INVEGA® SUSTENNA®. Recommended initiation of INVEGA® SUSTENNA® iswithadoseof234mgontreatmentday1and156mg one week later, both administered in the deltoid muscle [see Dosage and Administration (2.2)].PatientspreviouslystabilizedondifferentdosesofINVEGA® Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with INVEGA® SUSTENNA® monthly doses as depicted in Table 4. Table 4. Doses of INVEGA® and INVEGA® SUSTENNA® needed to attain similar

steady-state paliperidone exposure during maintenance treatment

Formulation INVEGA®

Extended-Release TabletINVEGA® SUSTENNA®

Injection

DosingFrequency OnceDaily Onceevery4weeks

Dose (mg)12 2346 1173 39-78

2.6.2SwitchingfromLong-ActingInjectableAntipsychoticsFor patients who have never taken oral paliperidone or oral or injectablerisperidone, tolerability should be established with oral paliperidone or oralrisperidonepriortoinitiatingtreatmentwithINVEGA® SUSTENNA®.When switching patients currently at steady-state on a long-acting injectableantipsychotic, initiate INVEGA® SUSTENNA® therapy in place of the next scheduled injection. INVEGA® SUSTENNA® should then be continued at monthly intervals.Theone-week initiationdosing regimenasdescribed inSection2.2 isnotrequired.SeeTable1aboveforrecommendedmonthlymaintenancedosing.Based on previous clinical history of tolerability and/or efficacy, some patientsmay benefit from lower or higher maintenance doses within the availablestrengths (39mg,78mg,117mg,156mg,and234mg).The39mgstrengthwasnotstudiedinthelong-termschizoaffectivedisorderstudy.Monthlymaintenancedoses can be administered in either the deltoid or gluteal muscle [see Dosage and Administration (2.2)].If INVEGA® SUSTENNA® is discontinued, its prolonged-release characteristics mustbeconsidered.Asrecommendedwithotherantipsychoticmedications,theneedforcontinuingexistingextrapyramidalsymptoms(EPS)medicationshouldbere-evaluatedperiodically.2.7 Instructions for UseEach injection must be administered only by a health care professional.The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gaugeneedle and a 1-inch 23 gauge needle) for intramuscular injection.

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INVEGA® SUSTENNA® is for single use only.a. Shake the syringe vigorously for a minimum of 10 seconds to ensure a

homogeneous suspension.

b. Select the appropriate needle. ForDELTOIDinjection: • Ifthepatientweighslessthan90kg,usethe1-inch23 gauge needle (needle

withblue colored hub). • Ifthepatientweighs90kgormore,usethe1½-inch22 gauge needle (needle

withgray colored hub). ForGLUTEALinjection: Use the 1½-inch 22gaugeneedle(needlewithgray colored hub) regardless of

patient’sweight.

c. While holding the syringe upright, remove the rubber tip cap with an easyclockwisetwistingmotion.

d. Peel the safetyneedlepouchhalfwayopen.Grasp theneedle sheathusingthe plastic peel pouch. Attach the safety needle to the luer connection of the syringewithaneasyclockwisetwistingmotion.

e. Pulltheneedlesheathawayfromtheneedlewithastraightpull.Donottwist the sheath as the needle may be loosened from the syringe.

f. Bring the syringewith the attached needle in upright position to de-aerate. De-aeratethesyringebymovingtheplungerrodcarefullyforward.

g. Injecttheentirecontentsintramuscularlyslowly,deepintotheselecteddeltoidor gluteal muscle of the patient. Do not administer by any other route.

h. After the injection is complete, use either thumb or finger of one hand (h1,h2)oraflatsurface(h3)toactivatetheneedleprotectionsystem.Theneedleprotectionsystemisfullyactivatedwhena‘click’isheard.Discardthesyringewithneedleappropriately.

h1

h2

h3

3 DOSAGE FORMS AND STRENGTHSINVEGA® SUSTENNA® is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 39mg,78mg,117mg,156mg,and234mgpaliperidonepalmitate.4 CONTRAINDICATIONSINVEGA® SUSTENNA® is contraindicated in patients with a known hyper-sensitivity to either paliperidone or risperidone, or to any of the excipients inthe INVEGA® SUSTENNA® formulation. Hypersensitivity reactions, includinganaphylacticreactionsandangioedema,havebeenobservedinpatientstreatedwith risperidone and paliperidone. Paliperidone palmitate is converted topaliperidone,whichisametaboliteofrisperidone.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 typical 10-weekcontrolledtrial,therateofdeathindrug-treatedpatientswasabout4.5%,comparedtoarateofabout2.6%in theplacebogroup.Althoughthecausesofdeathwerevaried,mostofthedeathsappearedtobeeithercardiovascular(e.g.,heartfailure,suddendeath)orinfectious(e.g.,pneumonia)innature.Observationalstudies suggest that, similar to atypical antipsychotic drugs, treatment withconventional antipsychotic drugs may increase mortality. The extent to whichthefindingsof increasedmortality inobservationalstudiesmaybeattributed tothe antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA® SUSTENNA®(paliperidonepalmitate)isnotapprovedforthetreatmentofpatientswithdementia-relatedpsychosis[see Boxed Warning].5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients

withDementia-RelatedPsychosisIn placebo-controlled trials with risperidone, aripiprazole, and olanzapine inelderlysubjectswithdementia,therewasahigherincidenceofcerebrovascularadverse reactions (cerebrovascular accidents and transient ischemic attacks)including fatalities compared to placebo-treated subjects. Oral paliperidone

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and INVEGA® SUSTENNA® were notmarketed at the time these studieswereperformed and are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].5.3 Neuroleptic Malignant SyndromeA potentially fatal symptom complex sometimes referred to as Neuroleptic MalignantSyndrome(NMS)hasbeenreportedinassociationwithantipsychoticdrugs, including INVEGA® SUSTENNA®.ClinicalmanifestationsofNMSarehyperpyrexia,musclerigidity,alteredmentalstatus,andevidenceofautonomicinstability(irregularpulseorbloodpressure,tachycardia,diaphoresis,andcardiacdysrhythmia).Additionalsignsmayincludeelevatedcreatinephosphokinase,myoglobinuria(rhabdomyolysis),andacuterenalfailure.Thediagnosticevaluationofpatientswiththissyndromeiscomplicated.Inarrivingatadiagnosis,it isimportanttoidentifycasesinwhichtheclinicalpresentationincludes both serious medical illness (e.g., pneumonia, systemic infection, etc.) anduntreatedorinadequatelytreatedextrapyramidalsignsandsymptoms(EPS).Other important considerations in the differential diagnosis include centralanticholinergic toxicity, heat stroke, drug fever, and primary central nervoussystem pathology.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) treatmentof any concomitant serious medical problems for which specific treatmentsare available. There is no general agreement about specific pharmacologicaltreatmentregimensforuncomplicatedNMS.If a patient appears to require antipsychotic drug treatment after recoveryfrom NMS, reintroduction of drug therapy should be closely monitored, sincerecurrencesofNMShavebeenreported.5.4 QT ProlongationPaliperidone causes amodest increase in the correctedQT (QTc) interval. Theuseofpaliperidoneshouldbeavoided incombinationwithotherdrugs thatareknowntoprolongQTcincludingClass1A(e.g.,quinidine,procainamide)orClassIII(e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g.,chlorpromazine,thioridazine),antibiotics(e.g.,gatifloxacin,moxifloxacin),oranyotherclassofmedicationsknown toprolong theQTc interval.Paliperidoneshould also be avoided in patients with congenital long QT syndrome and inpatientswithahistoryofcardiacarrhythmias.Certain circumstances may increase the risk of the occurrence of Torsades depointesand/orsuddendeathinassociationwiththeuseofdrugsthatprolongtheQTcinterval, including(1)bradycardia;(2)hypokalemiaorhypomagnesemia; (3)concomitantuseofotherdrugsthatprolongtheQTcinterval;and(4)presenceofcongenitalprolongationoftheQTinterval.Theeffectsoforalpaliperidoneon theQT intervalwereevaluated inadouble-blind,active-controlled(moxifloxacin400mgsingledose),multicenterQTstudyinadultswithschizophreniaandschizoaffectivedisorder,andinthreeplacebo-andactive-controlled6-week,fixed-doseefficacytrialsinadultswithschizophrenia.In the QT study (n=141), the 8mg dose of immediate-release oral paliperidone(n=50) showed amean placebo-subtracted increase from baseline in QTcLD of12.3msec(90%CI:8.9;15.6)onday8at1.5hourspost-dose.Themeansteady-state peak plasma concentration for this 8mg dose of paliperidone immediaterelease (Cmax ss = 113ng/mL)wasmore than2-fold theexposureobservedwiththe maximum recommended 234 mg dose of INVEGA® SUSTENNA® administered inthedeltoidmuscle(predictedmedianCmax ss=50ng/mL).Inthissamestudy,a4mgdoseof the immediate-releaseoral formulationof paliperidone, forwhich Cmax ss =35ng/mL,showedan increasedplacebo-subtractedQTcLDof6.8msec(90%CI:3.6;10.1)onday2at1.5hourspost-dose.Inthethreefixed-doseefficacystudiesoforalpaliperidoneextendedreleaseinsubjects with schizophrenia, electrocardiogram (ECG) measurements taken atvarioustimepointsshowedonlyonesubjectintheoralpaliperidone12mggrouphad a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).Inthefourfixed-doseefficacystudiesofINVEGA® SUSTENNA®insubjectswithschizophreniaandinthelong-termstudyinsubjectswithschizoaffectivedisorder,nosubjectexperiencedachangeinQTcLDexceeding60msecandnosubjecthadaQTcLDvalueof>500msecatanytimepoint.Inthemaintenancestudyinsubjectswithschizophrenia,nosubjecthadaQTcLDchange>60msec,andonesubjecthadaQTcLD valueof 507msec (Bazett’sQTcorrected interval [QTcB] valueof 483 msec); this latter subject also had a heart rate of 45 beats per minute.5.5 Tardive DyskinesiaAsyndromeofpotentiallyirreversible,involuntary,dyskineticmovementsmaydevelopinpatientstreatedwithantipsychoticdrugs.Althoughtheprevalenceofthesyndromeappearstobehighestamongtheelderly,especiallyelderlywomen,itisimpossibleto predictwhich patientswill develop the syndrome.Whether antipsychotic drugproductsdifferintheirpotentialtocausetardivedyskinesiaisunknown.The risk of developing tardive dyskinesia and the likelihood that itwill becomeirreversible appear to increase as the duration of treatment and the totalcumulativedoseofantipsychoticdrugsadministeredtothepatientincrease,butthesyndromecandevelopafter relativelybrief treatmentperiodsat lowdoses,although this is uncommon.

There is no known treatment for established tardive dyskinesia, although thesyndromemayremit,partiallyorcompletely,ifantipsychotictreatmentiswithdrawn.Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptomsofthesyndromeandmaythusmasktheunderlyingprocess.Theeffectofsymptomaticsuppressiononthelong-termcourseofthesyndromeisunknown.Given these considerations, INVEGA® SUSTENNA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.Chronic antipsychotic treatment should generally be reserved for patientswhosufferfromachronic illnessthat isknowntorespondtoantipsychoticdrugs.Inpatientswho do require chronic treatment, the smallest dose and the shortestduration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.If signs and symptoms of tardive dyskinesia appear in a patient treated withINVEGA® SUSTENNA®, drug discontinuation should be considered. However,some patients may require treatment with INVEGA® SUSTENNA® despite the presence of the syndrome.5.6 Metabolic ChangesAtypicalantipsychoticdrugshavebeenassociatedwithmetabolicchangesthatmay increase cardiovascular/cerebrovascular risk. These metabolic changesincludehyperglycemia,dyslipidemia,andbodyweightgain.Whileallofthedrugsintheclasshavebeenshowntoproducesomemetabolicchanges,eachdrughasitsownspecificriskprofile.HyperglycemiaandDiabetesMellitusHyperglycemia and diabetes mellitus, in some cases extreme and associatedwithketoacidosisorhyperosmolarcomaordeath,havebeenreportedinpatientstreatedwithallatypicalantipsychotics.Thesecaseswere,forthemostpart,seeninpost-marketingclinicaluseandepidemiologicstudies,notinclinicaltrials,andtherehavebeenfewreportsofhyperglycemiaordiabetesintrialsubjectstreatedwith INVEGA® SUSTENNA®. Assessment of the relationship between atypicalantipsychotic use and glucose abnormalities is complicated by the possibility of anincreasedbackgroundriskofdiabetesmellitusinpatientswithschizophreniaand the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic useand hyperglycemia-related adverse reactions is not completely understood.However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.BecauseINVEGA® SUSTENNA®wasnotmarketedatthetimethesestudieswereperformed,itisnotknownifINVEGA® SUSTENNA®isassociatedwiththisrisk.Patientswith an established diagnosis of diabetesmellituswho are started onatypical antipsychotics shouldbemonitored regularly forworseningof glucosecontrol.Patientswithriskfactorsfordiabetesmellitus(e.g.,obesity,familyhistoryofdiabetes)whoarestartingtreatmentwithatypicalantipsychoticsshouldundergofasting blood glucose testing at the beginning of treatment and periodically during treatment.Anypatient treatedwithatypicalantipsychoticsshouldbemonitoredfor symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatmentwith atypical antipsychotics should undergo fasting blood glucose testing. Insome cases, hyperglycemia has resolvedwhen the atypical antipsychoticwasdiscontinued; however, some patients required continuation of anti-diabetictreatment despite discontinuation of the suspect drug.Pooled data from the four placebo-controlled (one 9-week and three 13-week),fixed-dosestudiesinsubjectswithschizophreniaarepresentedinTable5.Table 5. Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week,

Fixed-DoseStudiesinSubjectswithSchizophreniaINVEGA® SUSTENNA®

Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga

Mean change from baseline (mg/dL)n=367 n=86 n=244 n=238 n=110 n=126 n=115

Serum Glucose Change from baseline

-1.3 1.3 3.5 0.1 3.4 1.8 -0.2

ProportionofPatientswithShiftsSerum Glucose Normal to High (<100 mg/dL to ≥126 mg/dL)

4.6%(11/241)

6.3%(4/64)

6.4%(11/173)

3.9%(6/154)

2.5%(2/79)

7.0%(6/86)

6.6%(5/76)

aInitialdeltoidinjectionof234mgfollowedbyeither39mg,156mg,or234mgevery 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156mg)arefromstudiesinvolvingonlyglutealinjection.[See Clinical Studies (14.1)].

In a long-term open-label pharmacokinetic and safety study in subjects withschizophrenia inwhichthehighestdoseavailable(234mg)wasevaluated,INVEGA® SUSTENNA® was associated with a mean change in glucose of -0.4mg/dLatWeek29(n=109)and+6.8mg/dLatWeek53(n=100).

5



During the initial 25-week open-label period of a long-term study in subjectswithschizoaffectivedisorder,INVEGA® SUSTENNA®wasassociatedwithmeanchange in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent15-month double-blind period of the study, INVEGA® SUSTENNA®wasassociatedwith a mean change in glucose of +0.3 mg/dL (n=131) compared with a meanchangeof+4.0mg/dLintheplacebogroup(n=120).DyslipidemiaUndesirable alterations in lipids have been observed in patients treated withatypical antipsychotics.Pooled data from the four placebo-controlled (one 9-week and three 13-week),fixed-dosestudiesinsubjectswithschizophreniaarepresentedinTable6.Table 6. Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week,

Fixed-DoseStudiesinSubjectswithSchizophreniaINVEGA® SUSTENNA®


Mean change from baseline (mg/dL)Cholesterol Change from baseline

n=366-6.6

n=89-6.4

n=244-5.8

n=232-7.1

n=105-0.9

n=119-4.2

n=1209.4

LDL Change from baseline

n=275-6.0

n=80-4.8

n=164-5.6

n=141-4.8

n=1040.9

n=117-2.4

n=1085.2

HDL Change from baseline

n=2860.7

n=892.1

n=1650.6

n=1500.3

n=1051.5

n=1181.1

n=1150.0

Triglycerides Change from baseline

n=366-16.7

n=897.6

n=244-9.0

n=232-11.5

n=105-14.1

n=119-20.0

n=12011.9

ProportionofPatientswithShiftsCholesterol Normal to High (<200 mg/dL to ≥240 mg/dL)

3.2%(7/222)

2.0%(1/51)

2.0%(3/147)

2.1%(3/141)

0%(0/69)

3.1%(2/65)

7.1%(6/84)

LDL Normal to High (<100 mg/dL to ≥160 mg/dL)

1.1%(1/95)

0%(0/29)

0%(0/67)

0%(0/46)

0%(0/41)

0%(0/37)

0%(0/44)

HDL NormaltoLow(≥40 mg/dL to <40 mg/dL)

13.8%(28/203)

14.8%(9/61)

9.6%(11/115)

14.2%(15/106)

12.7%(9/71)

10.5%(8/76)

16.0%(13/81)

Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL)

3.6%(8/221)

6.1%(3/49)

9.2%(14/153)

7.2%(10/139)

1.3%(1/79)

3.7%(3/82)

10.7%(9/84)

aInitialdeltoidinjectionof234mgfollowedbyeither39mg,156mg,or234mg every4weeksbydeltoidorglutealinjection.Otherdosegroups(39mg,78mg, and156mg)arefromstudiesinvolvingonlyglutealinjection.[See Clinical Studies (14.1)].

In a long-term open-label pharmacokinetic and safety study in subjects withschizophrenia inwhich the highest dose available (234mg)was evaluated, themeanchangesfrombaselineinlipidvaluesarepresentedinTable7.

Table 7. Change in Fasting Lipids from Long-term Open-label Pharmacokinetic andSafetyStudyinSubjectswithSchizophrenia

INVEGA® SUSTENNA® 234 mgWeek 29 Week 53Mean change from baseline (mg/dL)

Cholesterol n=112 n=100Change from baseline -1.2 0.1

LDL n=107 n=89Change from baseline -2.7 -2.3

HDL n=112 n=98Change from baseline -0.8 -2.6

Triglycerides n=112 n=100Change from baseline 16.2 37.4

Themeanchanges frombaseline in lipidvaluesduring the initial25-weekopen-label period and at the endpoint of the subsequent 15-month double-blind period in along-termstudyinsubjectswithschizoaffectivedisorderarepresentedinTable8.

Table 8. Change in Fasting Lipids from an Open-Label and Double-Blind Periods ofaLong-TermStudyinSubjectswithSchizoaffectiveDisorder

Open-Label Period Double-Blind PeriodINVEGA® SUSTENNA® Placebo INVEGA® SUSTENNA®

Mean change from baseline (mg/dL)Cholesterol n=198 n=119 n=132Change from baseline

-3.9 -4.2 2.3

LDL n=198 n=117 n=130Change from baseline

-2.7 -2.8 5.9

HDL n=198 n=119 n=131Change from baseline

-2.7 -0.9 -0.7

Triglycerides n=198 n=119 n=132Change from baseline

7.0 2.5 -12.3

WeightGainWeightgainhasbeenobservedwithatypicalantipsychoticuse.Clinicalmonitoringofweightisrecommended.Dataonmeanchangesinbodyweightandtheproportionofsubjectsmeetingaweightgaincriterionof≥7%ofbodyweightfromthefourplacebo-controlled(one9-weekandthree13-week),fixed-dosestudiesinsubjectswithschizophreniaarepresentedinTable9.Table9.MeanChangeinBodyWeight(kg)andtheProportionofSubjectswith

≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-DoseStudiesinSubjectswithSchizophrenia

INVEGA® SUSTENNA®


n=451 n=116 n=280 n=267 n=137 n=144 n=145

Weight (kg) Change from baseline

-0.4 0.4 0.8 1.4 0.4 0.7 1.4

Weight Gain ≥ 7% increase from baseline

3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1%

aInitialdeltoidinjectionof234mgfollowedbyeither39mg,156mg,or234mgevery 4weeksbydeltoidorglutealinjection.Otherdosegroups(39mg,78mg,and156mg)arefromstudiesinvolvingonlyglutealinjection.[See Clinical Studies (14.1)].

Inalong-termopen-labelpharmacokineticandsafetystudyinwhichthehighestdoseavailable (234mg)wasevaluated, INVEGA® SUSTENNA®wasassociatedwith a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week53(n=113).Duringtheinitial25-weekopen-labelperiodofalong-termstudyinsubjectswithschizoaffective disorder, INVEGA® SUSTENNA® was associated with a meanchangeinweightof+2.2kgand18.4%ofsubjectshadanincreaseinbodyweightof≥7%(n=653).Attheendpointofthesubsequent15-monthdouble-blindperiodof the study, INVEGA® SUSTENNA®wasassociatedwithameanchangeinweightof-0.2kgand13.0%ofsubjectshadanincreaseinbodyweightof≥7%(n=161);theplacebogrouphadameanchangeinweightof-0.8kgand6.0%ofsubjectshadanincreaseinbodyweightof≥7%(n=168).5.7 Orthostatic Hypotension and SyncopePaliperidonecan induceorthostatic hypotensionand syncope in somepatientsbecauseofitsalpha-blockingactivity.Syncopewasreportedin<1%(4/1293)ofsubjects treated with INVEGA® SUSTENNA® in the recommended dose range of39mgto234mginthefourfixed-dose,double-blind,placebo-controlledtrialscompared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotensionwas reported as an adverse event by < 1% (2/1293) of INVEGA® SUSTENNA®- treatedsubjectscomparedto0%(0/510)withplacebo.Incidencesoforthostatichypotensionandsyncopeinthelong-termstudiesinsubjectswithschizophreniaand schizoaffective disorder were similar to those observed in the short-termstudies.

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INVEGA® SUSTENNA® should be used with caution in patients with knowncardiovascular disease (e.g., heart failure, history of myocardial infarction orischemia, conduction abnormalities), cerebrovascular disease, or conditionsthat predispose the patient to hypotension (e.g., dehydration, hypovolemia, andtreatmentwithantihypertensivemedications).Monitoringoforthostaticvitalsignsshouldbeconsideredinpatientswhoarevulnerabletohypotension.5.8 Leukopenia, Neutropenia, and AgranulocytosisInclinicaltrialand/orpostmarketingexperience,eventsofleukopenia/neutropeniahavebeenreportedtemporallyrelatedtoantipsychoticagents,includingINVEGA®, an oral form of paliperidone. Agranulocytosis has also been reported.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/neutropenia should have their complete blood count (CBC)monitored frequentlyduring thefirst fewmonthsof therapyanddiscontinuationof INVEGA® SUSTENNA® should be considered at the first sign of a clinicallysignificantdeclineinWBCintheabsenceofothercausativefactors.Patients with clinically significant neutropenia should be carefully monitoredfor fever or other symptoms or signs of infection and treated promptly if suchsymptomsorsignsoccur.Patientswithsevereneutropenia(absoluteneutrophilcount<1000/mm3) should discontinue INVEGA® SUSTENNA®andhavetheirWBCfolloweduntilrecovery.5.9 HyperprolactinemiaLike other drugs that antagonize dopamine D2 receptors, paliperidone elevatesprolactin levels and the elevation persists during chronic administration.Paliperidonehasaprolactin-elevatingeffectsimilartothatseenwithrisperidone,adrugthatisassociatedwithhigherlevelsofprolactinthanotherantipsychoticdrugs.Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH,resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female andmale patients. Galactorrhea, amenorrhea, gynecomastia, and impotence havebeenreportedinpatientsreceivingprolactin-elevatingcompounds.Long-standinghyperprolactinemiawhenassociatedwithhypogonadismmayleadtodecreasedbone density in both female and male subjects.Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patientwith previously detectedbreast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas)was observed in the risperidonecarcinogenicity studiesconducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studiesnorepidemiologicstudiesconductedtodatehaveshownanassociationbetween chronic administration of this class of drugs and tumorigenesis inhumans,buttheavailableevidenceistoolimitedtobeconclusive.5.10 Potential for Cognitive and Motor ImpairmentSomnolence, sedation, and dizziness were reported as adverse reactions insubjects treated with INVEGA® SUSTENNA® [see Adverse Reactions (6.1)]. Antipsychotics, including INVEGA® SUSTENNA®, have the potential to impairjudgment,thinking,ormotorskills.Patientsshouldbecautionedaboutperformingactivities requiring mental alertness, such as operating hazardous machineryoroperatingamotorvehicle,until theyarereasonablycertainthatpaliperidonetherapydoesnotadverselyaffectthem.5.11 SeizuresIn the four fixed-dose double-blind placebo-controlled studies in subjects withschizophrenia, <1% (1/1293) of subjects treated with INVEGA® SUSTENNA® in the recommended dose range of 39 mg to 234 mg experienced an adverseeventofconvulsioncomparedwith<1%(1/510)ofplacebo-treatedsubjectswhoexperiencedanadverseeventofgrandmalconvulsion.Likeotherantipsychoticdrugs,INVEGA® SUSTENNA® should be used cautiously in patientswith a history of seizures or other conditions that potentially lowerthe seizure threshold.Conditions that lower the seizure thresholdmaybemoreprevalentinpatients65yearsorolder.5.12 DysphagiaEsophageal dysmotility andaspirationhavebeenassociatedwithantipsychoticdrug use. Aspiration pneumonia is a common cause of morbidity and mortality in patientswithadvancedAlzheimer’sdementia. INVEGA® SUSTENNA® and other antipsychotic drugs should be used cautiously in patients at risk for aspirationpneumonia.5.13 PriapismDrugs with alpha-adrenergic blocking effects have been reported to inducepriapism.AlthoughnocasesofpriapismhavebeenreportedinclinicaltrialswithINVEGA® SUSTENNA®,priapismhasbeenreportedwithoralpaliperidoneduringpostmarketingsurveillance.Severepriapismmayrequiresurgicalintervention.

5.14 Disruption of Body Temperature RegulationDisruption of the body’s ability to reduce core body temperature has beenattributedtoantipsychoticagents.AppropriatecareisadvisedwhenprescribingINVEGA® SUSTENNA®topatientswhowillbeexperiencingconditionswhichmaycontributetoanelevationincorebodytemperature,e.g.,exercisingstrenuously,exposuretoextremeheat,receivingconcomitantmedicationwithanticholinergicactivity,orbeingsubjecttodehydration.6 ADVERSE REACTIONSThefollowingarediscussedinmoredetailinothersectionsofthelabeling:• Increased mortality in elderly patients with dementia-related psychosis [see

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

dementia-related psychosis [see Warnings and Precautions (5.2)]• Neurolepticmalignantsyndrome[see Warnings and Precautions (5.3)]• QTprolongation[see Warnings and Precautions (5.4)]• Tardivedyskinesia[see Warnings and Precautions (5.5)]• Metabolicchanges[see Warnings and Precautions (5.6)]• Orthostatichypotensionandsyncope[see Warnings and Precautions (5.7)]• Leukopenia,neutropenia,andagranulocytosis[see Warnings and Precautions (5.8)]• Hyperprolactinemia[See Warnings and Precautions (5.9)]• Potentialforcognitiveandmotorimpairment [see Warnings and Precautions (5.10)]• Seizures [see Warnings and Precautions (5.11)]• Dysphagia[see Warnings and Precautions (5.12)]• Priapism[see Warnings and Precautions (5.13)]• Disruptionofbodytemperatureregulation[see Warnings and Precautions (5.14)]

Themost common (at least 5% in any INVEGA® SUSTENNA® group) and likelydrug-related(adverseeventsforwhichthedrugrateisatleasttwicetheplaceborate)adversereactionsfromthedouble-blind,placebo-controlledtrialsinsubjectswithschizophreniawereinjectionsitereactions,somnolence/sedation,dizziness,akathisia,andextrapyramidaldisorder.Nooccurrencesofadverseeventsreachedthis threshold in the long-term double-blind, placebo-controlled study in subjects withschizoaffectivedisorder.The data described in this section are derived from a clinical trial databaseconsisting of a total of 3817 subjects (approximately 1705 patient-years exposure) withschizophreniawhoreceivedat leastonedoseof INVEGA® SUSTENNA® in therecommendeddoserangeof39mgto234mgandatotalof510subjectswithschizophrenia who received placebo. Among the 3817 INVEGA® SUSTENNA®-treated subjects, 1293 received INVEGA® SUSTENNA® in four fixed-dose,double-blind,placebo-controlled trials (one9-weekand three13-weekstudies),849 received INVEGA® SUSTENNA® in the maintenance trial (median exposure 229daysduring the initial33-weekopen-labelphaseof thisstudy,ofwhom205continued to receive INVEGA® SUSTENNA® during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1675 receivedINVEGA® SUSTENNA® infivenon-placebocontrolled trials (threenoninferiorityactive-comparator trials, one long-term open-label pharmacokinetic and safetystudy,andaninjectionsite[deltoid-gluteal]cross-overtrial).Oneofthe13-weekstudies included a 234 mg INVEGA® SUSTENNA® initiation dose followed bytreatmentwitheither39mg,156mg,or234mgevery4weeks.The safety of INVEGA® SUSTENNA® was also evaluated in a long-termstudy in adult subjects with schizoaffective disorder. A total of 667 subjectsreceived INVEGA® SUSTENNA® during the initial 25-week open-label periodof this study (median exposure 147 days); 164 subjects continued to receiveINVEGA® SUSTENNA® during the 15-month double-blind placebo-controlled periodofthisstudy(medianexposure446days).Adversereactionsthatoccurredmore frequently in the INVEGA® SUSTENNA® than the placebo group (a 2%difference or more between groups) were weight increased, nasopharyngitis,headache, hyperprolactinemia, and pyrexia.6.1 Clinical Trials ExperienceBecauseclinical trials areconductedunderwidely varyingconditions, adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedin clinical practice.Commonly Reported Adverse Reactions in Double-Blind, Placebo-ControlledClinicalTrialsTable10liststheadversereactionsreportedin2%ormoreofINVEGA® SUSTENNA®-treated subjects and at a greater proportion than in the placebo group withschizophreniainthefourfixed-dose,double-blind,placebo-controlledtrials.



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Table 10. Incidence of Adverse Reactions in ≥ 2% of INVEGA® SUSTENNA®-TreatedSubjects(andgreaterthanPlacebo)withSchizophreniainFourFixed-Dose, Double-Blind, Placebo-Controlled Trials

INVEGA® SUSTENNA®

System Organ Class AdverseEvent

Placeboa (N=510)

39 mg (N=130)

78 mg (N=302)

156 mg (N=312)

234/39 mgb (N=160)

234/156 mgb (N=165)

234/234 mgb (N=163)

Total percentage ofsubjectswithadverseevent

70 75 68 69 63 60 63

Gastrointestinal disorders Abdominal discomfort/abdominal pain upper

2 2 4 4 1 2 4

Diarrhea 2 0 3 2 1 2 2 Dry mouth 1 3 1 0 1 1 1 Nausea 3 4 4 3 2 2 2 Toothache 1 1 1 3 1 2 3 Vomiting 4 5 4 2 3 2 2General disorders and administration site conditions Asthenia 0 2 1 <1 0 1 1Fatigue 1 1 2 2 1 2 1 Injection site reactions

2 0 4 6 9 7 10

Infections and infestations Nasopharyngitis 2 0 2 2 4 2 2 Upper respiratory tract infection

2 2 2 2 1 2 4

Urinary tract infection

1 0 1 <1 1 1 2

InvestigationsWeight increased

1 4 4 1 1 1 2

Musculoskeletal and connective tissue disordersBackpain 2 2 1 3 1 1 1Musculoskeletalstiffness

1 1 <1 <1 1 1 2

Myalgia 1 2 1 <1 1 0 2Paininextremity

1 0 2 2 2 3 0

Nervous system disordersAkathisia 3 2 2 3 1 5 6Dizziness 1 6 2 4 1 4 2 Extrapyramidal disorder

1 5 2 3 1 0 0

Headache 12 11 11 15 11 7 6 Somnolence/sedation

3 5 7 4 1 5 5

Psychiatric disorders Agitation 7 10 5 9 8 5 4 Anxiety 7 8 5 3 5 6 6 Nightmare <1 2 0 0 0 0 0Respiratory, thoracic and mediastinal disordersCough 1 2 3 1 0 1 1Vascular disordersHypertension 1 2 1 1 1 1 0Percentages are rounded to whole numbers. Table includes adverse events thatwerereportedin2%ormoreofsubjectsinanyoftheINVEGA® SUSTENNA® dose groupsandwhichoccurredatgreaterincidencethanintheplacebogroup.aPlacebo group is pooled from all studies and included either deltoid or gluteal

injection depending on study design.bInitialdeltoidinjectionof234mgfollowedbyeither39mg,156mg,or234mgevery 4weeksbydeltoidorglutealinjection.Otherdosegroups(39mg,78mg,and156mg)arefromstudiesinvolvingonlyglutealinjection.[See Clinical Studies (14.1)]

AdverseeventsforwhichtheINVEGA® SUSTENNA® incidencewasequal toorlessthanplaceboarenotlistedinthetable,butincludedthefollowing:dyspepsia,psychoticdisorder,schizophrenia,andtremor.Thefollowingtermswerecombined:somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse events werecollapsed and are grouped under “Injection site reactions”.

Other Adverse Reactions Observed During the Clinical Trial Evaluation ofINVEGA® SUSTENNA®

Thefollowinglistdoesnot includereactions:1)alreadylistedinprevioustablesorelsewhereinlabeling,2)forwhichadrugcausewasremote,3)whichweresogeneralastobeuninformative,or4)whichwerenotconsideredtohavesignificantclinical implications.Cardiac disorders:atrioventricularblockfirstdegree,bradycardia,bundlebranchblock,palpitations,posturalorthostatictachycardiasyndrome,tachycardiaEar and labyrinth disorders:vertigoEye disorders:eyemovementdisorder,eyerolling,oculogyriccrisis,visionblurredGastrointestinal disorders:constipation,dyspepsia,flatulence,salivaryhypersecretionImmune system disorders:hypersensitivityInvestigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormalMetabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetiteMusculoskeletal and connective tissue disorders: arthralgia, joint stiffness, musclerigidity,musclespasms,muscletightness,muscletwitching,nuchalrigidityNervous system disorders: bradykinesia, cerebrovascular accident, convulsion,dizzinesspostural,drooling,dysarthria,dyskinesia,dystonia,hypertonia,lethargy,oromandibulardystonia,parkinsonism,psychomotorhyperactivity,syncopePsychiatric disorders: insomnia, restlessnessReproductive system and breast disorders: amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunctionRespiratory, thoracic and mediastinal disorders: nasal congestionSkin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized,rash,urticariaDiscontinuationsDuetoAdverseEventsThepercentageofsubjectswhodiscontinuedduetoadverseevents inthefourfixed-dose,double-blind,placebo-controlledschizophreniatrialsweresimilarforINVEGA® SUSTENNA®- and placebo-treated subjects.Thepercentageofsubjectswhodiscontinuedduetoadverseeventsintheopen-label period of the long-term study in subjects with schizoaffective disorderwas 7.5%.During the double-blind, placebo-controlled period of that study, thepercentagesofsubjectswhodiscontinuedduetoadverseeventswere5.5%and1.8%inINVEGA® SUSTENNA®-andplacebo-treatedsubjects,respectively.Dose-RelatedAdverseReactionsBased on the pooled data from the four fixed-dose, double-blind, placebo-controlledtrialsinsubjectswithschizophrenia,amongtheadversereactionsthatoccurredat≥2%incidenceinthesubjectstreatedwithINVEGA® SUSTENNA®, only akathisia increased with dose. Hyperprolactinemia also exhibited a doserelationship,butdidnotoccurat≥2%incidenceinINVEGA® SUSTENNA®-treated subjectsfromthefourfixed-dosestudies.Demographic DifferencesAn examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age,gender,orracealone;however,therewerefewsubjects≥65yearsofage.ExtrapyramidalSymptoms(EPS)Pooleddata fromthe twodouble-blind,placebo-controlled,13-week,fixed-dosetrials in adult subjects with schizophrenia provided information regarding EPS.SeveralmethodswereusedtomeasureEPS:(1)theSimpson-Angusglobalscore(meanchangefrombaselineorscoreattheendoftrial)whichbroadlyevaluatesParkinsonism, (2) theBarnesAkathisiaRatingScaleglobalclinical ratingscore(meanchangefrombaselineorscoreattheendoftrial)whichevaluatesakathisia,(3)useofanticholinergicmedicationstotreatEPS,(4) theAbnormalInvoluntaryMovementScalescores(meanchangefrombaselineorscoresattheendoftrial)(Table11),and(5)incidenceofspontaneousreportsofEPS(Table12).



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Table 11. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults

Percentage of SubjectsINVEGA® SUSTENNA®

Scale

Placebo (N=262)

39 mg (N=130)

78 mg (N=223)

156 mg (N=228)

Parkinsonisma 9 12 10 6Akathisiab 5 5 6 5Dyskinesiac 3 4 6 4 Use of Anticholinergic Medicationsd

12 10 12 11

aForParkinsonism,percentofsubjectswithSimpson-AngusTotalscore>0.3atendpoint(Totalscoredefinedastotalsumofitemsscoredividedbythenumber of items)

bForAkathisia,percentofsubjectswithBarnesAkathisiaRatingScaleglobalscore≥2atendpoint

cForDyskinesia,percentofsubjectswithascore≥3onanyofthefirst7itemsorascore≥2ontwoormoreofanyofthefirst7itemsoftheAbnormalInvoluntaryMovementScaleatendpoint

dPercentofsubjectswhoreceivedanticholinergicmedicationstotreatEPS

Table 12. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term – Schizophrenia Studies in Adults

Percentage of Subjects INVEGA® SUSTENNA®

EPS Group

Placebo (N=262)

39 mg (N=130)

78 mg (N=223)

156 mg (N=228)

OverallpercentageofsubjectswithEPS-relatedadverseevents

10 12 11 11

Parkinsonism 5 6 6 4Hyperkinesia 2 2 2 4Tremor 3 2 2 3Dyskinesia 1 2 3 1Dystonia 0 1 1 2Parkinsonismgroupincludes:Extrapyramidaldisorder,hypertonia,musculoskeletalstiffness,parkinsonism,drooling,maskedfacies,muscletightness,hypokinesiaHyperkinesiagroupincludes:Akathisia,restlesslegssyndrome,restlessnessDyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching,myoclonus,tardivedyskinesiaDystoniagroupincludes:Dystonia,musclespasms

Theresultsacrossallphasesofthemaintenancetrialinsubjectswithschizophreniaexhibitedcomparablefindings. In the9-week,fixed-dose,double-blind,placebo-controlled trial, the proportions of Parkinsonism and akathisia assessed byincidence of rating scales were higher in the INVEGA® SUSTENNA® 156 mg group(18%and11%,respectively)thanintheINVEGA® SUSTENNA® 78 mg group (9%and5%,respectively)andplacebogroup(7%and4%,respectively).In the 13-week study in subjects with schizophrenia involving 234 mg initiationdosing,theincidenceofanyEPSwassimilartothatoftheplacebogroup(8%),butexhibitedadose-relatedpatternwith6%,10%,and11%intheINVEGA® SUSTENNA® 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia wasthemost frequentcategoryofEPS-relatedadverseevents in thisstudy,andwasreportedatasimilarratebetweentheplacebo(4.9%)andINVEGA® SUSTENNA® 234/156mg(4.8%)and234/234mg(5.5%)groups,butatalowerrateinthe234/39mggroup(1.3%).Inthelong-termstudyinsubjectswithschizoaffectivedisorder,theEPSduringthe25-week open-label INVEGA® SUSTENNA® treatment were hyperkinesia (12.3%),parkinsonism(8.7%),tremor(3.4%),dyskinesia(2.5%),anddystonia(2.1%).Duringthe15-monthdouble-blindtreatment,theincidenceofanyEPSwassimilartothatoftheplacebogroup(8.5%and7.1%respectively).Themostcommonlyreportedtreatment-emergentEPS-relatedadverseevents(>2%) inanytreatmentgroup in thedouble-blind phase of the study (INVEGA® SUSTENNA®versusplacebo)werehyperkinesia(3.7%vs.2.9%),parkinsonism(3.0%vs.1.8%),andtremor(1.2%vs.2.4%).DystoniaSymptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur insusceptible individualsduring thefirst fewdaysof treatment.Dystonicsymptomsinclude:spasmoftheneckmuscles,sometimesprogressingtotightnessof the throat, swallowing difficulty, difficulty breathing, and/or protrusion of thetongue.Whilethesesymptomscanoccuratlowdoses,theyoccurmorefrequentlyandwithgreaterseveritywithhighpotencyandathigherdosesoffirstgenerationantipsychoticdrugs.Anelevatedriskofacutedystoniaisobservedinmalesandyounger age groups.LaboratoryTestAbnormalitiesInthepooleddatafromthetwodouble-blind,placebo-controlled,13-week,fixed-dosetrialsinsubjectswithschizophrenia,abetween-groupcomparisonrevealednomedicallyimportantdifferencesbetweenINVEGA® SUSTENNA® and placebo in the proportions of subjects experiencing potentially clinically significant

changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly,therewerenodifferencesbetweenINVEGA® SUSTENNA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide,triglycerides,HDL,LDL,andtotalcholesterolmeasurements.However,INVEGA® SUSTENNA® was associated with increases in serum prolactin [see Warnings and Precautions (5.9)]. The results from the 13-week study involving 234mginitiationdosing,the9-week,fixed-dose,double-blind,placebo-controlledtrial, and the double-blind phase of the maintenance trial in subjects withschizophreniaexhibitedcomparablefindings.PainAssessmentandLocalInjectionSiteReactionsIn the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlledtrialsinsubjectswithschizophrenia,themeanintensityofinjectionpainreportedbysubjectsusingavisualanalogscale(0=nopainto100=unbearablypainful) decreased in all treatment groups from the first to the last injection(placebo:10.9to9.8;39mg:10.3to7.7;78mg:10.0to9.2;156mg:11.1to8.8).Theresults from both the 9-week, fixed-dose, double-blind, placebo-controlled trialandthedouble-blindphaseofthemaintenancetrialexhibitedcomparablefindings.In the 13-week study involving 234 mg initiation dosing in subjects withschizophrenia, occurrences of induration, redness, or swelling, as assessedby blinded study personnel, were infrequent, generally mild, decreased overtime,andsimilar in incidencebetween the INVEGA® SUSTENNA® and placebo groups. Investigator ratings of injection pain were similar for the placebo andINVEGA® SUSTENNA®groups.Investigatorevaluationsoftheinjectionsiteafterthefirstinjectionforredness,swelling,induration,andpainwereratedasabsentfor69-100%ofsubjectsinboththeINVEGA® SUSTENNA® and placebo groups. At Day92,investigatorsratedabsenceofredness,swelling,induration,andpainin95-100%ofsubjectsinboththeINVEGA® SUSTENNA® and placebo groups.AdverseReactionsReportedinClinicalTrialswithOralPaliperidoneThefollowingisalistofadditionaladversereactionsthathavebeenreportedinclinicaltrialswithoralpaliperidone:Cardiac disorders:bundlebranchblockleft,sinusarrhythmiaGastrointestinal disorders: abdominal pain, small intestinal obstructionGeneral disorders and administration site conditions: edema, edema peripheralImmune system disorders: anaphylactic reactionInfections and infestations: rhinitisMusculoskeletal and connective tissue disorders: musculoskeletal pain,torticollis, trismusNervous system disorders:cogwheelrigidity,grandmalconvulsion,parkinsoniangait,transientischemicattackPsychiatric disorders: sleep disorderReproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculationRespiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, pneumonia aspirationSkin and subcutaneous tissue disorders: rash papularVascular disorders: hypotension, ischemia6.2 Postmarketing ExperienceThefollowingadversereactionshavebeenidentifiedduringpostapprovaluseofpaliperidone;becausethesereactionswerereportedvoluntarilyfromapopulationof uncertain size, it is not always possible to reliably estimate their frequencyor establish a causal relationship to drug exposure. Reactions already listed in other parts of ADVERSE REACTIONS (6), or those considered in WARNINGS AND PRECAUTIONS (5) are not listed here.Blood disorders: thrombotic thrombocytopenic purpuraGastrointestinal disorders: ileusGenitourinary disorders: urinary incontinence, urinary retentionImmune system disorders:angioedema,swollentongueCasesofanaphylactic reactionafter injectionwith INVEGA® SUSTENNA®havebeenreportedduringpostmarketingexperienceinpatientswhohavepreviouslytolerated oral risperidone or oral paliperidone.6.3 Adverse Reactions Reported With RisperidonePaliperidone is the major active metabolite of risperidone. Adverse reactionsreportedwithoralrisperidoneandrisperidonelong-actinginjectioncanbefoundin the ADVERSE REACTIONSsectionsofthepackageinsertsforthoseproducts.7 DRUG INTERACTIONSBecause paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)],resultsfromstudieswithoralpaliperidoneshouldbetakenintoconsiderationwhenassessingdrug-druginteractionpotential.7.1 Potential for INVEGA® SUSTENNA® to Affect Other DrugsPaliperidonemayantagonizetheeffectoflevodopaandotherdopamineagonists.Becauseof itspotential for inducingorthostatichypotension,anadditiveeffectmayoccurwhen INVEGA® SUSTENNA® is administeredwith other therapeuticagentsthathavethispotential[see Warnings and Precautions (5.7)].



9

No dose adjustment is necessary for lithium when it is coadministeredwith INVEGA® SUSTENNA®. Pharmacokinetic interaction betweenINVEGA® SUSTENNA®andlithiumisunlikely.No dose adjustment is necessary for valproate when INVEGA® SUSTENNA® is added to the therapy. Steady-state pharmacokinetics of valproate was notaffectedwhenpatientswerecoadministeredoralpaliperidoneextended-releasetablets [see Clinical Pharmacology (12.3)].Paliperidone is not expected to cause clinically important pharmacokineticinteractionswithdrugsthataremetabolizedbycytochromeP450 isozymes [see Clinical Pharmacology (12.3)].7.2 Potential for Other Drugs to Affect INVEGA® SUSTENNA®

On initiation of strong inducers of bothCYP3A4andP-gp (e.g., carbamazepine,rifampin, or St John’s wort), it may be necessary to increase the dose ofINVEGA® SUSTENNA®. Conversely, on discontinuation of the strong inducer, itmay be necessary to decrease the dose of INVEGA® SUSTENNA® [see Clinical Pharmacology (12.3)].No dose adjustment is necessary for INVEGA® SUSTENNA®when valproate isadded to treatment [see Clinical Pharmacology (12.3)].No dose adjustment is necessary for INVEGA® SUSTENNA® when itis coadministered with lithium. Pharmacokinetic interaction betweenINVEGA® SUSTENNA®andlithiumisunlikely.In vitrostudiesindicatethatCYP2D6andCYP3A4maybeinvolvedinpaliperidonemetabolism;however,thereisnoevidencein vivothatinhibitorsoftheseenzymessignificantlyaffectthemetabolismofpaliperidone.Paliperidoneisnotasubstrateof CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors orinducersoftheseisozymesisunlikely.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancyCategoryCRiskSummaryAdequateandwellcontrolledstudieswithINVEGA® SUSTENNA®havenotbeenconductedinpregnantwomen.Neonatesexposedtoantipsychoticdrugsduringthethirdtrimesterofpregnancyareatriskforextrapyramidaland/orwithdrawalsymptoms following delivery. INVEGA® SUSTENNA® should be used during pregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.ClinicalConsiderationsFetal/Neonatal Adverse ReactionsMonitor neonates exhibiting extrapyramidal or withdrawal symptoms. Someneonates recover within hours or days without specific treatment; others mayrequireprolongedhospitalization.DataHuman DataTherehavebeenreportsofagitation,hypertonia,hypotonia,tremor,somnolence,respiratorydistress,andfeedingdisorderinneonatesfollowingin utero exposure toantipsychoticsinthethirdtrimester.Thesecomplicationshavevariedinseverity;while insomecasessymptomshavebeenself-limited, inothercasesneonateshaverequiredintensivecareunitsupportandprolongedhospitalization.Animal DataThere were no treatment-related effects on the offspring when pregnant ratswere injected intramuscularly with paliperidone palmitate during the periodof organogenesis at doses up to 250 mg/kg, which is 10 times the maximumrecommended human 234 mg dose of INVEGA® SUSTENNA® on a mg/m2 body surface area basis.In studies in pregnant rats and rabbits in which paliperidonewas given orallyduringtheperiodoforganogenesis,therewerenoincreasesinfetalabnormalitiesuptothehighestdosestested(10mg/kg/day inratsand5mg/kg/day inrabbits,whichareeach8timesthemaximumrecommendedhumandoseof12mg/dayoforallyadministeredpaliperidone[INVEGA®]onamg/m2 body surface area basis).In rat reproduction studieswith risperidone, which is extensively converted topaliperidoneinratsandhumans,increasesinpupdeathswereseenatoraldoseswhicharelessthanthemaximumrecommendedhumandoseofrisperidoneonamg/m2bodysurfaceareabasis(seeRISPERDAL®packageinsert).8.2 Labor and DeliveryThe effect of INVEGA® SUSTENNA®onlaboranddeliveryinhumansisunknown.8.3 Nursing MothersIn animal studies with paliperidone and in human studies with risperidone,paliperidonewasexcretedinthemilk.Becauseofthepotentialforseriousadversereactions innursing infants,adecisionshouldbemadewhether todiscontinuenursingortodiscontinuethedrug,takingintoaccounttheimportanceofthedrugto the mother.8.4 Pediatric UseSafetyandeffectivenessofINVEGA® SUSTENNA® inpatients<18yearsofagehavenotbeenestablished.

Ina study inwhich juvenile ratswere treatedwithoral paliperidone fromdays24to73ofage,areversibleimpairmentofperformanceinatestoflearningandmemorywasseen,infemalesonly,withano-effectdoseof0.63mg/kg/day,whichproducedplasmalevels(AUC)ofpaliperidonesimilartothoseinadolescents.Noother consistent effects on neurobehavioral or reproductive developmentwereseenuptothehighestdosetested(2.5mg/kg/day),whichproducedplasmalevelsof paliperidone 2-3 times those in adolescents.Juveniledogsweretreatedfor40weekswithoralrisperidone,whichisextensivelymetabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5mg/kg/day.Decreasedbonelengthanddensitywereseenwithano-effectdoseof0.31mg/kg/day,whichproducedplasmalevels(AUC)ofrisperidonepluspaliperidonewhichwere similar to those in children and adolescents receiving themaximumrecommended human dose of risperidone. In addition, a delay in sexual maturation wasseenatalldosesinbothmalesandfemales.Theaboveeffectsshowedlittleornoreversibilityinfemalesaftera12-weekdrug-freerecoveryperiod.Thelong-termeffectsofpaliperidoneongrowthandsexualmaturationhavenotbeenfullyevaluatedinchildrenandadolescents.8.5 Geriatric UseClinical studies of INVEGA® SUSTENNA® did not include sufficient numbers ofsubjects aged 65 and over to determinewhether they respond differently fromyoungersubjects.Otherreportedclinicalexperiencehasnotidentifieddifferencesinresponsesbetweentheelderlyandyoungerpatients.Thisdrug is known tobesubstantiallyexcretedby thekidneyandclearance isdecreased inpatientswith renal impairment [see Clinical Pharmacology (12.3)], whoshouldbegivenreduceddoses.Becauseelderlypatientsaremorelikelytohavedecreasedrenalfunction,adjustdosebasedonrenalfunction[see Dosage and Administration (2.5)].8.6 Renal ImpairmentUse of INVEGA® SUSTENNA® is not recommended in patients with moderateor severe renal impairment (creatinineclearance< 50mL/min).Dose reductionis recommended for patients with mild renal impairment (creatinine clearance≥ 50mL/min to < 80mL/min) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].8.7 Hepatic Impairment INVEGA® SUSTENNA®hasnotbeenstudiedinpatientswithhepaticimpairment.Basedonastudywithoralpaliperidone,nodoseadjustmentisrequiredinpatientswithmildormoderatehepatic impairment.Paliperidonehasnotbeenstudied inpatientswithseverehepaticimpairment.8.8 PatientswithParkinson’sDiseaseorLewyBodyDementiaPatientswithParkinson’sDiseaseorDementiawithLewyBodiescanexperienceincreased sensitivity to INVEGA® SUSTENNA®. Manifestations can includeconfusion, obtundation, postural instability with frequent falls, extrapyramidalsymptoms,andclinicalfeaturesconsistentwithneurolepticmalignantsyndrome.9 DRUG ABUSE AND DEPENDENCE9.1 Controlled SubstanceINVEGA® SUSTENNA® (paliperidone) is not a controlled substance.9.2 AbusePaliperidone has not been systematically studied in animals or humans for itspotential for abuse.9.3 DependencePaliperidone has not been systematically studied in animals or humans for itspotential for tolerance or physical dependence.10 OVERDOSAGE10.1 Human ExperienceNo cases of overdose were reported in premarketing studies withINVEGA® SUSTENNA®.BecauseINVEGA® SUSTENNA® is to be administered by healthcareprofessionals,thepotentialforoverdosagebypatientsislow.While experience with paliperidone overdose is limited, among the few casesof overdose reported in premarketing trials with oral paliperidone, the highestestimated ingestion was 405 mg. Observed signs and symptoms includedextrapyramidal symptoms and gait unsteadiness. Other potential signs andsymptoms include those resulting from an exaggeration of paliperidone’sknownpharmacological effects, i.e., drowsiness and sedation, tachycardia andhypotension,andQTprolongation.Torsadesdepointesandventricularfibrillationhavebeenreportedinapatientinthesettingofoverdosewithoralpaliperidone.Paliperidone is themajoractivemetaboliteofrisperidone.Overdoseexperiencereported with risperidone can be found in the OVERDOSAGE section of the risperidonepackageinsert.10.2 Management of OverdosageContact a Certified Poison Control Center for the most up to date informationon the management of INVEGA® SUSTENNA® overdosage (1-800-222-1222 orwww.poison.org). Provide supportive care, including closemedical supervisionand monitoring. Treatment should consist of general measures employed in the



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managementofoverdosagewithanydrug.Considerthepossibilityofmultipledrugoverdosage. Ensure an adequate airway, oxygenation, and ventilation.Monitorcardiacrhythmandvitalsigns.Usesupportiveandsymptomaticmeasures.Thereisnospecificantidotetopaliperidone.Consider the prolonged-release characteristics of INVEGA® SUSTENNA® and the longapparenthalf-lifeofpaliperidonewhenassessingtreatmentneedsandrecovery.11 DESCRIPTIONINVEGA® SUSTENNA® is an atypical antipsychotic. INVEGA® SUSTENNA® containspaliperidonepalmitate.Theactiveingredient,paliperidonepalmitate,isapsychotropicagentbelongingtothechemicalclassofbenzisoxazolederivatives.INVEGA® SUSTENNA® contains a racemicmixture of (+)- and (-)- paliperidonepalmitate. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-ylhexadecanoate.ItsmolecularformulaisC39H57FN4O4anditsmolecularweightis664.89.Thestructuralformulais:

Paliperidonepalmitateisveryslightlysolubleinethanolandmethanol,practicallyinsoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.INVEGA® SUSTENNA®isavailableasawhitetooff-whitesterileaqueousextended-releasesuspensionforintramuscularinjectioninthefollowingdosestrengthsofpaliperidonepalmitate(anddeliverablevolumesoftheprefilledsyringes):39mg(0.25mL),78mg(0.5mL),117mg(0.75mL),156mg(1.0mL),and234mg(1.5mL).Thedrugproducthydrolyzestotheactivemoiety,paliperidone,resultingindosestrengthsof25mg,50mg,75mg,100mg,and150mgofpaliperidone,respectively.Theinactiveingredientsarepolysorbate20(12mg/mL),polyethyleneglycol4000(30 mg/mL), citric acid monohydrate (5 mg/mL), disodium hydrogen phosphateanhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and waterforinjection.INVEGA® SUSTENNA® isprovided inaprefilledsyringe (cyclic-olefin-copolymer)withaplungerstopperandtipcap(bromobutylrubber).Thekitalsocontains2safetyneedles (a 1½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionPaliperidonepalmitate ishydrolyzed topaliperidone [see Clinical Pharmacology (12.3)].Paliperidoneisthemajoractivemetaboliteofrisperidone.Themechanismof action of paliperidone is unknown. However, it has been proposed that thedrug’stherapeuticactivityinschizophreniaismediatedthroughacombinationofcentral dopamine Type 2 (D2)andserotoninType2(5HT2A) receptor antagonism.12.2 PharmacodynamicsPaliperidone isacentrallyactivedopamineType2 (D2) receptor antagonist and aserotoninType2(5HT2A)receptorantagonist.Paliperidoneisalsoactiveasanantagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors,which may explain some of the other effects of the drug. Paliperidone hasno affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers isqualitativelyandquantitativelysimilarin vitro.12.3 PharmacokineticsAbsorption and DistributionDue to its extremely low water solubility, paliperidone palmitate dissolvesslowlyafter intramuscular injectionbeforebeinghydrolyzedtopaliperidoneandabsorbedintothesystemiccirculation.Followingasingleintramusculardose,theplasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.Following intramuscular injectionofsingledoses (39mg-234mg) in thedeltoidmuscle,onaverage,a28%higherCmaxwasobservedcomparedwithinjectionintheglutealmuscle.Thetwoinitialdeltoidintramuscularinjectionsof234mgonday1and156mgonday8helpattaintherapeuticconcentrationsrapidly.Thereleaseprofileand dosing regimen of INVEGA® SUSTENNA® results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA® SUSTENNA® administrationwasdose-proportionalovera39mg-234mgdoserange,and lessthandose-proportionalforCmax for doses exceeding 78 mg. The mean steady-state peak:troughratioforanINVEGA® SUSTENNA®doseof156mgwas1.8followingglutealadministrationand2.2followingdeltoidadministration.Followingadministrationofpaliperidonepalmitatethe(+)and(-)enantiomersofpaliperidoneinterconvert,reachinganAUC(+)to(-)ratioofapproximately1.6–1.8.

Basedonapopulationanalysis,theapparentvolumeofdistributionofpaliperidoneis391L.Theplasmaproteinbindingofracemicpaliperidoneis74%.MetabolismandEliminationIn a study with oral immediate-release 14C-paliperidone, one week followingadministration of a single oral dose of 1 mg immediate-release 14C-paliperidone,59%ofthedosewasexcretedunchangedintourine,indicatingthatpaliperidoneisnotextensivelymetabolizedintheliver.Approximately80%oftheadministeredradioactivitywasrecoveredinurineand11%inthefeces.Fourmetabolicpathwayshavebeenidentified in vivo,noneofwhichaccountedformorethan10%ofthedose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.Although in vitrostudiessuggestedaroleforCYP2D6andCYP3A4inthemetabolismofpaliperidone,thereisnoevidencein vivothattheseisozymesplayasignificantrole in the metabolism of paliperidone. Population pharmacokinetics analysesindicated no discernible difference on the apparent clearance of paliperidone afteradministrationoforalpaliperidonebetweenextensivemetabolizersandpoormetabolizersofCYP2D6substrates.The median apparent half-life of paliperidone following INVEGA® SUSTENNA® single-doseadministrationover thedose rangeof 39mg - 234mg ranged from 25days-49days.Long-Acting Paliperidone Palmitate Injection versus Oral Extended-ReleasePaliperidoneINVEGA® SUSTENNA®isdesignedtodeliverpaliperidoneoveramonthlyperiodwhile extended-release oral paliperidone is administered on a daily basis. Theinitiation regimen for INVEGA® SUSTENNA® (234 mg/156 mg in the deltoid muscleonDay1/Day8)wasdesignedtorapidlyattainsteady-statepaliperidoneconcentrationswheninitiatingtherapywithouttheuseoforalsupplementation.Ingeneral,overallinitiationplasmalevelswithINVEGA® SUSTENNA®werewithintheexposurerangeobservedwith6-12mgextended-releaseoralpaliperidone.Theuse of the INVEGA® SUSTENNA®initiationregimenallowedpatientstostayinthisexposurewindowof6-12mgextended-releaseoralpaliperidoneevenontroughpre-dose days (Day 8 and Day 36). The intersubject variability for paliperidonepharmacokinetics following delivery from INVEGA® SUSTENNA® was lowerrelative to the variability determined from extended-release oral paliperidonetablets.Becauseof thedifference inmedianpharmacokineticprofilesbetweenthetwoproducts,cautionshouldbeexercisedwhenmakingadirectcomparisonoftheirpharmacokineticproperties.Drug Interaction StudiesPotential for INVEGA® SUSTENNA® to Affect Other DrugsIn vitrostudies inhumanlivermicrosomesdemonstratedthatpaliperidonedoesnotsubstantiallyinhibitthemetabolismofdrugsmetabolizedbycytochromeP450isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4,andCYP3A5.Therefore,paliperidoneisnotexpectedtoinhibitclearanceofdrugsthataremetabolizedbythesemetabolicpathwaysinaclinicallyrelevantmanner.Paliperidoneisalsonotexpectedtohaveenzymeinducingproperties.PaliperidoneisaweakinhibitorofP-glycoprotein(P-gp)athighconcentrations.No in vivodataareavailable,andtheclinicalrelevanceisunknown.In a drug interaction study, co-administration of oral paliperidone extended-release tablets (12mgoncedaily for 5days)withdivalproex sodiumextended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized onvalproate.Inaclinicalstudy,subjectsonstabledosesofvalproatehadcomparablevalproate average plasma concentrations when oral paliperidone extended-releasetablets3-15mg/daywasaddedtotheirexistingvalproatetreatment[see Drug Interactions (7.1)].Potential for Other Drugs to Affect INVEGA® SUSTENNA®

Whilein vitrostudiesindicatethatCYP2D6andCYP3A4maybeminimallyinvolvedin paliperidone metabolism, in vivo studies did not demonstrate decreased eliminationbytheseisozymes;theycontributetoonlyasmallfractionoftotalbodyclearance. In vitrostudiesdemonstratedthatpaliperidoneisaP-gpsubstrate[see Drug Interactions (7.2)].Co-administration of oral paliperidone extended-release 6 mg once daily withcarbamazepine,astronginducerofbothCYP3A4andP-gp,at200mgtwicedailycaused a decrease of approximately 37% in the mean steady-state Cmax and AUCofpaliperidone.Thisdecreaseiscaused,toasubstantialdegree,bya35%increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect onthe CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration [see Drug Interactions (7.2)].Co-administrationof a singledoseof oral paliperidoneextended-release 12mgtabletwithdivalproexsodiumextended-releasetablets(two500mgtabletsoncedaily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied withINVEGA® SUSTENNA®,aclinicallysignificantinteractionwouldnotbeexpectedbetween divalproex sodium and INVEGA® SUSTENNA® intramuscular injection [see Drug Interactions (7.2)].



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PaliperidoneismetabolizedtoalimitedextentbyCYP2D6.Inaninteractionstudyin healthy subjects inwhicha single 3mgdoseof oral paliperidoneextended-release was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90%CI:4,30)higherinCYP2D6extensivemetabolizers.Higherdosesofparoxetinehavenotbeenstudied.Theclinicalrelevanceisunknown.SpecificPopulationsRenal ImpairmentINVEGA® SUSTENNA®hasnotbeensystematicallystudiedinpatientswithrenalimpairment.BasedonalimitednumberofobservationswithINVEGA® SUSTENNA® in subjects with mild renal impairment and pharmacokinetic simulations, thedose of INVEGA® SUSTENNA® should be reduced in patients with mild renalimpairment; INVEGA® SUSTENNA®isnotrecommendedinpatientswithmoderateorsevererenal impairment.AlthoughINVEGA® SUSTENNA®wasnotstudied inpatients with moderate or severe renal impairment, the disposition of a singleoral dose paliperidone 3 mg extended-release tablet was studied in subjectswith varying degrees of renal function. Elimination of paliperidone decreasedwithdecreasingestimatedcreatinineclearance.Totalclearanceofpaliperidonewasreducedinsubjectswithimpairedrenalfunctionby32%onaverageinmild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to <50mL/min),and71%insevere(CrCl=10mL/minto<30mL/min)renalimpairment,correspondingtoanaverageincreaseinexposure(AUCinf) of 1.5 fold, 2.6 fold, and 4.8fold,respectively,comparedtohealthysubjects[see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].Hepatic ImpairmentINVEGA® SUSTENNA®hasnotbeenstudiedinpatientswithhepaticimpairment.Based on a study with oral paliperidone in subjects with moderate hepaticimpairment (Child-Pugh class B), no dose adjustment is required in patientswith mild or moderate hepatic impairment. In the study with oral paliperidonein subjectswithmoderatehepatic impairment (Child-PughclassB), theplasmaconcentrations of free paliperidone were similar to those of healthy subjects,although total paliperidone exposure decreased because of a decrease in proteinbinding.Paliperidonehasnotbeenstudiedinpatientswithseverehepaticimpairment [see Use in Specific Populations (8.7)].ElderlyNo dosage adjustment is recommended based on age alone. However, doseadjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and Dosage and Administration (2.5)].RaceNo dosage adjustment is recommended based on race. No differences in pharmacokineticswereobservedbetweenJapaneseandCaucasians.GenderNo dosage adjustment is recommended based on gender, although slowerabsorptionwasobservedinfemalesinapopulationpharmacokineticanalysis.SmokingNo dosage adjustment is recommended based on smoking status. Based on in vitrostudiesutilizinghumanliverenzymes,paliperidoneisnotasubstrateforCYP1A2;smokingshould, therefore,nothaveaneffectonthepharmacokineticsof paliperidone.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisThecarcinogenicpotentialofintramuscularlyinjectedpaliperidonepalmitatewasassessedinrats.Therewasanincreaseinmammaryglandadenocarcinomasinfemaleratsat16,47,and94mg/kg/month,whichis0.6,2,and4times,respectively,the maximum recommended human 234 mg dose of INVEGA® SUSTENNA® on a mg/m2 body surface area basis. A no-effect dosewas not established.Malerats showed an increase in mammary gland adenomas, fibroadenomas, andcarcinomasat47mgand94mg/kg/month.Acarcinogenicitystudyinmicehasnotbeenconductedwithpaliperidonepalmitate.Carcinogenicity studies of risperidone, which is extensively converted topaliperidoneinrats,mice,andhumans,wereconductedinSwissalbinomiceandWistarrats.Risperidonewasadministered in thedietatdailydosesof0.63,2.5,and10mg/kgfor18monthstomiceandfor25monthstorats.Amaximumtolerateddosewasnotachievedinmalemice.Therewerestatisticallysignificantincreasesin pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas.Theno-effectdoseforthesetumorswaslessthanorequaltothe maximum recommended human dose of risperidone on a mg/m2 body surface

areabasis(seeRISPERDAL®packageinsert).Anincreaseinmammary,pituitary,and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. The relevanceof thesetumorfindings inrodents in termsofhumanrisk isunknown[see Warnings and Precautions (5.9)].MutagenesisPaliperidone palmitate showed no genotoxic potential in the Ames reversemutationtestorthemouselymphomaassay.NoevidenceofgenotoxicpotentialforpaliperidonewasfoundintheAmesreversemutationtest,themouselymphomaassay, or the in vivo rat micronucleus test.ImpairmentofFertilityFertilitystudiesofpaliperidonepalmitatehavenotbeenperformed.In a study of fertility conducted with orally administered paliperidone, thepercentage of treated female rats that became pregnant was not affected atdosesofpaliperidoneofupto2.5mg/kg/day.However,pre-andpost-implantationlosswereincreased,andthenumberofliveembryoswasslightlydecreased,at 2.5mg/kg,adosethatalsocausedslightmaternaltoxicity.Theseparameterswerenotaffectedatadoseof0.63mg/kg,whichishalfofthemaximumrecommendedhuman dose (12 mg/day) of orally administered paliperidone (INVEGA®) on a mg/m2 body surface area basis.Thefertilityofmaleratswasnotaffectedatoraldosesofpaliperidoneofup to 2.5mg/kg/day,althoughspermcountandspermviabilitystudieswerenotconductedwithpaliperidone.InasubchronicstudyinBeagledogswithrisperidone,whichis extensively converted to paliperidone in dogs and humans, all doses tested (0.31mg/kg-5.0mg/kg)resultedindecreasesinserumtestosteroneandinspermmotility and concentration. Serum testosterone and sperm parameters partially recovered,butremaineddecreasedafterthelastobservation(twomonthsaftertreatmentwasdiscontinued).14 CLINICAL STUDIESTheefficacyofINVEGA® SUSTENNA®wasestablishedinthefollowingadequateandwell-controlledtrials:• Four short-term, fixed-dose trials and one maintenance trial in adults with

schizophreniaasmonotherapy[see Clinical Studies (14.1)]• One long-term, flexible-dosemaintenance trial in adultswith schizoaffective

disorder as monotherapy or as adjunctive therapy to a mood stabilizer orantidepressant [see Clinical Studies (14.2)]

14.1 SchizophreniaShort-TermMonotherapy(Studies1,2,3,4)The efficacy of INVEGA® SUSTENNA® in the acute treatment of schizophreniawas evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsedadult inpatientswhometDSM-IV criteria for schizophrenia. The fixed doses ofINVEGA® SUSTENNA® in these studieswere given on days 1, 8, and 36 in the9-weekstudy,andadditionallyonday64ofthe13-weekstudies,i.e.,ataweeklyintervalfortheinitialtwodosesandthenevery4weeksformaintenance.Efficacy was evaluated using the total score on the Positive and NegativeSyndromeScale(PANSS).ThePANSSisa30 itemscalethatmeasurespositivesymptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent)to7(extreme);totalPANSSscoresrangefrom30to210.In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses ofINVEGA® SUSTENNA® (initial deltoid injection of 234 mg followed by 3 glutealordeltoiddosesofeither39mg/4weeks,156mg/4weeksor234mg/4weeks)toplacebo, all three doses of INVEGA® SUSTENNA®were superior to placebo inimprovingthePANSStotalscore.InStudy2(PSY-3003),another13-weekstudy(n=349)comparingthreefixeddosesof INVEGA® SUSTENNA®(78mg/4weeks,156mg/4weeks,and234mg/4weeks)toplacebo,only156mg/4weeksofINVEGA® SUSTENNA®wassuperiortoplaceboinimprovingthePANSStotalscore.InStudy3(PSY-3004),athird13-weekstudy(n=513)comparingthreefixeddosesof INVEGA® SUSTENNA® (39mg/4weeks,78mg/4weeks,and156mg/4weeks)to placebo, all three doses of INVEGA® SUSTENNA®weresuperiortoplaceboinimprovingthePANSStotalscore.In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses ofINVEGA® SUSTENNA®(78mg/4weeksand156mg/4weeks)toplacebo,bothdosesof INVEGA® SUSTENNA®weresuperiortoplaceboinimprovingPANSStotalscore.



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AsummaryofthemeanbaselinePANSSscoresalongwiththemeanchangesfrombaselineinthefourshort-termacuteschizophreniastudiesareprovidedinTable13.Table 13. Schizophrenia Short-term Studies

Study Number

Treatment Group Primary Efficacy Measure: PANSS Total Score

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1 INVEGA® SUSTENNA® (39mg/4weeks)*

86.9(11.99) -11.2(1.69) -5.1 (-9.01,-1.10)

INVEGA® SUSTENNA® (156mg/4weeks)*

86.2 (10.77) -14.8 (1.68) -8.7 (-12.62, -4.78)


88.4 (11.70) -15.9(1.70) -9.8 (-13.71, -5.85)

Placebo 86.8 (10.31) -6.1(1.69) --Study 2b INVEGA® SUSTENNA®

(78mg/4weeks)89.9(10.78) -6.9(2.50) -3.5

(-8.73, 1.77)INVEGA® SUSTENNA® (156mg/4weeks)*

90.1(11.66) -10.4 (2.47) -6.9 (-12.12, -1.68)

Placebo 92.4(12.55) -3.5 (2.15) --Study 3 INVEGA® SUSTENNA®

(39mg/4weeks)*90.7(12.25) -19.8(2.19) -6.6

(-11.40, -1.73)INVEGA® SUSTENNA® (78mg/4weeks)*

91.2(12.02) -19.2(2.19) -5.9 (-10.76, -1.07)


90.8(11.70) -22.5 (2.18) -9.2 (-14.07, -4.43)

Placebo 90.7(12.22) -13.3 (2.21) --Study 4 INVEGA® SUSTENNA®

(78mg/4weeks)*88.0(12.39) -4.6 (2.43) -11.2

(-16.85, -5.57)INVEGA® SUSTENNA® (156mg/4weeks)*

85.2(11.09) -7.4 (2.45) -14.0 (-19.51,-8.58)

Placebo 87.8(13.90) 6.6 (2.45) --SD:standarddeviation;SE:standarderror;LSMean:least-squaresmean; CI:unadjustedconfidenceinterval.a Difference (drug minus placebo) in least-squares mean change from baseline. bBecauseaninsufficientnumberofsubjectsreceivedthe234mg/4weeksdose,

results from this group are not included.*p<0.05(Dosesstatisticallysignificantlysuperiortoplacebo).

MaintenanceMonotherapyTreatment(Study5:PSY-3001)The efficacy of INVEGA® SUSTENNA® in maintaining symptomatic control in schizophreniawasestablishedinalonger-termdouble-blind,placebo-controlled,flexible-dose study involving adult subjects who met DSM-IV criteria forschizophrenia. This study includedaminimum12-week, fixed-dose stabilizationphase,andarandomized,placebo-controlledphasetoobserveforrelapse.Duringthe double-blind phase, patients were randomized to either the same dose ofINVEGA® SUSTENNA® they receivedduring the stabilizationphase, i.e., 39mg, 78mg,or156mgadministeredevery4weeks,ortoplacebo.Atotalof410stabilizedpatientswererandomizedtoeitherINVEGA® SUSTENNA® or to placebo until they experienceda relapseofschizophreniasymptoms.Relapsewaspre-definedastimetofirstemergenceofoneormoreofthefollowing:psychiatrichospitalization,≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if thebaselinescorewas≤40)intotalPANSSscoreontwoconsecutiveassessments,deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a scoreof≥5 (if themaximumbaselinescorewas≤3)or≥6 (if themaximumbaselinescorewas4)ontwoconsecutiveassessmentsofthespecificPANSSitems.Theprimary efficacy variable was time to relapse. A pre-planned interim analysisshowedastatisticallysignificantlylongertimetorelapseinpatientstreatedwithINVEGA® SUSTENNA® compared to placebo, and the studywas stopped earlybecausemaintenanceofefficacywasdemonstrated.Thirty-fourpercent(34%)ofsubjectsintheplacebogroupand10%ofsubjectsintheINVEGA® SUSTENNA® groupexperiencedarelapseevent.TherewasastatisticallysignificantdifferencebetweenthetreatmentgroupsinfavorofINVEGA® SUSTENNA®.AKaplan-MeierplotoftimetorelapsebytreatmentgroupisshowninFigure1.Thetimetorelapsefor subjects in theplacebogroupwasstatistically significantly shorter than forthe INVEGA® SUSTENNA® group. An examination of population subgroups did notrevealanyclinicallysignificantdifferencesinresponsivenessonthebasisofgender, age, or race.

Figure 1:Kaplan-Meier Plot of Cumulative Proportion of Subjects with RelapseOverTime(SchizophreniaStudy5)

14.2 Schizoaffective DisorderMaintenance Treatment – Monotherapy and as Adjunct to Mood Stabilizer orAntidepressant(SAffStudy1:SCA-3004)The efficacy of INVEGA® SUSTENNA® in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled,flexible-doserandomized-withdrawalstudydesignedtodelayrelapseinadultsubjectswhometDSM-IVcriteriaforschizoaffectivedisorder,asconfirmedbytheStructuredClinicalInterviewforDSM-IVDisorders.Thepopulationincludedsubjects with schizoaffective bipolar and depressive types. Subjects receivedINVEGA® SUSTENNA® either as monotherapy or as an adjunct to stable doses of antidepressantormoodstabilizers.Thisstudyincludeda13-week,open-label,flexible-dose(INVEGA® SUSTENNA® 78mg, 117mg, 156mg, or 234mg) lead-in periodwhich enrolled a total of 667subjectswhohad1)acuteexacerbationofpsychoticsymptoms;2)score≥4on≥3PANSSitemsofdelusions,conceptualdisorganization,hallucinatorybehavior,excitement, suspiciousness/persecution, hostility, uncooperativeness, tension,and poor impulse control; and 3) prominent mood symptoms ≥16 on the YoungMania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-itemversion(HAM-D-21).Subjectswere19to66yearsold(mean39.5years)and53.5%weremale.Themeanscoresatopen-labelenrollmentofPANSStotalwas85.8 (range42 to128),HAM-D-21was20.4 (range3 to43),YMRSwas18.6(range0to50),andCGI-S-SCAwas4.4(range2to6).After the 13-week open-label flexible-dose INVEGA® SUSTENNA® treatment, 432 subjects met stabilization criteria (PANSS total score ≤70, YMRS ≤12, andHAM-D-21≤12)andcontinuedintothe12-weekopen-labelfixed-dosestabilizationperiod.Atotalof334subjectswhometstabilizationcriteriafor12consecutiveweekswererandomized(1:1)tocontinuethesamedoseofINVEGA® SUSTENNA® or to placebo inthe15-month,double-blind,maintenanceperiod.Forthe164subjectswhowererandomizedtoINVEGA® SUSTENNA®,dosedistributionwas78mg(4.9%),117mg(9.8%),156mg(47.0%),and234mg(38.4%).Theprimaryefficacyvariablewastimetorelapse.Relapsewasdefinedasthefirstoccurrenceofoneormoreofthefollowing:1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3)clinicallysignificantself-injury,suicidalorhomicidalideationorviolentbehavior;4)ascoreof≥6(ifthescorewas≤4atrandomization)ofanyoftheindividualPANSSitems: delusions, conceptual disorganization, hallucinatory behavior, excitement,suspiciousness/persecution,hostility,uncooperativeness,orpoorimpulsecontrol;5)ontwoconsecutiveassessmentswithin7days:≥25%increase(ifthescoreatrandomizationwas>45)or≥10-point increase (if thescoreat randomizationwas≤45)intotalPANSSscore;ascoreof≥5(ifthescorewas≤3atrandomization)ofanyoftheindividualPANSSitems:delusions,conceptualdisorganization,hallucinatorybehavior,excitement,suspiciousness/persecution,hostility,uncooperativeness,orpoorimpulsecontrol;anincreaseof≥2points(ifthescorewas1[notill]to3[mildlyill]atrandomization)orincreaseof≥1point(ifthescorewas≥4[moderatelyillorworse]atrandomization)inCGI-S-SCAoverallscore.There was a statistically significant difference in time to relapse between thetreatmentgroupsinfavorofINVEGA® SUSTENNA®.AKaplan-MeierplotoftimetorelapsebytreatmentgroupisshowninFigure2.



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Figure 2:Kaplan-Meier Plot of Cumulative Proportion of Subjects with RelapseOverTime(SAffStudy1)

Table14summarizesthenumberofsubjectswithrelapseintheoverallpopulation,bysubgroup(monotherapyvs.adjunctivetherapy),andbysymptomtypeatthefirstoccurrence of relapse.Table 14. Summary of Relapse Rates (SAff Study 1).

Number (Percent) of Subjects Who RelapsedPlacebo N=170

INVEGA® SUSTENNA® N=164

All Subjects 57(33.5%) 25(15.2%) Monotherapy subset N=73

24(32.9%)N=78

9(11.5%) Adjunct to Antidepressants

or Mood Stabilizer subsetN=97

33(34.0%)N=86

16(18.6%)Psychotic Symptomsa 53(31.2%) 21(12.8%)Mood Symptomsb

Any Mood Symptoms 48(28.2%) 18(11.0%) Manic 16(9.4%) 5(3.0%) Depressive 23(13.5%) 8(4.9%) Mixed 9(5.3%) 5(3.0%)

a8subjectsexperiencedarelapsewithoutpsychoticsymptoms.b16subjectsexperiencedarelapsewithoutanymoodsymptoms.

16 HOW SUPPLIED/STORAGE AND HANDLINGINVEGA® SUSTENNA® is available as a white to off-white sterile aqueousextended-release suspension for intramuscular injection in dose strengths of 39mg,78mg,117mg,156mg,and234mgpaliperidonepalmitate.Thekitcontainsaprefilledsyringeand2safetyneedles(a1½-inch22gaugesafetyneedleanda1-inch 23 gauge safety needle).39mgpaliperidonepalmitatekit(NDC50458-560-01)78mgpaliperidonepalmitatekit(NDC50458-561-01)117mgpaliperidonepalmitatekit(NDC50458-562-01)156mgpaliperidonepalmitatekit(NDC50458-563-01)234mgpaliperidonepalmitatekit(NDC50458-564-01)Storage and HandlingStore at room temperature (25°C, 77°F); excursions between 15°C and 30°C(between59°Fand86°F)arepermitted.17 PATIENT COUNSELING INFORMATIONSeeFDA-approvedpatientlabeling(PatientInformation)Physiciansareadvisedtodiscussthefollowingissueswithpatientsforwhomtheyprescribe INVEGA® SUSTENNA®.Orthostatic HypotensionPatientsshouldbeadvisedthatthereisriskoforthostatichypotension,particularlyat the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)].InterferencewithCognitiveandMotorPerformancePatients should be cautioned about operating hazardous machinery, includingautomobiles, until they are reasonably certain that INVEGA® SUSTENNA® therapy does not affect them adversely, as INVEGA® SUSTENNA® has the potential to impairjudgment,thinking,ormotorskills[see Warnings and Precautions (5.10)].

PregnancyPatientsshouldbeadvised tonotify theirphysician if theybecomepregnantorintendtobecomepregnantduringtreatmentwithINVEGA® SUSTENNA® [see Use in Specific Populations (8.1)].NursingInformpatientsandcaregivers that INVEGA® SUSTENNA® is present in human breastmilk; there isapotential forseriousadversereactions innursing infants.Advisepatientsthatthedecisionwhethertodiscontinuenursingortodiscontinuethedrugshouldtakeintoaccounttheimportanceofthedrugtothepatient[see Use in Specific Populations (8.3)].Concomitant MedicationPatientsshouldbeadvised to inform theirphysicians if theyare taking,orplanto take, any prescription or over-the-counter drugs, as there is a potential forinteractions [see Drug Interactions (7.1, 7.2)].Heat Exposure and DehydrationPatientsshouldbeadvisedregardingappropriatecareinavoidingoverheatinganddehydration [see Warnings and Precautions (5.14)].INVEGA® SUSTENNA® (paliperidone palmitate) Extended-Release Injectable SuspensionProductofIrelandManufacturedby: JanssenPharmaceuticaN.V. Beerse,BelgiumManufacturedfor: JanssenPharmaceuticals,Inc. Titusville,NJ08560©JanssenPharmaceuticals,Inc.2009

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PATIENT INFORMATION INVEGA® SUSTENNA® (In-VEY-guh Suss-TEN-uh)

(paliperidone palmitate) Extended-Release Injectable Suspension

Read this Patient Information carefully before you receiveINVEGA SUSTENNA and each time you receive it. There maybenewinformation.Thisinformationdoesnottaketheplaceoftalkingtoyourhealthcareprovideraboutyourmedicalconditionor your treatment.What is the most important information I should know aboutINVEGA SUSTENNA?INVEGA SUSTENNA can cause serious side effects, including:• Increased riskof death inelderly peoplewhoareconfused,

havememorylossandhavelosttouchwithreality(dementia-related psychosis). INVEGA SUSTENNA is not for treating dementia-related psychosis.

What is INVEGA SUSTENNA?INVEGA SUSTENNAisaprescriptionmedicinegivenbyinjectionbyahealthcareprofessionalandusedtotreat:• schizophrenia• schizoaffective disorder either alone orwith othermedicinessuchasmoodstabilizersorantidepressants

It is not known if INVEGA SUSTENNA is safe and effective inchildren under 18 years of age.Who should not receive INVEGA SUSTENNA?Do not receive INVEGA SUSTENNA if you:• areallergictopaliperidone,risperidone,oranyoftheingredientsinINVEGA SUSTENNA.SeetheendofthisPatientInformationleaflet for a complete list of ingredients in INVEGA SUSTENNA.

What should I tell my healthcare provider before receiving INVEGA SUSTENNA?Before you receive INVEGA SUSTENNA, tell your healthcareprovideraboutallyourmedicalconditions,includingifyou:• havehadNeurolepticMalignantSyndrome(NMS)• haveorhavehadheartproblems,includingaheartattack,heartfailure,abnormalheartrhythm,orlongQTsyndrome

• haveorhavehadlowlevelsofpotassiumormagnesiuminyourblood

• haveorhavehaduncontrolledmovementsofyourtongue,face,mouth,orjaw(tardivedyskinesia)

• haveorhavehadkidneyorliverproblems• havediabetesorhaveafamilyhistoryofdiabetes• havehadalowwhitebloodcellcount• have had problems with dizziness or fainting or are being

treated for high blood pressure• haveorhavehadseizuresorepilepsy• haveanyothermedicalconditions• are pregnant or plan to become pregnant. It is not known ifINVEGA SUSTENNAwillharmyourunbornbaby.

• are breastfeeding or plan to breastfeed. INVEGA SUSTENNAcanpass into your breastmilk andmayharmyour baby. YouandyourhealthcareprovidershoulddecideifyouwillreceiveINVEGA SUSTENNAorbreastfeed.Youshouldnotdoboth.

Tell your healthcare provider about all themedicines you take,includingprescriptionandover-the-countermedicines,vitamins,and herbal supplements.

Knowthemedicinesyoutake.Keepalistofthemtoshowtoyourhealthcareproviderorpharmacistwhenyougetanewmedicine.HowwillIreceiveINVEGA SUSTENNA?• TakeINVEGA SUSTENNAexactlyasyourhealthcareprovider

tells you to.• Your healthcare provider will tell you how muchINVEGA SUSTENNA you will receive and when you will receiveit.

• INVEGA SUSTENNAisgivenasaninjectionbyyourhealthcareproviderintothemuscle(intramuscularly)ofyourarmoryourbuttocks.

• Whenyou receiveyourfirstdoseof INVEGA SUSTENNAyouwillneedtogetaseconddose1weeklater.Afterthatyouwillonly need to get a dose 1 time a month.

WhatshouldIavoidwhilereceivingINVEGA SUSTENNA?• INVEGA SUSTENNAmayaffectyourabilitytomakedecisions,think clearly, or react quickly. Do not drive, operate heavymachinery,ordootherdangerousactivitiesuntilyouknowhowINVEGA SUSTENNA affects you.

• Avoidgettingoverheatedordehydrated.What are the possible side effects of INVEGA SUSTENNA?INVEGA SUSTENNA may cause serious side effects, including:• See “What is themost important information I should know

about INVEGA SUSTENNA?”• strokeinelderlypeople (cerebrovascularproblems) thatcan

lead to death• NeurolepticMalignant Syndrome (NMS).NMS is a rare butvery seriousproblem thatcanhappen inpeoplewho receiveINVEGA SUSTENNA. NMS can cause death and must betreatedinahospital.Callyourhealthcareproviderrightawayifyoubecomeseverelyillandhaveanyofthesesymptoms:

° highfever ° severemusclestiffness ° confusion ° loss of consciousness ° changes in your breathing, heartbeat and blood pressure• problemswithyourheartbeat. These heart problems can cause death.Callyourhealthcareproviderrightawayifyouhaveanyofthesesymptoms:

° passingoutorfeelinglikeyouwillpassout ° dizziness ° feeling as if your heart is pounding or missing beats• uncontrolledmovementsof your tongue, face,mouth, or jaw

(tardive dyskinesia)• metabolicchanges.Metabolicchangesmayincludehighblood

sugar (hyperglycemia), diabetes mellitus and changes in the fat levelsinyourblood(dyslipidemia),andweightgain.

• lowbloodpressureandfainting• changesinyourbloodcellcounts• high level of prolactin in your blood (hyperprolactemia).INVEGA SUSTENNAmaycausearise inthebloodlevelsofahormone called prolactin (hyperprolactemia) that may cause sideeffectsincludingmissedmenstrualperiods,leakageofmilkfromthebreasts,developmentofbreastsinmen,orproblemswitherection

• problemsthinkingclearlyandmovingyourbody• seizures• difficultyswallowingthatcancausefoodorliquidtogetinto

your lungs

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• prolongedorpainfulerection lastingmore than4hours.Callyourhealthcareproviderorgotoyournearestemergencyroomrightawayifyouhaveanerectionthatlastsmorethan4hours.

• problems with control of your body temperature especiallywhen you exercise a lot or spend time doing things thatmakeyouwarm.Itisimportantforyoutodrinkwatertoavoiddehydration.

The most common side effects of INVEGA SUSTENNA include:• injectionsitereactions• sleepinessordrowsiness• dizziness• feelingofinnerrestlessnessorneedingtobeconstantlymoving• abnormal muscle movements, including tremor (shaking),shuffling, uncontrolled involuntary movements, and abnormalmovementsofyoureyes

Tell your healthcare provider if you have any side effect thatbothersyouordoesnotgoaway.Thesearenotallthepossibleside effects of INVEGA SUSTENNA. For more information, askyourhealthcareproviderorpharmacist.Callyourdoctor formedicaladviceaboutsideeffects.YoumayreportsideeffectstotheFDAat1-800-FDA-1088.General information about the safe and effective use of INVEGA SUSTENNA.This Patient Information leaflet summarizes themost importantinformation about INVEGA SUSTENNA. If you would like moreinformation,talkwithyourhealthcareprovider.You can ask your healthcare provider or pharmacist for moreinformation that is written for healthcare professionals. For more information, go to www.invegasustenna.com or call 1-800-526-7736.What are the ingredients in INVEGA SUSTENNA?Active ingredient: paliperidone palmitateInactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide,andwaterforinjection

Manufacturedby: JanssenPharmaceuticals,Inc. Titusville,NJ08560©JanssenPharmaceuticals,Inc.2009ThisPatientInformationhasbeenapprovedbythe U.S.FoodandDrugAdministrationRevised:November2014024972-141209


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dosing & administration - mental illness treatment .... resume regular monthly dosing in either...

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