NDA 20-272/8-008 & 20-588/8-004 - Food and Drug ... FOR DRUG EV ALUA TION AND RESEARCH wroval...

CENTER FOR DRUG EV ALUA TION AND RESEARCH

wroval Packa2e for:

APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

Trade Name: Risperdal Tablets 0.25, 0.5, 1, 2, 3 and 4 mg &Risperdal Oral Solution 1 mg/mL

Generic Name: risperidone

Sponsor: Janssen Pharmaceutica

Approval Date: 03/03/2002

Indications: F or the treatment of schizophrenia.

CENTER FOR DRUG EVALUATION ANDRESEARCH

APPLICATION NUMBER:

NDA 20-272/8-008& 20-588/8-004

CONTENTS

Reviews / Information Included in this NDA Review.

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x


APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

APPROVAL LETTER

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(:. ~: DEPARTMENT OF HEALTH & HUMAN SERVICES~;:Public Health Service

Food and Drug AdministrationRockvile MD 20857

NDA 20-272/S-008NDA 20-588/S-004

Johnson & Johnson Pharmaceutical Research & Development, L.L.c.Attention: Edward G. Brann .Director, Regulatory Affairs1125 Trenton-Harbourton RoadTitusvile, NJ 08560

Dear Mr. Brann:

Please refer to your supplemental new drug applications dated March 12, 1997, received March 12,1997, submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Risperdal(risperidone) tablets and oral solution.

We acknowledge receipt of your submission dated January 28,2002, which constituted a completeresponse to our January 11,2002 action letter.

These supplemental new drug applications provide for the longer-term efficacy for risperidone in thetreatment of schizophrenia.

We have completed the review ofthese supplemental applications, as amended, and have concludedthat adequate information has been presented to demonstrate that the drug products are safe andeffective for use as recommended in the agreed upon enclosed labeling text. We note thatmodifications oflabeling text to more clearly state that this agent is indicated for the treatment ofschizophrenia (requested in our letter of September 25,2000) have been effected. Accordingly, thesesupplemental applications are approved effective on the date ofthis letter.

The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert).

Please submit the copies offinal printed labeling (FPL) electronically to each application according to

the guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDA

(January 1999). Alternatively, you may submit 20 paper copies of the FPL as soon as it is available butno more than 30 days after it is printed. Please individually mount ten ofthe copies on heavy-weightpaper or similar materiaL. For administrative purposes, these submissions should be designated "FPLfor approved supplement NDA 20-272/S-008, 20-588/S-004." Approval ofthese submissions by FDAis not required before the labeling is used.

Be advised that, as of April 1, 1999, all applications for new active ingredients, new dosage forms, newindications, new routes of administration, and new dosing regimens must contain an assessment of thesafety and effectiveness of the product in pediatric patients unless FDA waives or defers therequirement (63 FR 66632) (21 CFR 314.55). The Agency has not made a determination if a health

NDA 20-272/S-008NDA 20-588/S-004Page 2

benefit would be gained by studying risperidone in pediatric patients for its approved indication. FDAis deferring submission of the pediatric assessments of safety and effectiveness that may be requiredunder these regulations until February 1,2005.

If a letter communicating important information about this drug product (i.e., a "Dear Health CareProfessional" letter) is issued to physicians and others responsible for patient care, we request that yousubmit a copy ofthe letter to this NDA and a copy to the following address:

MEDWATCH, HF-2FDA5600 Fishers LaneRockvile, MD 20857

We remind you that you must comply with the requirements for an approved NDA set forth under21 CFR 314.80 and 314.81.

If you have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager, at(301) 594-5525.

Sincerely,

(See appended electronic signature page)

Russell Katz, M.D.DirectorDivision of Neuropharmacological Drug ProductsOffice of Drug Evaluation ICenter for Drug Evaluation and Research

Enclosure

Description of revisions to Risperdal (risperidone) Labeling

Section of Labeling Description ofRevision(s)

DESCRIPTION Paragraph i, sentence i: changed from "an antipsychoticagent" to "a psychotropic agent"

CLINCAL PHACOLOGY: Paragraph i, sentence i: changed "antipsychotic drugs"Pharacodynamics to "drugs used to treat schizophrenia" and "antipsychotic

activity" to "therapeutic activity in schizophrenia"

CLINCAL PHACOLOGY: Before paragaph i, added subheading "Short-Term

Clinical Trials Efficacy" .

Paragraph i, changed "management of the manifestationsof psychotic disorders" to "treatment of schizophrenia"

Paragraph 2, sentence i: changed "effects of drugtreatment in psychosis" to "effects of drug treatment inschizophrenia"

CLINCAL PHACOLOGY: Added subheading "Long-Term Effcacy" and paragraphClinical Trials to describe RIS-USA-79 study design and results

INICATIONS AND USAGE Pargraph i: changed "management of the manfestationsof psychotic disorders" to "treatment of schizophrenia"

Paragrph 2, changed "antipsychotic effcacy ofRISPERDAL~" to "effcacy ofRISPERDAL~ inschizophrenia"

Paragraph 3: replaced first sentence with FDA statementon use ofRisperdal in long-term treatment; last sentence:changed "Therefore" to Neverteless"

DOSAGE AND ADMISTRATION: Paragaph i: added "short-term" twice as descriptor ofUsual Initial Dose clincal trals and sentence on titration schedule from

long-term study

Paragraph 2, sentence i: changed "Antipsychoticeffcacy" to Efficacy in schizophrenia" for consistencywith the intent of FDA 9/25/00 letter and added "short-term" as descriptor for clinical trials

DOSAGE AND ADMISTRTION: Repositioned subsection to follow "Usual Initial Dose"Maintenance Therapy subsection

Revised paragph to provide description and titrationschedule from long-term study and to incorporate FDA'schanges

Added the word "schizophrenic" to describe patients inthe first sentence.

DOSAGE AND ADMISTRATION: Added "schizophrenic" as a descriptor for "patients" inSwitching from Other Antipsychotics three places and changed "other patients" to "others"

This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.

/s/Russell Katz3/3/02 11:33:45 AM


APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

APPRO V ABLE LETTER

('~~'È" ::.',Jtr't"l.ifl

DEPARTMENT OF HEALTH & HUAN SERVICES Public Health Service

Food and Drug AdministrationRockville MD 20857

NDA 20-272/S-008NDA 20-588/S-004

Janssen Research FoundationAttention: Edward G. BrannAssistant Director, Regulatory Affairsi 125 Trenton-Harbourton RoadP .O.Box 200Titusvile, NJ 08560-0200

Dear Mr. Brann:

Pleas refer to your supplemental new drug applications dated March 12, 1997, received March 12, 1997,submied under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Risperdal (risperidone)tablets and oral solution.

Your submissions of July 25, 2001, constituted a complete response to our action letter of January 13,1998.

These supplemental new drug applications provide for the longer-term efficacy for risperidone in thetreatment of schizophrenia.

We have completed the review ofthese applications, as amended, and they are approvable. Before these

applications may be approved, however, it wil be necessary for you to submit revised draft labeling. Wehave made revisions to the four sections of labeling for which you have proposed changes. Specifically:

Under CLINCAL lRS, Long-Term Effcacy. We request that you replace your suggestedparagraph under this heading with the following:

"In a longer-term trial, 365 adult outpatients predominantly meetinglDSM-IV I criteria forschizophrenia and who had been cliically stable for at least 4 weeks on an antipsychoticmedication were randomized to Risperdal (2-8 mglday) or to an active comparator, for 1 to 2years of observtion for relapse. Patients receivig Risperdal experienced a signifcantly longertime to relapse over this time period compared to those receivig the active comparator."

In keeping with the current focus in Risperdal labeling on schizophrenia as an indication, and thepredominance of schizophrenia in the sample for study 79, we have included mention only ofschizophrenia, in order to avoid confusion among prescribers.

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NDA 20-272/S-008

"NA 20-588/S-004Page 2

c =lWe have C :i time to relapse, the one outcome designatedprospectively as the primary outcome for study 79.

We have also made othereditorial changes to bring the language into consistency with standardlanguage for the longer-term claim.)

· Under INICA nONS AN USAGE. The following paragraph should be inserted as the finalparagraph in this subsection:

"The effcacy ofRiperdal in delaying relapse was demonstrated in schizophrenic patients whohad been cliically stable for at least 4 weeks before initiation of treatment with Riperdal oran acti comparator and who were then observed for relapse during a period of 1 to 2 years

(see cliical Trials, under Cliical Pharmacology). Nevertheless, the physician who elects touse Riperdal for extended periods should periodically re-evaluate the long-term usefulnessof the drug for the individual patient (see Dosage and Administration)."

.

i

L JUnder DOSAGE AN ADMllRTION. The following paragraphs should be inserted to replacethe curent language under the subsections entitled Usual Initial Dose and Maintenance Therapy. Wehave not removed the language explaining the basis for weekly dose adjustments, and we have madeother editorial changes.

"Usual Initial Dose: RISPERDAL ~ (risperidone) can be administered on either a BID or a QDschedule. In early short-term clinical trials, RISPERDAL ~ was generally administered at 1 mg BIDiniall, wit incres in increments of 1 mg BID on the second and third day, as tolerated, to a target

dose of 3 mg BID by the third day. Subsequent short-term controlled trials have indicated that totaldaily risperidone doses of up to 8 mg on a QD regimen are also safe and effective. In a long-term

NDA 20-272/S-008NDA 20-588/S-004Page 3

controlled trial in stable patients, RISPERDAL was administered on a QD schedule at 1 mg QDinitially, with increases to 2 mg QD on the second day and to a target dose of 4 mg QD on the thirdday. However, Regardless of which regimen is employed, in some patients a slower titration may bemedically appropriate. Further dosage adjustments, if indicated, should generally occur at intervals of

not less than 1 week, since steady state for the active metabolite would not be achieved forapproximately 1 week in the typical patient. When dosage adjustments are necessary, small doseincrements/decrements of 1-2 mg are recommended.

Antipsychotic effcacy was demonstrated in a dose range of 4 to 16 mglday in short-term clinical trialssupporting effectiveness ofRISPERDAL cI, however, maximal effect was generally seen in a rangeof 4 to 8 mglday. Doses above 6 mglday for BID dosing Were not demonstrated to be more efficaciousthan lower doses, were associated with more extrapyramidal symptoms and other adverse effects, andare not generally recommended. In a single study supporting QD dosing, the efficacy results weregenerall stonger for 8 mg than for 4 mg. The safety of doses above 16 mgl day has not been evaluatedin clinical trials.

Maintenance Therapy: While there is no body of evidence available to answer the question of howlong the patient treated with RISPERDAL should remain on it, the effectiveness ofRISPERDAL 2mgdayto 8 mglday at delaying relapse was demonstrated in a controlled trial in patients who had beencliically stable for at least 4 weeks and were then followed for a period of 1 to 2 years. In this trial,RISPERDAL was administered on a QD schedule, at 1 mg QD initially, with increases to 2 mg QDon the second day and to a target dose of 4 mg QD on the third day (see Clinical Trials, under Clinical

Pharmacology). Nevertheless, patients should be periodically reassessed to determine the need formaintenance treatment with appropriate dose."

The labeling should be identical in content to the enclosed labeling (text for the package insert), and allprevious revisions as reflected in the most recently approved labeling must be included. Further, thelabelig changes as requested in our letter of September 25, 2000, must be effected in your response to thisaction letter. Specifically, modifications of labeling text to more clearly state that this agent is indicatedfor the treatment of schizophrenia should be made.

To facilitate review of your submission, please submit a highlighted or marked-up copy of labeling thatshows the changes that are being made.

If additional information relating to the safety or effectiveness of this drug becomes available, furtherrevision ofthe labeling may be required.

Within 10 days after the date ofthis letter, you are required to amend the supplemental applications, notifyus of your intent to fie amendments, or follow one of your other options under 21 CFR 314.110. In theabsence of any such action FDA may proceed to withdraw the applications. Any amendment shouldrespond to all the deficiencies listed. We wil not process a partial reply as a major amendment nor wilthe review clock be reactivated until all deficiencies have been addressed.

NDA 20-272/S-008NDA 20-588/S-004Page 4

If you have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager, at (301)594-5525.

Sincerely,


Russell Katz, M.D.DirectorDivision of Neuropharmacological Drug ProductsOffce of Drug Evaluation ICenter for Drug Evaluation and Research

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.---------------------------------------------------------------------------------------------------------------------/s/

Russell Katz1/11/02 08: 02: 17 AM


APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

LABELING

NDA 20-272/20-588RISPERDAL ~ (risperidone) Tablets/Oral Solution

Part No. 7503220Physicians Insert

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Laø:.s82~oog lEtl) 23-¿NONo. .~~ 2.,2. Bdtr" ,

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ORIGiNAL

DESCRIPTION ,",RISPERDAL~ (nspendone) is a psychotropic agent belonging to a new chemical class, thebenzisoxazoledenvatives. The chemical designation is 3-(2-(4-(6-fiuoro' 1 ,2-benzisoxazol'3'yl)-1-pipendinYIJethYIJ-6,7,B,9-tetrahydro- 2-methyi-4H-pyndo(1 ,2-aJpynmidin-4-one. its molecuiar formula is C~HvFN.O, and its molecularweight is 41 OA9. The structurai formula is: ' .

a"yCH'"Y'CH.-CH,-()Ô

F

Risperidone is a white to slightly beige powder. It i5practically insol~b!e .in water, freely soluble in methylenechlonde, and soluble in meihanol and 0.1 !' HCI. '.RiSPERDAL~taiets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown),Jmg (w~ite), 2 mg(orage),3 mg (yellow), and 4 mg (green) strengths. Inactive ingredients'are colloidal silcon (,lioxide, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystallne cellu.lose, propyle".e glycol, sodium)aurylsulfate, and starch (corn). Tablets of 0.25, 0.5, 2, 3, and 4 mg also.contain talc and,ìilaniumdiox.icie. The0.25 mgtablets contain yellow iron oxide; the q.5 mg tablets contaiíi red iron oxide, th~:2 mg tablets:sOntainFP&C YellOW NO.6 Aluminum Lake; the.3 mg and 4 mg tablets contain D&Ç'Yellow N0,10; the 4 mg tabletscontain FD&C Blue No.2 Aluminum Lake. ,.' . ..'.",., " .RISPERDAL ~ is al~o available as.a 1 mgÍmL oral solution. The inactive ingredients .lor this solution aretartanc acid, benzoic acid, sodium hydroxideand purified water.

CLINICAL PHARMACOLOGYPharmacodynaniicsThe mechanism ofaction,ofHISPERDAL~(rispendone), as with other drugs Used to treat schizophrenia, isunknown, However, it has been proposed that this drug's therapeutic activity in schizophrenia is mediatedthrough... combination 01. dopamine type 2 (0,) and serotonin type 2 (5HT,) antagonism. Antagonismat receptors other than 0, and.5HT, may explain some of the other effects of RISPERDAL~.RiSPERDAL~ is a selective monoaminergic antagonist with highaffinity(Ki of O. t2 to 7:.3 nM)for theserotonin type 2 (5HT,), dopamine type 2 (0,), lX', and", adrenergic, and H, histaminergic receptors.RISPERDAL~antagonizes other receptors, but with lower potency. RISPERDAL~ has low to moderateaffinity (Ki of 47 to 253 nM)for the serotonin 5HT", 5HTm, and.5HT" receptors, weak affnity(Ki of 620 toBOO nM) for the dopamine 0, and haloperidol-sensitive sigma site,' and no.affinity .(when te~ted atconcentrations ::10'5 M) for c~olinergic muscarinic or ß1 and ß2 adra.r!ergic recepto~s: . ,,-PharmacokineticsRispendone is well absorbed; as illustrated by a mass balance study involving asingle.t mgoral dose of"C-risperidone 'as a solution in three healthy male volunteers, Total recovery of radloactivity..i.one weekwas B5%, including 70% in the unne and t S% in the feces. ....."Risperidone is extensively metabolized in the liver by cytochrôme P.~IID. to a 'major actiVe metabolite,9-hydroiinspendone,'which i5the predominant circulating specie, and appears approximately equi-effectivewith nspendone with respect to receptor binding activity and some effects in animals. (A second minor pathwayis Ndealkylation). Consequently, the c1inièal effect of the drug likely results from the combined concentrationsof rispendone plus 9-hydroxyrisperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone, andnspendone plus 9-hydroxyrispendone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 toB mg BID). The relative oral bioavailabilty 01 rispendone lrom a tablet was 94% (CV~1 0%) when compared toa solution. Food does not affect either the rate or extent 01 absorption of risperidone. Thus; rispendone canbe'given with or without meals. The absolute oral bioavailabilty of risperidone was 70% (CV~25%).. Theehzynie catalyzing hYdroxYI.ation 01

risperidone' to 9-hydroxyrisperidohe, iscytochrome.p.~IID., also called deb'risoquinhydroxyiase, the 'enzyme responsible lormetaliolism 01 many neuroleptics, antidepres-sants, antiarrhythmics, and other drugs.Cytochro'me. P,';IID. is .subject: to. g'eneticpolymorphism (about 6'B% 01 Caucasians; and avery low percent of Asians have IiUle or no activitand are "poor metabolizers') and to inhibition bya vanety of substrates and some non-substrates;notably quinidin.e., Extensive metabolizers convertrisperidone rapidly. into g-hydroxyrispe(idone,while poor metabol.izers convert .it much moreslowly. Extensive. metabolizers, 'therelore, .havelower risperidone and higher 9-hydroxyrisperi-done concentrations than poor meiabolizers.Fôllowing oral administration of solution or tablet,mean peak plasma concentrations occurred atabout i hoW. PE,ak 9-hydroxyrisperidoneoccurred at about 3 hours i.nextensivemetabolizers, and 17 hours in poor rretabolizers.The apparent half-life of risperid~n.e Y¡as three.

JAN 1 4 200

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Clinical TrialsThe efficacy of RISPERDAL~ in the treatmentof,'schizophrenia was established. in lour short,term (4 to.B-week) .controlled trials of psychotic inpatients.whomet DSM-II-R critena. for schizpphrenia.Sev.eralinstruments were used lor assessing psychiatnc signs and Symptoms in these studies, among themthe Brief Psychiatnc Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionallyused to evaluate the effects 01 drug treatment in,schizophrenia. The BPRSpsY~hosis cluster (conceptualdisorganization, hallucinatory behavior, suspiciousness,:-and unusual thought cbrient) is' considered aparticularly useful subset for assessing actively psychotic schizophrenic,pat.ients. A seQol1dJraditionalassessment, the Clinica Global Impression (CGI), reflects the impression of. a skiled observeI;,fullyAamilarwith the manifestations of schizophrenia, about the overalhclinicalstate.of the: patient. In addition, tWo morerecently develPPed,butless well evaluated ~ales,. were employed; th~se included the Positive ,and NegativeSyndrome Seale (PANSS) and the Scalè l?r,AssesingNegative. Symptoms (SANS):' .Theresulls oltlÌe tnals follow: ': ..... '.(1,) In a 9. ,ow. ee,k; Placebo-con,t. roo I,ied tnal (n~160) i,n, vO,lvin, g,t~ra, t, i,O,"', Of" R,IS,PERDAL ..In, doses up to 10,m. gJday(BID schedule), RISPERDAL. was generally superior tò' pJacebo on the BPRS .total score, on the BPRSpsychosis cluster, and marginally superior to placebo on the SANS.

(2) In'an B-week;plac~bo-controlled tnal (n~S13) invoiiìing 4 fixed doses of RISPERDAL. (2,6,10, and16 mgJday, on a BID schedule), all 4 RISPERDAL~ gr()ups weregeneraly supenor to placeDo on the BPRS totalsère,aPR§ psych?sis cluster, and CGI.seventy SCOre;Jl;~ 3, ~igheSt .RI§p.l~RDAL ~ dose groups,l'~re gen,erallysupenor to placebo on the PANSS negatlvesuoscae',ThemQ$t oonsl'Jentl posit)ie reSponsesanail meiureswere seen for the 6 mg dose group,. and there was no 'suggestion of .increased benefr.lrom larger doses. .

(3) In an,B-week, dose comparison tnal¡n~1356) involving'S fixed doses. of RISPÉRDAL~ (1.4.B, 12, and16 mgJday, on a BID schedule),'the fourhighest RISPERDAl~dose group~were geDerally'supenor tothe t mgRISPERDAL~ dose group on BPRS totalscore, BPRS psychosis cluster,and CGI. seventy scre: Nöne'of thedose groups were supenor to the 1 mg groû'p on the PANSS negatiye subscale. The'most conšísienilý'positiveresponses were seen for the 4 mg dose group. '. - '. ,.(4) In a 4-week; placebcntròlleddose'cómpanson tnal (n,,,246) ,inVOlVing 2 lixed:doses of RISPERD. AL ~(4 and B mg¡day on a QDschedule), both RISPERDAL~'doše:groups were generally.supenor to placebo' onseveral PANSSmeasures, including'a response:measurEf(,;20%'reduction in PANSS.total score), PANSStotal score, and the BPRS psychosis clusier (denved fromPANSS). The,results were generally stronger lorthe B mg than for the 4 mg dose group. " ,Long-Term EfficacyIna longer-term trial, 365 adult outpatients predomihantly meeting DSM-ii" eriterialorschizÒphrenia'àndwho had been clinically stable for at least 4weeks on an antipsychotic medication were randomized toRISPERDAL. (2-B mgJday) or to an' actve èomparätòr, lor 1 to 2 years 61 observation ior relapse: PatientsreCeiving RISPERDAL ~ expenenced a significantly longer time to relapse over this time penod compared tothose receiving the active comparator, . .INDICATlaNS AND USAGE .Ri'SPERDAL ~ (risperidóne) is indicated for the treatment of schizophrenia.The efficacy of RISPERDAL. in schizophrenià was estab.lished in short-term (6 to B-weeks) controlledtrials of schizophrenic inpatients (See CLINICAL PHARMACOLOGY).The effcacy of RISPERDAL~ in delaying relapse was demonstrated in schizophrenic patients who had beenclinically stable for at least 4 weeks before initiation,of treatment with RISPERDAL~ or an active comparatorand who were then observed for relapse dunng a p,eriod 011 to 2 years (See Clinical Tnals, under CLINICALPHARMACOLOGY). Nevertheless, the physician whO elec,ts to use RISPERDAL ~ for extended periodsshould penodically re-evaluate the long,term usefulness of the drug for the individual patient (See DOSAGEAND ADMINISTRATION).

CONTRAINDICATIONSRISPERDAL ~ (risperidone) is contraindicated'in patients with a known hypersensitivity to the product.

WARNINGS. . .NeurClleptit Malignant Syndrome (NMS). .' ' ,A potentially fatal symptom complex:sometimes relerred to.as NeùrolepticMalignant.Syndrome (NMS) hasbeen reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia,muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or bJood pres-sure, tachYcardia, diaphoresis and cardiac dysrhythmia). Additional sighs may include elevated creatinephosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis; it isimportant to identify cases where the clinical presentation includes both serious medical illness (e.g.,pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal, signs andsymptoms (EPS), Other important considerations in the differential diagnosis include central anticholinergictoxicity, heat stroke, drug fever, and primary central nerVous system pathology. .The management ofNMS should include: 1)immediaíe discontinuation otantipsychotic drugs and: otherdrugs not essenlial to concurrent therapy; 2) intensive symptomatic treatment and medical monitonng; and3) treatment of any concomitant senous medical problems for which specific treatments are available. Thereis no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.Ii a patient requires antipsychotic.drug treatmentafler recovery from NMS, the potential reintroduction ofdrug therapy should be carefully considered. The patient should be carefully monitored, since recurrences 01N~A~ h::VA_hp.An ri:mnrted.

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ut o

bser

vatio

ns in

am

odes

t num

ber

(n=

70)

of p

oorm

etáb

oliz

ers

give

n ris

perid

one.

dono

t sug

gest

.im

port

ant

diff

eren

ces

betw

een

poor

and

ext

ensi

vem

etab

oliz

ers.

It w

ould

ais

o be

pos

sibl

e,lo

rri

sper

idpn

e to

inle

rfer

e ",

ith m

etab

olis

m o

f :o

ther

drug

s m

etab

oliz

edb1

\cyt

oc~

'orn

e_p"

,I.D

,.R

elat

ivel

y w

eak

bind

ingo

tris

peri

done

to. t

heen

zym

e su

gges

ts th

is is

unl

iKel

y (S

eeP

RE

CA

UT

ION

S a

nd D

RU

G IN

TE

RA

CT

ION

S).

The

pla

sma

prot

ein

bind

ing

of r

ispe

ridon

e w

as a

bout

90%

ove

r th

e in

vitr

o co

ncen

trat

ion

rang

e,

of 0

:5 to

200

ng/m

L an

d in

crea

sed

with

incr

easi

ng c

once

ntra

tions

of a

,-ac

id g

iyco

prot

ein.

Tne

pla

sma

bind

ing

of9-

hydr

oxyr

ispe

ridon

e w

as 7

7%. N

eith

er th

e pa

rent

nor

the

met

abol

ite d

ispl

aced

eac

h ot

her

from

the

plà~

ma

bind

ing,

site

s, H

igh

ther

apeu

tic c

once

ntra

tions

of s

ulfa

met

hazi

ne (

100

~g/

mL)

, war

farin

(10

~g/

mL)

and

carb

amaz

epin

eJ10

~g1

mL)

cau

sed

only

a s

light

incr

eas"

.in. t

he fr

ee .t

ract

ion

of r

ispe

ridon

e at

10

nglm

L an

d9-hydroxyrrspendone at 50 nglmL, changes of unknown climcal significance. ,,, '.'

Spe

cial

Pop

ulat

ions

Ren

al

Impa

irmen

t: In

pat

ient

s w

ith m

oder

ate

to s

ever

e re

nal d

isea

se, d

lear

aric

e of

the

sum

of r

ispe

ridon

ean

d its

act

ive

met

abol

ite d

ecre

ased

by

60%

com

pare

d to

you

ng h

ealth

y su

bjec

ts. R

ISP

ER

DA

L ~

dos

es s

houl

dbe

red

uced

in p

atie

nts

with

ren

al d

isea

se (

See

PR

EC

AU

TIO

NS

an

d D

OS

AG

EA

ND

,AD

MIN

IST

RA

TIO

N),

Hep

atic

Im

pair

men

t: W

hile

the

phar

mac

okin

etic

s of

ris

peri

done

in s

ubje

cts

wit

liver

-dis

ease

wer

e co

mpa

rabl

eto

thos

e in

you

ng h

ealth

y su

bjec

ts, t

he m

ean

free

frac

tion

of r

ispe

ridon

e in

pla

sma

was

incr

ease

db¥

abou

t35

% b

ecau

se o

f th

e di

min

ishe

d co

ncen

trat

ion

of b

oth

albu

min

and

a,a

cid

glyc

opro

tein

, RIS

PER

DA

L d

oses

shou

ld b

e re

d~ce

d in

pat

ient

s w

ith li

ver

dise

ase

(See

PR

EC

AU

TIO

NS

and

, D

OS

AG

E A

ND

AD

MIN

iST

RA

TIO

N),

Eld

erly

: In

h'ea

lthy

elde

rly s

ubje

cts

rena

l cle

aran

ce o

f bot

h ris

perid

one

and9

-hyd

roxy

rispe

ridon

e'w

asd.

ecre

ased

, and

-,el

imin

atio

n ha

lf-liv

es w

ere

prol

onge

d co

mpa

red

to y

oung

hea

lthy

subj

ects

. Oos

ings

houl

dbe

mod

ifed.

acco

rdin

gly

in th

e ei

derly

pat

ient

s (S

ee D

OS

AG

E A

ND

AD

MIN

IST

RA

TIO

N).

Rac

e an

d G

ende

r E

ffect

s: N

o sp

ecifi

c ph

arm

acok

inet

ic s

tudy

was

con

duct

ed to

inve

stig

ate

race

and

gend

er e

ffect

s, b

ut a

pop

ulat

ion

phar

mac

okin

etic

ana

lysi

s di

d no

t ide

ntiy

impo

rtan

t diff

eren

ces

in th

edi

spos

ition

of r

ispe

ridon

e du

e to

gen

der

(whe

ther

cor

rect

ed fo

r bo

dy w

eigh

t or

not)

or

race

.

~~~

::r-

vl-

ilUl

~:!"

§8 (T

, ~.~

::vi

vO p ;i'

3 r:

~

IIL

.~~ "

;7~2

Yg~ ~

~ (

f gr

¡;i~

,&i

~~ (f

:o~.

m Z75

0322

0

i'àic

fiye

Dys

kine

sìa

A s

yndr

ome

of p

oten

tially

irre

vers

ible

; inv

oiun

tary

, dys

kine

tic m

ovem

ents

may

dev

elop

in ,p

atie

nts

trea

ted

With

ant

ipsy

chot

ic d

rÙgs

., A

lthou

gh th

e pr

eval

ence

of

the

synd

rom

e ap

pear

s to

'be

high

est a

mon

g th

e el

derly

,es

peci

ally

eld

erly

wom

en, i

t is

impo

ssib

le to

rel

y up

on p

reva

lenc

e es

timat

es to

pre

dict

, at t

he in

cept

ion

ofan

tipsy

chot

ic tr

eatm

ent,

whi

chpa

tient

s.ar

e lik

ely,

to d

evei

op th

e"sy

n,dr

ome.

whe

ther

an

tipsy

chot

ic d

rug

prod

ucts

diff

er in

thei

r po

tent

ial t

o ca

use

tard

ive

dysk

ines

ia is

unk

now

n.T

he r

isk

Of d

evel

opin

g ta

rdiv

e dy

skin

esia

an

d th

e lik

elih

ood

that

it w

il be

com

e ir

reve

rsib

le a

re b

elie

ved

toin

crea

se a

s. th

e du

ratio

n oU

reat

men

t and

the

tota

l cum

ulat

ive

dose

,of

antip

sych

otic

dru

gs a

dmin

iste

red

toth

e pa

tient

incr

ease

. How

ever

, the

syn

drom

e ca

n de

velo

p, a

lthou

gh m

uch

less

com

mon

ly, a

fter

rela

tivel

ybr

ief t

reat

men

t per

iods

at/o

w d

oses

.T

here

is n

o kn

own

trea

tmen

t fo

r es

tabl

ishe

d ca

ses

of ta

rdiv

e dy

skin

esia

, alth

ough

the

synd

rom

e m

ay r

emit,

part

ially

or,

co

mpl

etel

y,

if a

ntip

sych

otic

trea

tmen

t is

with

draw

n. A

ntip

sych

otic

trea

tmen

t, its

elf;

how

ever

, may

supp

ress

(or

par

tially

sup

pres

s) th

e si

gnS

' and

sym

ptom

s of

the

synd

rom

e an

d th

ereb

y m

ay p

ossi

bly

mas

k th

eU

nder

lyin

g pr

oces

s. T

he e

ffect

that

sym

ptom

atic

su

ppre

ssio

n ha

s up

on th

e lo

ng-t

erm

cou

rse

of th

e,~

yndr

ome

is u

nkno

wn.

Giv

en th

ese

cons

ider

atio

,ns,

.i;l,

ISP

ER

DA

L ~

(ris

perid

one)

sho

uld

be p

resc

ribed

in a

man

ner

that

is m

ost,

likel

y to

min

imiz

e th

e oc

urre

nce

of. t

ardi

ve d

yski

ne,s

ia..

Chr

onic

ant

ipsy

chot

ic tr

eatm

ent s

houl

d ,g

ener

aliy

be

rese

rved

for

patie

nts

who

suf

fer

from

a q

iiron

ic il

ness

that

(1)

i",k

now

n to

res

pond

,to

ant

ipsy

chot

ic

drug

s, a

nd (

2) fo

r w

hom

alte

mat

ive,

equ

ally

ef

fect

e, b

ut p

oten

tially

less

ham

iful t

reat

men

ts a

re n

ot a

vaila

ble

or a

ppro

prja

te. I

n pa

tient

s w

hodo

req

uire

chr

onic

trea

tmen

t, th

ß sm

alle

st d

ose

and

the

shpr

test

dur

atio

n of

trea

tmen

tpro

duci

ng a

sati"

f¡ic

tory

clin

ical

res

pons

e sh

ould

be,

sou

ght T

he n

eed

for

cont

inue

d tr

eatm

ent s

haul

d be

'reas

sess

ed p

erio

dica

llIf

sign

s an

d sy

mpt

oms

of ta

rdiv

e dy

skin

esia

app

ear

in a

pat

ient

on

RIS

PE

RD

AL~

¡dru

g di

scon

iinua

tion

sl)o

uld

be c

onsi

dere

d, H

,ow

ever

, som

e, p

atie

nts

may

req

uire

trea

tmen

t with

RIS

P.E

RD

AL

~de

spite

the

pres

ence

of t

he s

yndr

ome.

Pote

ntia

l for

Pro

arrh

ythm

ic E

ffec

t~: R

ispe

rido

ne a

ndlo

r9,h

ydro

xyri

sper

idon

e ap

pear

s to

leng

tnen

the

OT

inte

rval

in s

ome

patie

nts,

alth

ough

ther

e i"

no a

vera

ge in

crea

se in

trea

ted

patie

nts,

eve

n at

12-

16 n

ig/d

ay,

wel

l abo

ve th

e re

com

men

ded

dose

. Oth

er d

rugs

that

pro

long

the

OT

inte

rva,

l hav

e be

en a

ssoc

iate

d w

it!)

the

occu

rren

ce o

f tor

sade

sde

poin

tes,

a li

fe-t

hrea

teni

ng, a

rrhy

thni

ia, B

rady

card

ia, e

lect

roly

te im

bala

nce,

conc

omita

nt' u

se w

ith o

ther

dru

gs' t

hat p

rolo

ng O

T, o

r th

e pr

esen

ce o

f con

geni

tal p

roio

ngat

ion

in O

T c

anin

crea

se th

e ri

sk f

or o

ccur

renc

e of

this

arr

hyth

mia

. 'PR

EèA

UT

ION

SG

ener

al ,

Orthostatic Hypotenslori:RISPERDAL ~ (risperidone) may induce

orth

osta

tic h

ypot

ensi

on ¡

¡¡¡s

ecia

ted,

with

dizz

ines

s, ta

chyc

ardi

a, a

nd in

som

e pa

tient

s, s

ynco

pe, e

spec

iallý

dur

ing

the

initi

al d

ose'

i¡tra

tion

perip

d,pr

obab

ly

refle

ctin

g its

alp

ha:a

dren

ergi

c an

tago

nist

ic

prop

ertie

s, S

ynco

p~w

as r

epor

ted

1n 0

.2%

'(6/2

607)

of

RIS

PE

RD

AL

~ tr

eate

d pa

tient

s in

' pha

se 2

'3 s

tudi

es:'T

he' r

isk

of o

rtho

stat

ic h

ypot

ensi

on a

nd s

ynco

pe m

ay b

em

inim

ized

by

limiti

ng th

e in

itial

dos

e to

2m

g to

tal (

eith

er'O

D o

r t m

gBID

) iri

'Orm

al a

dults

ana

O,5

'mg'

BID

in the elderly and patients with renal or hepatic impairment (See DOSAGE

AN

D A

DM

INIS

TR

AT

ION

),M

onito

ring

of o

rtho

stat

ic v

itai s

igns

sho

uld

be

cons

ider

ed in

pat

ient

s fo

r w

hom

mis

is o

f co

ncem

"A d

ose

redu

ctio

n sh

ould

be

cons

ider

ed. i

f hy

pote

nsio

n oc

curs

, RIS

P,E

RD

AL

~ s

l)oul

d be

,use

d w

ith p

artic

ular

'cau

tion

in p

atie

nts

with

kno

wn

card

iova

"cul

ar d

isea

se .(

hist

ory

of m

yoqa

rdia

i inf

arct

ion

9r is

cher

nia,

hea

rt/a

ilure

, or

cond

uctio

n ab

norn

ialit

ies)

; cer

ebro

vasc

ular

dis

ease

, and

con

ditio

ns w

hich

woO

ld p

redi

spos

e pa

tient

s to

hypo

tens

ion

e.g:

, deh

ydra

tion

and

hypo

vole

mia

. Clin

ical

ly s

igni

fican

t hyp

oten

sion

has

bee

n ob

serv

ed w

ithconcomitant use of RISPERDAL~arlantihypertensive medication, _

Sei

zuiis

: Dur

ing

prem

arke

ting

test

ing,

sei

zure

s oc

urre

d in

0.3

% (

9/26

07)

of R

ISP

ER

DA

L ~

trea

ted

patie

nts,

'tw

oin

ass

ocia

tion

with

hyp

onat

rem

ia. R

ISP

ER

DA

L~ s

houl

d be

use

d ca

utio

usly

in p

atie

nts

with

a,h

isto

ry o

f sei

zure

s.D

ysph

agia

: Eso

phag

eal d

ysm

otili

ty,a

ndas

pira

tion

have

bee

n as

soci

ated

with

ant

ipsy

chot

ic

drug

use

. Asp

iratio

npn

eum

onia

is a

com

mon

caus

e,of

.mor

bidi

ty a

nd m

orta

lity

in p

atie

nts

with

adv

ance

d A

lzhe

imet

s de

men

tia.

RIS

PE

RD

AL~

and

oth

er a

ntip

sych

otic

dru

gs

shou

ld b

e us

ed

caut

ious

ly in

pat

ient

s at

ris

k fo

r as

pira

tion

pneu

mon

ia.

, Hyp

erpr

olac

tinei

nia:

As

wiih

' btn

er d

rugs

that

ant

agen

iie d

opam

ineD

, rec

epto

rs, r

ispe

ridô

na e

leva

tes

prol

actin

,leve

ls a

nd th

e el

evat

ion

pers

ists

'dur

ing

chro

nic

adm

inis

trat

ion.

Tis

sue

cultu

re e

Xpe

rimen

ts in

dica

te'

that

appr

oxim

atel

y on

e-th

ird o

f hum

ari'b

reas

t can

cers

are

pro

lact

in d

epen

aent

in v

.itro

: 'a

fact

or e

fpot

entia

i im

port

ance

if th

e pr

escr

iptio

n of

the

se

drug

s is

con

teni

plat

ed in

a pa

tient

with

pre

viou

sly

dete

cted

bre

aste

aric

er, A

ltoug

h di

str-

banc

es s

uch

as g

alac

torr

ea; a

meh

orre

a, g

yecs

ta, a

nd im

pote

nce

have

bee

n re

port

ed w

ipro

lact

n-el

evat

ing

com

poun

ds, t

he c

linic

al s

igni

fican

ce o

f ele

vate

d se

rum

pro

lact

in le

vels

is u

nknO

Wn

for

mos

t pat

ient

s. A

s is

com

mon

with

com

poun

ds w

hich

. inc

reas

e pr

olac

tin r

elea

se, a

n in

crea

se

in p

itu"a

ry g

land

, m

amm

ary

glan

d, a

ndpa

ncr~

¡itic

isle

t cel

l hyp

erpl

asia

and

lor

neop

lasi

a w

as, o

bser

ved

in,.h

eris

perid

one

carc

inog

enic

ity,s

tudi

esconducted in mice,and rats,(See CARCINOI3ENESIS).However, neither clipical studies.

nor

epid

emio

logi

cst

udie

s co

nduc

ted

to d

ate

have

sho

wn

an a

ssoc

iatio

n be

twee

n ch

roni

c ad

min

istr

atio

n of

this

cla

ss o

f dru

gsan

d tu

mor

igen

esis

in h

uman

s; th

e av

aila

ble

evid

ence

is c

onsi

dere

d to

o lim

ited

to b

e co

nclu

sive

at t

his

time.

--

~IPotential for Cognitive and Motorlmpairment:Somnolence was a commonly re

port

ed a

dver

se e

vent

asso

ciat

ed w

ith R

ISP

ER

DA

L~ tr

eatm

erit,

espe

cial

lyw

hen

asce

rtai

ned

by

dire

ct q

uest

ioni

ng o

f pa

tient

s. T

his

adve

rse

even

t is

dose

rel

ated

, and

ina

stud

y ut

ilizi

ng a

che

cklis

t to

dete

ct a

dver

se e

vent

s, 4

1 %

of t

he h

igh

dose

patients (RISPERDAL~ 16 mg/day) reported somnolence compared

to 1

6% o

f pla

cebo

pa

tient

s. D

irect

ques

tioni

ng is

m

ore

sens

itive

for

dete

ctin

g ad

vers

e ev

ents

than

:spo

ntan

eous

rep

ortin

g, b

y w

hich

8%

of

RISPERDAL~ 16 m~day patients and 1% of placebo patients reported somnolence as an

adve

rse

even

t.Since,RISPERDAL has the potential to impair.judgment, thinking, or motor skills, patients

shou

ld b

eca

utio

ned

abou

t ope

ratin

g ha

zard

ous

mac

hine

ry, i

nciu

ding

aut

omob

iles,

. un

ti th

ey a

re

reas

onab

ly c

erta

inth

at R

iSP

E.R

DA

L~ th

erap

y do

es n

ot a

ffect

them

adv

erse

ly.

Pria

pism

: Rar

e ca

ses

of p

riapi

sm h

ave

been

rep

orte

d. W

hile

the

rela

tions

hip

of th

e ev

ents

to R

ISP

ER

DA

L ~

use

has

not b

een

esta

blis

hed,

oth

er d

rugs

with

alp

ha-a

dren

ergi

c bl

ocki

ng e

ffect

s ha

ve b

een

repo

rted

toin

duce

pria

pism

, and

it is

pos

sibl

e th

at R

ISP

ER

DA

L ~

may

sha

re th

is c

apac

ity. S

ever

e.

pria

pism

may

req

uire

surg

ical

inte

rven

tion.

Thr

ombo

tic T

hrom

bocy

tqpe

nic

Purp

ura

(TP)

: A s

ingl

e ca

se o

f T

IP w

a.s

repo

rted

in a

28

year

-oid

fem

ale

patie

nt r

ecei

ving

RIS

PE

RD

AL~

in a

larg

e,

open

pre

mar

ketin

g ex

perie

nce

(app

roxi

mat

ely

1300

.pat

ient

s). S

heex

peri

ence

d ja

undi

ce, f

ever

, and

bru

isin

g, b

ut e

vent

ually

rec

over

ed a

fter

rec

eivi

ng p

lasm

aphe

resi

s. T

here

latio

nshi

p to

RIS

PE

RD

AL

~ th

erap

y is

unk

now

n.A

ntie

met

ic e

ffec

t: R

ispe

rido

ne h

as a

n an

tiem

etic

eff

ect i

n an

imal

s; th

is e

ffec

t may

als

o oc

cur

in h

uman

s,an

d m

ay m

ask

sign

s an

d sy

mpt

oms

of o

verd

osag

e w

ith c

erta

in d

rugs

or

of c

ondi

tions

suc

h as

inte

stin

alob

stru

ctio

n, R

eye:

s sy

ndro

me,

and

bra

in tu

mor

.Body Temperatwe Regulation: Disruption of

body

tem

pera

ture

reg

ulat

ion

has

been

attr

ibut

ed

to a

ntip

sych

otic

agents.. Both hyperthermia and hypothermia haved,een reported

in a

ssoc

iatio

n w

ith R

ISP

ER

DA

L~: u

se.

Cau

tion

is a

dvis

ed w

hen

pres

crib

ing

for

patie

nts

who

will

be

expo

sed

to te

mpe

ratu

re e

xtre

mes

.S

uici

de:T

hepo

ssib

ility

of a

sui

cide

atte

mpt

is in

here

nt in

sc

hizo

phre

nia,

and

clo

se s

uper

Vis

ion

of h

igh

risk

patie

nts

shou

ld a

ccom

pany

diu

g th

erap

y, P

resc

riptio

ns fo

r'RIS

PE

RD

AL

~ s

houl

d be

writ

ten

for

the

smal

lest

quan

tity

of ta

blet

s co

nsis

tent

with

'goo

d pa

tient

man

agem

ent,

in o

rder

to r

educ

e th

e ris

k of

ove

rdos

e.U

se in

Pat

ient

s w

ith C

onco

mita

nt II

ness

: Clin

icai

exp

erie

nce

with

RIS

PE

RD

AL

~ in

pat

ient

s w

ith c

erta

inconcomitant systemic ilnesses

is li

mite

d. C

autio

n is

adv

isab

le.in

usi

ng R

ISP

ER

DA

L~ in

pat

ient

s W

ithdi

seas

es o

r co

nditi

ons

that

cou

ld

affe

ct m

etab

olis

m o

r he

mod

ynam

ic

resp

onse

s.RISPERDAL~ has

not b

een

evai

uate

d or

use

d to

any

app

reci

able

ext

ent i

n pa

tient

s w

ith. a

rec

ent h

isto

ry o

fm

yoca

rdia

l inf

arct

ion

or u

nsta

ble

hear

t dis

ease

. Pat

ient

s w

ith th

ese

diag

nose

s w

ere

excl

uded

from

clin

ical

stu

dies

durin

g th

e pr

oduc

t's p

rem

arke

t tes

ting.

The

ele

ctro

card

iogr

ams

of a

ppro

xim

atel

y 38

0'pa

tient

s w

hô r

ecei

ved

RIS

PE

RD

AL~

and

120

pat

ient

s w

ho r

ecei

ved

plac

ebo

in tw

o do

uble

-blin

d, p

lace

bo-c

ontr

olle

d tr

ials

wer

eev

alua

ted

and

the

data

rev

eale

d on

e fin

ding

of p

oten

tial c

once

m, i

.e,;

8 pa

tient

s'ta

king

RIS

PE

RD

AL

$ w

hose

baseline OTcinterval was iessthan 450

mse

c,

wer

e ob

serv

ed to

hav

e O

Tc

inte

rval

s gr

eate

r th

an 4

50 m

sec

duri

ng tr

eatm

ent;

no s

uch

prol

onga

tions

wer

e se

en in

the

smal

ler

plac

ebo

grou

p. T

here

wer

e 3

such

epi

sode

s in

the

appr

oxim

atel

y 12

5 pa

tient

s w

ho r

ecei

ved:

halo

perid

ol:B

ecau

se o

f the

'risk

s of

ort

host

atic

hyp

oten

sion

and

OT

pro

long

atio

n, c

autio

n sh

ould

be

obse

rved

In c

ardi

ac p

atie

nts

(See

WA

RN

ING

S a

nd P

RE

CA

UT

ION

S),

Incr

ease

d pl

asm

a'co

ncen

trat

ions

ofris

perid

one

and

9-hy

drox

yris

perid

one

occu

r in

pat

ient

s w

ith s

ever

ere

nal i

mpa

irmen

t (c

reat

ìnin

e cl

eara

nce

,,30

mU

min

/1.7

3 01

'), a

nd a

n in

crea

se in

the

free

frac

tion

of th

eris

perid

one

is s

een

in p

atie

nts

with

sev

ere

hepa

tic im

pairm

ent.

A lo

wer

sta

rtin

g do

se s

houl

d be

use

d in

suc

hpa

tient

s (S

ee D

OSA

GE

AN

D A

DM

iNIS

TR

AT

ION

). .

Information for Patients .

Phy

sici

ans

are

advi

sed

to d

iscu

ss th

e fo

llow

ing

issu

es w

ith p

atie

nts

for

who

m th

ey p

resc

ribe

RIS

PE

RD

AL~

,O

rtho

stat

ic H

ypot

ensi

on: P

atie

nts

shou

ld b

e ad

vise

d of

the

risk

of o

rtho

stat

ic h

ypot

ensi

on, e

spec

ially

dur

ing

the

perio

d of

initi

al d

ose

titra

tion,

Inte

rfer

ence

With

Cog

nitiv

e an

d..M

otor

Per

form

ance

: Sin

ce R

ISP

ER

DA

L $

has

the.

pot

entia

l to

impa

irju

dgm

ent,

th,in

king

, or

mot

or s

kils

, pat

ient

s sh

ould

be

caut

ione

d ab

out p

pera

ting

haza

rdou

s m

achi

nery

, inc

ludi

ngau

tom

obile

s, u

ntil

they

are

rea

sona

bly

cert

ain

that

RiS

PE

RD

AL~

ther

apy

does

not

affe

ct th

em a

dver

sely

.P

regn

ancy

: Pat

ient

s sh

ould

be

advi

sed

to n

otify

thei

r ph

ysic

ian

if th

ey b

ecom

e pr

egna

nt o

r in

tend

to b

ecom

epregnant during therapy, .'. '.' . .' .

Nur

sing

: Pat

ient

s sh

ould

. be

advi

sed

not t

Q b

reas

t fee

d an

infa

nt if

they

.are

taki

ng R

ISP

ER

DA

L~,

Con

c.om

itant

Med

icat

ion:

Pat

ient

s sh

ould

be

advi

sed

to in

fonn

thei

r ph

ysic

ians

if th

ey a

re ta

king

, or

plan

tota

ke, a

ny p

resc

riptio

n or

ove

r-th

e-co

unte

r dr

ugs,

sin

ce th

ere

is a

pot

entia

l for

inte

ract

ions

.A

lcoh

ol:

Pat

ient

s sh

ouid

be

advi

sed

to a

void

alc

ohol

whi

le ta

king

RiS

PE

RD

AL~

., L

abor

ator

y T

ests

No

spec

ific

labo

rato

ry te

sts

are

reC

Om

men

ded.

Dru

g In

tera

ctio

nsT

he in

tera

ctiO

ns o

f RiS

PE

RD

AL

~ a

nd o

ther

dru

gs h

ave

not b

een

syst

emat

ical

ly e

valu

ated

. Giv

en th

e pr

imar

yC

NS

effe

cts

olris

perid

one,

cau

tion

shou

ld b

e us

ed w

hen

RIS

PE

RD

AL~

is ta

ken

in c

ombi

natio

n w

ith o

ther

cent

rally

act

ing

drug

s an

d al

coho

L.

Bec

au"e

of i

ts p

oten

tial f

or in

duci

ng h

ypot

ensi

on, R

ISP

ER

DA

L ~

may

enh

ance

the

hypo

tens

ive

effe

cts

ofot

her

ther

apeu

tic a

gent

s' w

ith th

is p

Ote

ntia

L.R

ISP

ER

DA

L ~

may

ant

agon

ize

the

effe

cts

of le

vodo

pa a

nd d

opam

ine

agon

ists

.C

hron

ic a

dmin

istr

atio

n of

car

bam

azep

ine

with

ris

perid

one

may

incr

ease

the

clea

ranc

of r

ispe

ridon

e.C

hron

ic a

dmin

istr

atio

n of

clo

zapi

ne w

ith r

ispe

ridon

e m

ay d

ecre

ase

the

clea

ranc

e of

ris

perid

one.

Flu

oxet

ine

may

incr

ease

the

plas

ma

conc

entr

atio

n of

the

anti-

psyc

hotic

frac

tiOn

(ris

pedd

one

plus

9-h

ydro

xy-

risp

erid

one)

b¥.

r~is

in.~

.th.e

_ C

?n""

nt.r

~ti~

!,_

of. ~

s!?,

,!!~

?_n.

e:!l

lipu¥

!:n?

t,th"

_è'..

tiV!~

:t~~.

~I!!

~2;!

'J~;

.~~:

i~R

~~!~

o,n;

:.,

Dru

gslh

st in

~iE

ìfêY

ióc¡

¡õm

e'í;~

;iìòi

~iid

'()t~

èrFt

šòzY

;ñ¡l

š!A

ìšPë

RêJ

dnW

¡"~r

ñéft

föf~

xy"

~ri

sper

idon

e by

byt

ochr

omep

,,,II

D,,

an e

rizy

met

hat i

spol

ymor

ptiic

in th

e po

pula

tion

a,nd

that

can

be

inhi

bite

dby

a v

arie

ty o

f Psy

chpt

ropi

c 'a

nd

othe

r drugs (See CUNI,CALPHARMACOLOGY). Drug interactions' th

atre

duce

the

met

abol

ism

of r

isp~

ridon

e'to

9-h

ydro

xyris

perid

one

wou

ld in

crea

s,eJ

he p

lasm

a co

ncen

trat

ions

of

rispe

ridon

e an

d lo

wer

the'

con

cent

ratip

ns q

f"g-

hydr

oxyr

ispe

ridon

e. A

naly

sis

of c

linic

al s

tudi

es in

volv

ing

am

odes

t num

ber

of p

oor

met

abòl

ize'

rs'(n

=70

) do

es n

ot s

ugge

st th

at p

oor

and

exte

nsiv

e m

etab

oliz

ers

have

diffe

rent

rat

es o

f adv

erse

effe

cts.

No

com

paris

on

,at '

effe

ctiv

enes

s'

in th

e tw

o gr

oups

has

bee

n m

ade.

In v

itro

stud

ies

show

ed th

at d

rugs

met

abol

ized

bý

othe

r P

,,, is

ozým

es"in

clud

ing

1A1,

lA2,

IIC

9, M

P, a

ndIII

A4,

are

onl

y w

eak

inhi

bito

rs a

t ris

perid

onem

etab

olis

m.

Dru

gs M

etab

oliz

ed b

y C

yoch

rom

e P

",IID

,: in

vitr

o st

udie

s in

dica

te th

at r

ispe

ridon

e is

a r

eiat

ivel

ywea

k in

hibi

tor

of c

ytoc

hrom

e P

,,,IID

,. T

here

fore

, R.lS

PE

RD

AL.

is n

ot e

xpec

ted

to s

ubst

antia

liy In

hibi

t the

cle

aran

ce o

f dru

gs th

atar

e m

etab

oliz

ed b

y th

is e

nzym

atic

pat

hWay

. How

ever

, clin

icai

dat

a to

con

firm

this

exp

ecta

tion

are

not a

vaila

bie.

Car

cino

gene

sis,

Mut

agen

esis

, Im

pair

men

t of

Fert

ilty

Car

cino

gene

sis:

Car

cino

geni

city

stu

dies

wer

e co

nduc

ted

in S

wis

s al

bino

mic

e an

d W

ista

r ra

t~. F

ii~pe

ridon

ew

as a

dmin

iste

red

in th

e di

et a

t dos

espt

0.6

3,2.

5, a

nd 1

0 m

g/kg

for

18 m

onth

s to

mic

e an

d fo

r 25

mon

ths

tora

ts. T

hese

dos

es a

re e

quiv

alen

t to

'2:4

, 904

and

37.

5 tim

es th

e m

axim

um h

uman

dos

e (1

6 m

g/da

y) o

n a

mg/

kg b

asis

or

0.2,

0.75

and

3

times

the

max

imum

hum

an d

ose

(mic

e) o

rOA

, 1.5

, and

6

times

the-

max

imum

hum

an d

ose

(rat

s) o

n a

mg/

m2

basi

s, A

max

imum

tole

rate

d do

se w

as n

ot a

chie

ved

in m

ale

mic

e:J~

,her

e w

ere

stat

istic

aliy

sig

nific

ant i

ncre

ases

in p

ituita

ry g

land

ade

nom

as, e

ndoc

rine

panc

reas

ade

nom

as' a

nd

mam

mar

ygi

and

aden

ocar

cino

mas

. The

fol

low

ing

tabl

e su

mm

ariz

es th

e m

uitip

les

of th

e hu

man

dos

e, o

n a

mgi

m2

(mg/

kg)

basi

s at

whi

ch th

ese

tum

ors

occu

rred

MU

LTIP

LE O

F M

AX

IMU

M H

UM

AN

DO

SE

in m

gim

2 (m

gikg

)T

UM

OR

TY

PE

SPE

CIE

SSE

XL

OW

EST

HIG

HE

STE

FFE

CT

NO

EFF

EC

TL

EV

EL

LE

VE

LP

ituita

ry a

deno

mas

mou

sefe

mal

e0.

75 (

9.4)

0:2,

(2,4

)E

ndoc

rine

panc

reas

rat

mal

e1.

5 (9

.4)

0:4

(2.4

)ad

enom

asM

amm

ary

glan

dm

ouse

fem

ale

0.2

(2.4

)no

nead

enoc

arci

nom

asra

tte

mai

e00

4 (2

.4)

none

rat

mal

e6

(37.

5)1.

5 (9

.4)

Mam

mar

y gi

and

rat

mai

e1.

5 (9

.4)

0:4

(2.4

)ne

opla

sms,

Tot

al

Ant

ipsy

chot

ic d

rugs

hav

e be

en s

how

n to

chr

onic

ally

ele

vate

pro

lact

in ie

vels

in r

oden

ts. S

erum

pro

iact

inle

vels

wer

e no

t mea

sure

d du

ring

the

rispe

ridon

e ca

rcin

ogen

icity

stu

dies

; how

ever

, mèa

sure

men

ts d

urin

gsu

bchr

onic

toxi

city

stu

dies

sho

wed

that

ris

perid

one

elev

ated

ser

um p

rola

ctin

leve

ls 5

to 6

fold

'in m

ice

and

rats

at t

he s

ame

dose

s us

ed in

tlie

car

cino

geni

city

stu

dies

.-A

n in

crea

se in

mam

mar

y, p

itUita

ry, a

nden

docr

ine

panc

reas

neo

plas

ms

has

been

foun

d in

rod

ents

afte

r ch

roni

c ad

min

istr

atio

n of

oth

er

antip

sych

otic

drug

s an

d is

con

side

red

to b

e pr

olac

tin m

edia

ted.

The

rel

evan

ce fo

r hu

man

ris

k of

the

find

ings

of

prol

actin

-",

edia

ted

endo

crin

e tu

mor

s in

rod

ents

, is

unkn

own

(See

Hyp

rpro

lact

inem

ia u

nder

PR

EC

AU

TIO

NS

" G

EN

ER

AL)

.M

utag

enes

is: N

o ev

iden

ce a

t mut

agen

ic p

oten

tial f

ouis

perid

one

was

foun

d in

the

Am

es r

ever

se m

utat

ion

:est

, mou

se iy

mph

oma

assa

y, in

vitr

o ra

t hep

atoc

yte

DN

A-r

epai

r as

say,

in v

ivo

mic

ronu

cleu

s te

sUn

mic

e,:h

e se

x-lin

ked

rece

ssiv

e le

thai

test

in D

roso

phila

, or

thè

chro

mos

omal

abe

rrat

ion

test

in h

uman

lym

phoc

ytes

Jr Chinese hamster cells. ,

'mpa

irmen

t of F

ertil

ity: R

ispe

ridon

e (0

.16

to 5

mgi

g) w

as s

how

n to

impa

ir m

atin

g, b

ut n

ot fe

rtlit

y, in

Wis

tar

rats

n th

ree

repr

oduc

tive

stud

ies

(tw

o S

egm

ent I

and

a m

ultig

ener

atio

nal s

tudy

) at

dos

es 0

.1 to

3 ti

mes

the

max

imum

'eco

mm

ende

d hu

man

dos

e on

a m

g1m

2 ba

sis.

The

eff

ect a

ppea

red

to b

e in

fem

ales

sin

ce im

pair

ed m

atin

gie

havi

or w

as n

ot n

oted

in th

e S

egm

ent i

stu

dy in

whi

ch m

ales

onl

y w

ere

trea

ted.

In a

sub

chro

nic

stud

y in

Bea

gle

logs

in w

hich

ris

peri

done

was

adm

inis

tere

d at

dos

es o

f 0.

31 to

5 m

gig,

spe

rm m

otili

t and

con

cant

ratio

n w

ere

leer

ease

d at

dos

es 0

.6 to

10

times

the

hum

an d

ose

on a

mg/

m2

basi

s, D

ose-

rela

ted

deer

ease

s w

ere,

als

o, n

oted

1 se

rum

test

oste

rone

at t

he s

ame

dose

s. S

erum

test

oste

rone

and

spe

rm p

aram

eter

s pa

rtia

lly r

ecov

ered

but

emai

ned

decr

ease

d af

ter

trea

tmen

t was

dis

cont

inue

d. N

o no

-effe

ct d

oses

wer

e no

ted

in e

ither

ràt

or

dog.

'regn

ancy

''regnancyCategory C:The

tera

toge

nic

pote

ntia

l of

'risp

erid

onew

as

stud

ied

in th

ree

Seg

men

t II s

tudi

es in

.pra

gue-

Daw

ley

and

Wis

tar

rats

and

in o

ne S

egm

ent I

I stu

dy in

New

Zea

iand

rab

bits

. The

inci

denc

e of

ialfo

rmat

ions

was

not

incr

ease

d co

mpa

red

to c

ontr

oi in

offs

prin

g of

rat

s or

rab

bits

giv

en 0

04 to

6 ti

mes

the

J

Ihu

man

dos

e on

a m

g/m

' bas

is. I

n th

ree

repr

oduc

tive

stud

ies

in r

ats

(tw

o S

egm

ent I

I and

a m

ultig

ener

atio

nal

stud

y), t

here

was

an

incr

ease

in p

up d

eath

s du

ring

the

first

4 d

ays

oHac

tatio

n at

dos

es 0

.1 to

3 ti

mes

the

hum

ando

se o

n a

mg/

m' b

asis

. ltis

not

kno

wn

whe

ther

thes

e de

aths

wer

e,

due

to a

dir

ect'e

ffee

ton

the

fetu

ses

or p

ups

or to

effe

ets

on th

e da

ms.

The

rew

as n

o no

-effe

c do

se fo

r in

crea

sed

rat

pup

mor

talit

y. In

'oM

Seg

men

t II s

tudy

,th

ere

was

an

incr

ease

.in s

tiibo

m r

at p

ups

at a

do

se 1

.5 ti

mes

hig

hert

han

the

hum

an d

oseo

na m

g/m

' bas

is.

Pla

cent

al tr

ansf

er o

f ris

perid

one

occu

rs in

rat

pup

s. T

here

are

no

adeq

uate

and

w

ell-c

ontr

olle

d st

udie

s in

preg

nant

wom

en. H

owev

er, t

here

was

one

rep

ort o

f a c

ase

of a

gene

sis

of th

e co

rpus

cal

losu

m in

an

infa

ntex

pose

d to

ris

perid

one

in u

tero

. The

cau

sal r

elat

ions

hip

to R

ISP

ER

DA

L"'th

érap

y IS

'u

nkno

wn.

RiS

PE

RD

AL"

sho

uld

be u

sed

durin

g pr

egna

ncy

oniy

if th

e po

tent

ial'

beiie

fit ju

stifi

es th

e po

tent

ial r

isk

toth

e fe

tus.

Lábo

r an

d D

eliv

ery

The

eff

ect o

f R

ISPE

RD

ÀL

" on

labo

r an

d de

liver

y in

hum

ans

is u

nkno

wn.

Nursing Mothers " '

In a

nim

al s

tudi

es, r

ispe

ridon

e an

d 9-

hydr

oXys

perid

one

wer

e ex

cret

ed in

bre

asfr

iilk.

Ilha

s be

en d

emon

stra

ted

that

ris

perid

one

and

9-hy

drox

yris

perid

one

,are

als

o ex

cret

ed in

, hum

an b

reas

t milk

, The

refo

re, w

omen

rec

eivi

ngRISPERDAL" should not breast feed. '

Pedi

atri

c U

seS

afet

y an

d ef

fect

iven

ess

in c

hild

ren

have

not

bee

n es

tabl

ishe

d.G

eria

tric

Use

Clinical studies ?f RISPERDAL" did not include sufficient nùmbers of patients

aged

65

and

over

tode

term

irie

whe

ther

they

res

pond

dif

fere

ntly

fror

i you

nger

pat

ient

s: O

thêt

rep

orte

d cl

inic

al e

xper

ienc

e ha

sno

t ide

ntifi

ed d

iffer

ence

s in

res

pons

es b

etw

een

elde

riy a

nd y

oung

er p

atie

nts.

In g

ener

al, a

low

er s

tart

ing

dose

is r

ecom

m'e

nded

for

an e

lder

ly p

atie

nt, r

efle

ctin

g a

decr

ease

d ph

arm

acok

inet

iccl

eara

nce

in th

eel

derly

, as

wel

l as

a gr

eate

r fr

eque

ncy

of d

ecre

ased

hep

atic

, ren

al, o

r ca

rdia

c fu

nctio

n; a

nd

,of c

onco

mita

ntdi

seas

e or

oth

er

drug

ther

apy

(See

CliNICAL PHARMACOLOGY

and

DO

SA

GE

AN

D A

DM

INIS

TR

AT

ION

).W

hile

, el

derly

pat

ient

s ex

hibi

t a g

reat

er

tend

ency

to o

rtho

stat

ic h

ypot

ensi

on, i

ts r

isk

in th

e,el

deri

y m

ay, b

em

inim

ized

by

, lim

iting

the

initi

al d

ose

to,O

,5m

g8iD

fOllo

wed

by,c

aref

ul,ti

trat

ion

(See

PR

EC

AU

TIO

NS

).M

onito

ring

of

orth

osta

ticvi

tai s

igns

sho

uld

be c

onsi

dere

d .in

, pat

ient

s. f

or w

hom

this

is ,o

f co

ncer

n.T

his

drug

is k

now

n to

be

subs

tant

ially

exc

rete

d' b

y th

e ki

dney

, and

the

Jisk

of t

oxic

rea

ctio

ns to

this

dru

gmay be gr

eate

r in

pat

ient

s with impaired Jena

l fun

ctio

n. B

ecau

seei

derly

p¡iti

ents

are

mor

e lik

ely

to h

ave

decreased renal func

tion,

car

e sh

ould

,be

take

n in

,d

ose

sele

ctio

n, a

nd it

may

be

usef

ul to

mon

itor

rena

lfu

nctio

n (S

ee D

OS

AG

E A

ND

AD

MIN

IST

RA

TIO

N).

ADVERSE REACTfONS , .

Ass

ocia

ted

with

Dis

cont

inua

tion

of. T

reat

men

tApproximately,9% (244/2607Lof ,RISPERDAL" (risperidone)-treated patients in phase

2-3

stud

ies

disc

ontin

ued

trea

tmen

t due

to a

n ad

vers

e ev

ent,c

ompa

red

with

abo

ut 7

% o

n pl

aceb

o an

d 1.

0% o

n ac

tive

cont

roi d

rugs

. The

mor

e co

mm

on e

vent

s ("

0.3

%)

asso

ciat

ed w

ith d

isco

ntin

uatio

n an

d co

nsid

ered

to b

epo

ssib

iy o

r pr

obab

ly d

rug-

rela

ted

incl

uded

:

~~ RISPERDAL" ~

Ext

rapy

ram

idal

sym

ptom

s 2.

1 %

0%

Dizziness 0.7% 0%

Hyperkinesia 0.6% 0%

Somnolence 0.5% 0%

Nausea 0.3% 0%

Sui

cide

atte

mpt

was

ass

ocia

ted

with

dis

cont

inua

tion

in 1

.2%

of R

ISP

ER

DA

L"-t

reat

ed,p

atie

nts

com

pare

d to

0.6%

of p

lace

bo p

atie

nts,

but

; giv

en th

e al

mos

t 40-

fold

gre

ater

exp

osur

e, ti

me

in R

ISP

ER

DA

L" c

ompa

red

toplacebo patients, it is urilikelythat suicidealtempt is, a RISPERDAL"

rela

ted

adve

rse

even

t (Se

eP

RE

CA

UT

ION

S).

Dis

cont

inua

tion

for

extr

apyr

amid

al s

ympt

oms

was

0%

in p

lace

bo p

atie

nts

but 3

.8%

inactive-control patients in the phase 2-3 trials. .

inci

denc

e in

Con

trol

led

Tria

isC

omm

only

Obs

erve

d A

dver

se E

vent

s in

,Con

trol

led

CII

nica

l Tri

als:

In

two

6,10

8-w

eek

plac

ebo-

cont

rolle

dtr

ials

, spo

ntan

eous

ly-r

epor

ted,

trea

trie

nt-e

mer

gent

adve

rsè

even

ts w

ith

an' i

ncid

ence

of 5

% o

r gr

eate

r in

at

leas

t one

' of

the RISPERDAL" groups a

nd a

t lea

st

twic

e th

at

of p

iace

bo w

ere:

anx

iety

, som

nole

nce,

ext

ra-

pyra

mid

al s

ympt

oms,

diz

zine

ss, c

onst

ipat

ion,

nau

sèa,

dys

peps

ia, r

hini

tis, r

ash,

and

tach

ycar

dia.

Adv

erse

eve

nts

wer

e al

soel

ic~

ed in

one

of t

hese

two

tria

ls (

i.e"

In th

e fi

xed-

doSé

tria

l com

pari

ng R

ISPE

RD

AL

"at

dos

es o

f 2,6

,10,

and

16

mg/

dayw

ith p

lace

bo)

utili

zing

a

chec

klis

tfor

de

tect

ing

adve

rse

even

ts, a

met

hod

that

is m

ore

sens

itie

than

spo

ntan

eous

rep

ortin

g. B

y th

is m

etho

d, th

e fo

llow

ing:

addi

tiona

l com

mon

and

dru

g-re

iate

dad

vers

e ev

ents

wer

e pr

esen

t at a

t lea

st 5

% a

nd tw

ice

the

rate

of p

lace

bo: i

ncre

ased

dre

am a

ctiv

ity, i

ncre

ased

dura

tion

of s

leep

, acc

omm

oda~

on d

istu

rban

ces,

red

uces

aliv

atio

n,m

ictr

ition

dis

turb

ance

s,

diar

rhea

, wei

ght g

ain,

men

orra

gia,

dim

inis

hed

sex4

al d

esire

, ere

ctile

dys

fUnc

tion,

eja

cula

tory

dys

func

tiOn,

and

org

astic

dys

func

tion.

Adv

erse

Eve

nts

Occ

urrin

g at

an

Inci

denc

e of

1%

' or

Mor

e A

mon

g R

ISP

ER

DA

L"-T

reat

ed P

atie

nts:

The

tabl

etha

t fol

low

s en

umer

ates

adv

erse

eve

nts

that

occ

urre

d at

an

inci

denc

e of

1 %

or

mO

re, a

nd w

ere

at le

ast a

sfr

eque

nt a

mon

g R

ISP

ER

DA

L"-t

reat

ed p

atie

rits

trea

ted

at d

oses

ots

10

mg/

day'

than

am

ong

plac

ebo-

trea

ted

patie

nts

in th

e po

oled

res

ults

of t

wo

6 to

,8-w

eek

cont

rolle

d tr

ials

. Pat

ient

srec

eive

d R

ISP

ER

DA

L",d

oses

of 2

, 6,

10, o

r 16

mg/

day

in th

e do

se c

ompa

rison

trai

, or

Up

to a

max

imum

dos

e of

10

mg/

day

in th

e tit

ratio

n st

udy.

Thi

sta

ble

show

s th

e pe

rcen

tage

of

pat

ient

s in

ea

ch d

ose

grou

p (S

1o.

mg/

day

or 1

6 m

g/da

y) w

ho s

pont

aneo

usly

repo

rted

at i

east

Qne

epi

sode

of

an e

vent

at s

ome.

timed

urin

g th

eir

trea

tmen

t. Pa

tient

s gi

ven

dose

s of

2,6

, or

10 m

g di

d .n

ot d

iffer

mat

eria

lly in

thes

e ra

tes.

Rep

orte

d, a

dver

se e

vent

s w

ere

clas

sifie

d us

ing

the

Wor

id, J

jeal

ltQrq

apÎr

;itio

r:Ja

ffic

r.eq

taH

'is_:

wel

l. E

vent

s fo

r w

hich

the

RIS

PE

RD

AL

ø in

cide

nce

(in b

oth

dose

gro

ups)

was

equ

al to

or

less

than

plac

ebo

are

not l

iste

d in

the

tabl

e, b

ut in

clud

ed th

e fo

llow

ing:

ner

vous

ness

, inj

ury,

and

fung

al in

fect

ion.

, Inc

lude

s tr

emor

; dys

toni

a, h

ypok

ines

ia, h

yper

toni

a, h

yper

kine

sia:

ocu

logy

ric c

risis

, ata

xia,

abn

orm

al g

ait,

invo

lunt

ary

mus

cle

cont

ract

ions

, hyp

oref

lexi

a, a

kath

isia

, and

ext

rapy

ram

idal

dis

orde

rs. A

lthou

gh th

ein

cide

nce

of 'e

xtra

pyra

mid

al s

ympt

oms'

doe

s no

t app

ear

to d

iffer

for

the'

S 1

0 m

g/da

y' g

roup

and

pla

cebo

,th

e da

ta fo

r In

divi

dual

dos

e gr

oups

infix

ed d

ose

tria

ls d

o su

gges

t a d

ose/

resp

onse

rel

atio

nshi

p (S

eeD

OS

E D

EP

EN

DE

NC

Y

OF

AD

VE

RS

E E

VE

NT

S).

Dos

e D

epen

denc

y of

Adv

erse

Eve

nts:

Ext

rapy

ram

idal

sym

ptom

s: D

ata

from

two

fixe

d do

se tr

ials

pro

vide

d ev

iden

ce o

f do

se-r

eiat

edne

ss f

orex

trap

yram

idal

sym

ptom

s as

soci

ated

with

ris

perid

one

trea

tmen

t.T

wo

met

hods

wer

ë uS

,ed

tOni

easu

re e

xtra

pyra

mid

al s

ympt

oms

(EP

S)in

an

B,w

eek

tria

l com

parin

g fo

ur fi

xed

dose

s of

ris

perid

one

(2, 6

, 10,

and

16

mg/

day)

, inc

ludi

ng (

1) a

par

kins

onis

m s

core

(m

ean

chan

ge fr

om b

asel

ine)

from

the

Ext

rapy

ram

idal

Sym

ptom

Rat

ing

Sca

le a

nd (

2) in

cide

nce

of s

pont

aneo

us c

ompl

aint

s of

EP

S:

Dos

e G

roup

s'Pl

aceb

oR

is2

Rls

6R

is10

Ris

16

Park

inso

nism

1.2

d.g

1.8

2.4

2.6

EP

S In

cide

nce

"13

%13

%16

%20

%31

%S

imila

r m

ethò

ds w

e(e

used

to m

easu

re e

xtra

pyra

mid

al s

ympt

oms

(EP

S)

in a

n 8,

wee

k tr

ial c

ompa

ring

five

(ixed

dose

s of

ris

perid

one

(1, 4

, 8,1

2, a

nd 1

6.m

g/da

y): '

Ris

4R

is8

Ris

12

Ris

16

1.7

2.4

2.9

4.1

12%

18%

18%

21%

Oth

er A

dver

se E

vent

s: A

dver

se e

vent

dat

a el

icile

d by

a c

heck

list.f

or s

ide

effe

cts

from

a la

rge

stud

y co

mpa

ring

5 fix

ed d

oses

of R

iSP

ER

DA

L" (

r, 4

, 8, 1

2, a

nd 1

6 m

g/da

y) w

ere

expl

ored

for

dose

-rei

ated

ness

of a

dver

se e

vent

s.A

Coc

hran

-Arm

itage

Tes

t for

tren

d in

thes

e da

ta r

evea

led

a po

sitiv

e tr

end

(p~

0.05

) fo

r th

efol

iow

ing

adve

rse

even

ts: s

leep

ines

s; in

crea

sed

dura

tion

of s

leep

, 'ac

com

mod

atio

n di

stur

banc

es, o

rtho

stat

ic d

izzi

ness

, pal

pita

tions

,w

eigh

t gai

n, e

recl

ie d

ysfu

nctio

n, e

jacu

lato

ry d

ysfu

nctio

n, o

rgas

tic d

ysfu

nctio

n, a

sthe

nia/

assi

tude

fincr

ease

dfa

tigua

bilit

y, a

nd in

crea

sed

pigm

enta

tion.

Vita

l. S

ign

Clia

nges

: RIS

PE

RD

AL"

is a

ssoc

iate

d w

ith o

rtho

stat

ic h

ypot

ensi

on a

nd ta

chyc

ardi

a (S

eePRECAUTIONS). " ,

Wei

iiiit

Cha

nges

: The

pro

port

ions

of

RIS

PER

DA

L"

and

plac

ebo-

trea

ted

patie

nts

mee

ting

a w

eigh

t gai

ncr

iterio

n of

" 7%

of b

ody

wei

ght w

ere

com

pare

d in

a,p

ool o

f 6 to

8-w

eek

~Ia

cebo

-con

trol

ledt

riais

, rev

ealin

g a

stat

istic

ally

sig

nific

antly

gre

ater

inci

denc

e of

wei

ght g

ain

for

RIS

PE

RD

AL

(18%

) co

mpa

red

to p

lace

bo (

9%).

Labo

rato

ry C

hang

es: A

bet

wee

n gr

oup

com

paris

on fo

r 6

to 8

-wee

k pl

aceb

o-co

ntro

lled

tria

ls r

evea

led

nost

atis

tical

ly s

igni

fican

t RIS

PE

RD

AL

"/pl

aceb

o di

ffere

nces

in th

e pr

opor

tions

of p

atie

nts

expe

rienc

ing

pote

ntia

llyim

port

ant c

hang

es in

rou

tine

seru

m c

hem

istr

y, h

emat

olog

y, o

r ur

inal

ysis

par

amet

ers.

Sim

ilarly

, the

re w

ere

noRISPERDAL"/placebo differences in the

inci

denc

e of

dis

cont

inua

tions

for

chan

ges

in s

erum

che

mis

try,

hem

atol

ogy,

or

urin

alys

is. H

owev

er, R

ISP

ER

DA

L" a

dmin

istr

atio

n w

as a

ssoc

iate

d w

ith in

crea

ses

in s

erum

prol

actin

(Se

e PR

EC

AU

TIO

NS)

. ,E

CG

Cha

nges

: The

ele

ctro

card

iogr

ams

of a

ppro

xim

atel

y 38

0 pa

tient

s w

ho r

ecei

ved

RIS

PE

RD

AL"

and

120

patie

nts

who

rec

eive

dpla

cebO

.in tw

o do

uble

-blin

d, p

lace

boco

ntro

lled

tria

ls w

ere

eval

uate

d an

d re

veal

ed o

nefin

ding

of p

oten

tial c

once

m; i

.e.,

8 pa

tient

s ta

ngH

ISP

ER

DA

L" w

hose

bas

elin

e O

Tc

inte

rval

was

les

than

450

mse

cw

ere

obse

rved

to h

ave

OT

c in

terv

als

grea

ter

than

450

mse

e du

ring

trea

tmen

t (S

ee W

AR

NIN

GS

). C

hang

es o

fth

is ty

pe w

ere

not s

een

amon

g ab

out 1

20 p

lace

bo p

atie

nts,

but

wer

e se

en in

pat

ient

s re

ceiv

ing

halo

perid

ol (

3/12

6).

Oth

er E

vent

s O

bser

ved

Dur

ing

the

Pre

-Mar

ketin

g E

valu

atio

n of

RIS

PE

RD

AL"

Dur

ing

its p

rem

arke

ting

asse

ssm

ent,'

mul

tiple

dos

es o

f RIS

PE

RD

AL

" (r

ispe

ridon

e) w

ere

adm

inis

tere

d to

2607

pat

ient

s in

pha

se 2

and

3 s

tudi

es. T

he c

ondi

tions

and

dur

atio

n of

exp

osur

e to

RIS

PE

RD

AL"

var

ied.

grea

tly, a

nd in

clud

ed (

in o

verla

ppin

g ca

tego

ries)

ope

n an

d do

uble

-blin

d st

udie

s, u

ncon

trol

led-

arid

con

trol

led

ist

udie

s, in

patie

nt a

nd o

utpa

tient

stu

dies

, fix

ed-d

ose

and

titra

tion

stud

ies,

and

sho

rt-t

erm

or

long

er-t

erm

'ex

posu

re. I

n m

ost

stud

ies,

unt

owar

d ev

ents

ass

ocia

ted

with

this

exp

osur

e w

ere

obta

ined

by

spon

tane

ous:

repo

rt a

nd r

ecor

ded

by c

linic

al in

vest

igat

ors

usin

g te

rmin

olog

y of

thei

r ow

n ch

oosi

ng. C

onse

qu'e

ntly

, it i

s no

t jpo

ssib

ie to

pro

vide

a m

eani

ngfu

l est

imat

e. o

f th

e pr

opor

tion

of ,i

ndiv

idua

lsex

peri

enci

ng a

dver

se e

vent

s ¡

with

out f

irst g

'roup

irig

sim

ilar

type

s of

unt

owar

d ev

ents

into

a s

mal

ler

num

ber

of s

tand

ardi

zed

even

t ica

tego

ries.

In tw

o la

rge

stud

ies,

adv

erse

eve

nts

wer

e al

so e

licite

d ut

ilizi

ng th

e U

KU

(di

rect

que

stio

ning

) si

de ¡

effe

ct r

atin

g sc

ale,

and

thes

e ev

ents

wer

e no

t fur

ther

cat

egor

ized

usi

ng s

tand

ard

term

inol

ogy

(Not

e: T

hese

Ievents are marked with an asterisk in the listings that follow). ;

In th

e lis

tings

that

follo

w, s

pont

aneo

usly

rep

orte

d ad

vers

e ev

ents

wer

e cl

assi

fied

usin

g W

orld

Hea

lth:

Org

aniz

atio

n (W

HO

) pr

efer

red

term

s. T

he fr

eque

ncie

s pr

esen

ted,

ther

efor

e, r

epre

sent

the

prop

ortio

n of

the'

2607

pat

ient

s ex

pose

d to

mul

tiple

dos

es o

f RiS

PE

RD

AL"

who

exp

erie

nced

an

even

t of t

he

type

cite

d on

at

leas

t one

occ

asio

n w

hile

rec

eivi

ng R

ISP

ER

DA

L". A

ll re

port

ed e

vent

s ar

e in

clud

ed e

xcep

t tho

se a

lread

y I

liste

d in

Tab

le 1

, tho

se e

vent

s fo

r w

hich

a d

rug

caus

e w

as r

emot

e, a

nd th

ose

even

t ter

ms

whi

ch w

ere

so !

gene

ral a

s to

be

unin

form

ativ

e. It

is im

port

ant t

o em

phas

ize

that

, alth

ough

the

even

ts r

epor

ted

oCC

Urr

ed ¡

during treatment with RISPERDAL", they were not

necessarily caused by it. :

Eve

nts

are

furt

her

cate

goriz

ed b

y bo

dy s

yste

m a

nd li

sted

in o

rder

of d

ecre

asin

g fr

eque

ncy

acco

rdin

g to

the:

follo

win

g de

finiti

ons:

freq

uent

adv

erse

eve

nts

are

thos

e oc

curr

ing

in a

t lea

st 1

/ 00

patie

nts

(oni

y th

ose

not a

lread

y ¡

liste

d in

the

tabu

late

d re

su~t

s fr

o!"_

e~ac

eb.o

-con

trol

led

tri~

ls a

pe~¡

¡~~n

_~is

!~~.

~9U

~~~:

:\~_;

~t,a

,~~;

;;;~i

;~ls

J

nl:'f

lLrî

"u~

9am

iafiï

í"fr

rëiõ

r.u1

iõtiT

í'';,-

::,'-:

':::::

''':':;

: :.,

,- ,0

'.--

:.:! '

0:'_

':"T

ha p

rasc

ribar

sho

uld

ba a

war

a th

at th

asa

figur

as c

anno

t~aJ

jsad

.to p

radi

ctth

a.in

ci~

anca

of s

ida

affa

cts

Inth

a.co

ursa

of

usua

l mad

ical

pra

ctic

a w

h~ra

pat

lant

char

acta

ri~.

tiCs.

~'ri

d ot

hè; f

acto

rsdi

ffar

Jrom

thos

a w

hich

prav

aila

d in

this

clin

ic~

1 tr

i~I,

Sim

ilariy

, tha

cita

d fm

quan

cies

can

notb

epom

pam

d w

ithfig

uras

obt

aina

d fr

omot

har

clin

icai

inva

stig

atio

ns in

volv

ingd

iffar

arit

trea

tnia

ntsi

usaS

ànd.

inva

stig

atbr

s, T

ha c

itad

figur

as,

how

avar

, 'do

prov

ida

tha

.pra

scrib

ing

phys

icia

n w

ith.s

oma,

basi

s fo

r as

tiri~

ting'

.tha

rala

tlva

cont

ribut

ion

ofdr

ug a

nd n

ondr

ugJa

ctor

sto

tha

sida

~ffa

ct in

cidø

nce

rata

ìn,th

èpdp

ulat

i6n,

sNdi

ad,

Tabla 1: Traaimant-Emargant'Advarsa Exparlance iricidanca

in 6

.to'B

-Wae

k C

ontr

olla

d,C

linic

al T

rial

s'

RIS

PER

DA

L'"

$10 mglday 16 mg(day

(N;324)' (N;77)

Psyc

hiat

ric

Dis

orda

rsIn

som

nia

Agi

tatio

nA

n~ia

tySo

mno

lanc

aA

ggra

ssiv

a ra

actio

nN

arvo

us S

ysta

mE

xtra

pyra

mid

al s

ympt

oms'

Haa

dach

aD

izzi

ness

Gas

troi

rites

tinal

Sys

tam

Con

stip

atio

nN

ausa

aD

yspa

psia

VO

miti

ngA

bdom

inal

pai

nS

aliv

a in

cmas

adT

oot

hach

a ,

Ras

pirä

tory

Sys

tam

Rhi

nitis

'C

ough

ing

Sinu

sitis

Phar

yngi

tisD

yspn

aaBodyasa Whola

Bac

k pa

inC

hast

pai

n,F

avar

Dar

mat

olog

ical

, Ras

hD

ry s

kin

Sabo

rrea

'In

fact

ioiis

Upp

ar r

aspi

rato

ryV

isua

lA

bnor

mal

vis

ion

Mus

culO

'Ska

lata

lA

rthr

algi

aC

ardi

ovas

cula

rTachycardia 3% 5% 0%

t Eva

nts

mpo

rtad

by

at la

ast 1

% o

f pat

iant

s tm

atad

with

RiS

PE

RD

AL'

" $

10 m

glda

y ar

a in

clud

ad, a

nd a

mro

unda

dto

tha

naar

ast %

, Com

para

tiva

rata

sfor

RIS

PE

RD

AL

'",16

mgl

day

and

plac

aboa

m p

rovi

dada

s

Bod

y S

ysta

ml

Pra

fart

ad T

arm

2'è%

22%

12%

3% 1% 17%

14%

4% 7% 6% 5% 5% 4% 2% 2% 10%

3% 2% 2% 1% 2% 2% 2% '2% 2% 1% 3% .2% 2%

'23% 26

%¿ö

% 8% 3%

:34% 12

%7% 13

%'

4% 10%

7% .,1%

0% 0% 8% 3% 1% 3% 0% 0% 3% 3% 5% 4% 0% 3% 1% 3%

Plac

abo

(N;1

42)

'19%

'20

%9% 1% 1% 16

%:

12%

1% 3% 3% 4% 4% 0% 1% 0% 4% 1% 1% 0% 0% 1% 1% 0% 1% 0% 0% 1%.

1% 0%

~~

~th

~~

~ ;;

c~-;

~;¡

;;gi;¡

;7ic

öl~

'iïi O

'óO

¡'-;li

entš

';rar

ë-ëv

arIiS

àra

'thos

e oc

curr

ing

Tnf

awar

ihan

1/1

000

patia

nt,

Psyc

hIat

ric

Dis

orde

rs: F

requ

ent:

incr

easa

d dr

eam

act

ivity

', di

min

isha

d sa

xual

das

ira',

narv

ousn

as'

Infr

aque

nt: i

mpa

ired

conæ

ntra

tlon,

dap

rass

ion,

apa

thy,

cat

aton

ic r

aact

ion,

aup

horia

, inc

raas

ad li

bide

amna

sia"

Rar

a: a

mot

iona

llabi

lity,

nig

htm

aras

, dal

iriu

m, w

ithdr

awal

syn

drom

a, y

awni

ng,

Cen

tral

and

Per

iphe

ral N

ervo

us S

yste

m D

isor

ders

: Fre

quen

t: in

craa

sad

slaa

p du

ratio

n', I

nfre

quen

dysa

rthr

ia, v

arig

o, s

tupo

r, p

araa

stha

sia,

con

fusi

on, R

are:

aph

asia

, cho

linar

gic

synd

rom

a, h

ypoa

stha

sia

tong

ue p

aral

ysis

,lag

cram

ps, t

ortic

olls

,' hy

poto

nia,

com

a, m

igra

ine,

hyp

arre

fiaxi

a, c

hom

oath

atos

is,

Gas

tro-

inte

stin

al D

isor

dars

: Fra

quen

t: an

orax

ia; r

aduc

ad s

aliv

atio

n', I

nfra

quan

t: fla

tula

nca,

dia

rrha

ain

craa

sad

appa

tita;

stom

atiti

s, m

alan

a, d

ysph

agia

, ham

orrh

oids

, gas

triti

s,' R

are:

faca

i 'in

cont

inan

cear

ucta

tion,

gas

troa

soph

agea

l raf

lux,

gas

troa

ntar

itis,

aso

phag

itis,

tong

ua d

isco

lorä

.tion

,cho

lalih

iaS

iS, t

ongu

iad

ama,

div

artic

uliti

s, g

ingi

vitis

" di

scol

omd

faca

s, G

I ham

orrh

aga,

ham

atem

asis

,B

ody

as a

Who

fe/G

ener

af D

isor

ders

: Fre

quen

t: fa

tigua

, Inf

requ

ent:

adam

a, r

igor

s, m

alai

sa, i

nflu

anza

-Iik

isy

mpt

oms,

Rar

e:,p

allo

r, a

nlar

gad

abdo

man

, alle

rgic

rea

ctio

n, a

scita

s, s

arco

idos

is, f

lush

ing,

Ras

pira

tory

Sys

tem

Dis

orde

rs: I

nfre

quan

t: hy

parv

antil

atio

n, b

ronc

hosp

asm

, pna

umon

ia, s

trid

or, R

arE

asth

ma,

incr

easa

d sp

utum

, asp

iratio

n,S

kfn

and

App

enda

ge D

isor

ders

:Fre

quen

t: in

crea

sed

pigm

anta

tion'

; pho

tose

nsili

vity

', In

freq

uent

: inc

reas

eisw

aatin

g, a

cna,

dac

mas

ad s

wea

ting,

alo

peci

a, h

ypar

kara

tosi

s, p

rurit

us, s

kin

axfo

liàtio

n, R

are:

bùl

louc

erup

tion,

ski

n ul

cara

tio'n

, agg

rava

tad

psor

iasi

s, fu

runc

ulos

is, v

erru

cà; d

arm

atiti

s lic

hano

id, h

ypar

tric

hoS

i,ga

nita

l pru

ritu

s, u

rtic

aria

, 'C

ardi

ovas

cula

r D

isor

ders

: Inf

requ

ent:

paip

itatio

n, h

ypar

tans

ion,

hyp

otan

sion

, AV

blo

ck, m

yoca

rdiE

infa

rctio

n,' R

are:

van

tric

ular

tach

ycar

dia,

ang

ina

pact

oris

, pm

mat

ura

atria

l con

trac

tions

, T w

ava

inva

rsio

n,va

ntric

ular

axtr

asys

tola

s, S

T d

apre

ssio

n, m

yoca

rditi

s,V

isio

n D

isor

ders

: Inf

requ

ent:

abno

rmal

acc

omm

odat

ion,

xar

opht

halm

ia, R

are:

dip

lopi

a, e

ya p

ain,

bla

phar

iti¡

phot

opsi

a, p

hoto

phob

ia, a

bnor

mai

lacr

imat

ion.

Met

abol

ic a

nd N

utri

tiona

fDis

orde

rs: I

nfre

quen

t: hy

pona

tram

ia, w

aigh

t inc

reas

e, c

mat

ina

phos

phok

inas

'in

crea

se, t

hirs

t, w

aigh

t dac

reas

e, d

iaba

tas

mal

litus

., R

are:

dac

raas

ad s

arum

iron

, cac

hexi

a, d

ahyd

ratio

rhy

poka

lem

ia, h

ypop

rota

inem

ia, h

yper

phos

phat

amia

, hyp

ertr

igly

carid

amia

, hyp

erur

icem

ia, h

ypog

lyca

mia

,U

rinar

y S

ystm

D

isor

ders

:Fre

iiant

:.pol

yuri

a/po

lydi

psia

', In

freu

ant:

urin

ary

inco

ntin

al1,

hem

atur

ia, d

ysur

iER

are:

uri

narY

rat

antio

n, c

ystti

s, ;a

nal i

nsuf

fcia

ncy,

Mus

cufo

-ske

teta

l Sys

tem

Dis

orde

r: I

nfru

ent:

mya

lgia

, Rar

e: a

rtro

sis,

syo

stos

is, b

ursi

ts, a

rtri

s, s

kale

tal p

air

Rep

rodu

ctiv

e D

isor

ders

, Fem

ale:

Fre

quan

t: m

anor

rhag

ia',

orga

stic

dys

func

tion'

, dry

vag

ina'

, tnf

requ

enno

npua

rpar

alla

ctat

ion,

am

anor

raa,

fam

ala

braa

st p

ain,

leuk

orrh

aa, m

astit

is, d

ysm

anor

rhaa

,. fa

mal

a pa

rina¡

pain

; int

arm

enst

rual

blea

ding

,yag

inal

hat

norr

haga

,L

ive'

rand

Bif

ialy

:Sys

tam

'Dis

orde

rs: i

nfre

quen

t: in

crea

sadS

GO

T, i

ncra

asad

SG

PT, R

are:

hap

atic

fai

lure

chól

asta

tic h

apat

itls,

chó

lacy

stiti

s"ch

olal

ithia

sis,

hap

atiti

s, h

apat

ocal

lula

r da

mag

i"Pl

atet

et, B

1ead

inga

nd C

lottl

ng'D

isor

ders

: Inf

requ

ant,'

api

stax

is, p

urpu

ra, R

are:

ham

orrh

age,

supa

rtic

i,ph

lebi

tis, t

hrom

boph

labi

tis, t

hrom

bocy

topa

nia,

Hea

ring

and

Ves

tibul

arD

isor

dars

:Rar

e:tin

nitu

s, h

ypar

acus

is, d

acea

sed

hear

ing,

Red

B

food

Cel

/Dis

orde

rs: I

nfre

quan

t: an

amia

, hyp

ochr

omic

ane

mia

, Rar

e: n

orm

ocyt

ic a

nem

ia,

Rep

rodu

ctiv

epfs

orde

rs¡

Mal

e: F

requ

ent:

arac

tia d

ySfu

hcjio

n', I

pfre

quan

t: ej

acul

atio

n fa

ilura

,W

hIte

Cel

/ iin

d R

esis

lanc

ii'D

isor

ders

: Rar

e: la

ukoc

osis

, iyp

hada

nopa

lhy,

lauc

opan

ia, p

alge

r-H

uat a

nom

ali

End

ocrin

e D

isor

ders

: Rar

e: g

ynac

omas

tia, m

ale

braa

st p

ain,

ant

idiu

mtic

hor

mon

a di

sord

ar,

Spe

claf

San

ses:

Rar

e: b

iltar

tast

a,. I

ncid

enca

bas

ad o

n el

icila

d,ra

port

s,P

ostln

trod

uctio

n R

epor

ts: A

dver

se'e

vant

s re

port

ad s

inca

mar

kat i

ntro

duct

ion

whi

ch

wer

e ta

mpo

rally

(bi

not n

aces

saril

y ca

usal

ly)

rala

tad

to R

ISP

ER

DA

L"!th

arap

y, in

clud

etha

follo

win

g: a

naph

ylac

tic r

aact

ior

angi

oade

ma.

apn

aa; a

tria

l fib

rilla

tion,

cam

brov

ascu

lar

diso

rdar

, inc

ludi

ng c

embr

ovas

cula

r ac

cida

nt, .

diE

bate

s m

alltu

s ag

grav

ated

, inc

ludi

ng d

iaba

tic k

etoa

cido

sis,

inta

stin

al,o

bstr

uctio

n, ja

undi

ca, m

ania

, pan

CrE

atiti

s, P

arki

nson

's d

lsea

sa a

ggra

vata

d,pu

lmon

ary.

ambo

lism

, Tha

m h

ave

bean

,r

are

rapo

rts

of s

Ud,

dan

deat

and/

or c

ardi

opul

mon

ary

arra

st in

pat

ient

s ra

caiv

ing

.RIS

PE

RD

AL

'", A

.cau

salra

latio

nshi

p w

ith R

ISP

ER

DA

lha

s no

t bae

n as

tabl

isha

d, It

is im

port

ant t

o no

te

that

sud

dan

and

unex

pact

ad d

eath

may

occ

ur in

psy

chot

ipa

tiant

s w

hath

erth

aym

rnai

n un

trêa

tad

or w

heth

ar th

eyar

a tr

aata

d w

ithot

har

antip

sych

otic

dru

gs,

DR

UG

AB

USE

AN

D D

EPE

ND

EN

CE

Con

trol

/ed

Sub

stan

ce C

lass

: RIS

PE

RD

AL

'"(ris

parid

ona)

is n

ot a

con

trol

led

subs

tanc

e,P

hysi

calå

ndP

sýèh

olôg

iè,D

epen

denc

e: R

ISP

ER

DA

L'"

has

not b

een

syst

amat

ical

ly s

tudi

ad in

ani

mai

s(hu

man

s fo

r its

' pot

entia

l for

abù

sa, t

olar

anca

or

phys

icai

dap

anda

nca,

Whi

lath

e cl

inic

al tr

ials

did

nbt

rev

e,

any

tend

ency

for

any

drug

,see

king

beh

avio

r, th

ese

obse

rvat

ions

wer

e no

t sys

tem

atic

and

it is

not

pos

sibl

e to

pred

ict o

n ,th

e ba

sis

of th

is lim

ited

expe

rienc

e th

e ex

tent

to w

hich

a C

NS

-act

ive

drug

wil

be m

isug

ed, d

iver

ted

and/or abused once marketed. Consequently, patients should be evaluated carefully

for

a hi

stor

y of

dru

gabuse"and such patients should be observed closely

for

sign

s of

RIS

PE

RD

AL"

mis

use

or a

buse

(e.

g.,

deve

lopm

ent o

f tol

eran

ce, i

ncre

ases

In d

ose,

dru

g-se

ekin

g be

havi

or).

OV

ER

DO

SAG

EH

uman

Exp

erie

nce:

Pre

mar

ketln

g ex

perie

nce

incl

uded

eig

ht r

epor

ts o

f acu

te R

ISP

ER

DA

L" (

rispe

ridon

e)ov

erdo

sage

with

est

imat

ed d

oses

ran

ging

from

20

to 3

00 m

g an

d no

fata

litie

s. In

gen

eral

, rep

orte

d si

gns

and

sym

ptom

s w

ere

thos

e re

sulti

ng fr

om a

n ex

agge

ratio

n of

the

drug

's k

now

n ph

arm

acol

ogic

al e

ffect

s, i.

e.,

drow

sine

ss a

nd s

edat

ion,

tach

ycar

dia

and

hypo

tens

ion,

and

ext

rapy

ram

idal

sym

ptom

s. O

ne c

ase,

invo

lvin

g an

estim

ated

ove

rdos

e of

240

mg,

was

ass

ocia

ted

with

hyp

onat

rem

ia, h

ypok

alem

ia, p

rolo

nged

OT

, and

wid

ened

OR

S. A

noth

er c

ase,

invo

lvng

an

estim

ated

ove

rdos

e of

36

mg,

was

ass

ocia

ted,

with

a s

eizu

re. p

ostm

arke

ting

expe

rienc

e in

clud

es r

epor

ts o

f acu

te R

ISP

ER

DA

L" o

vera

osag

e, w

ith e

stim

ated

dos

es o

f up

to 3

60 m

g. In

gene

ral,

the

mos

t fre

quen

tly r

epor

ted

sign

s an

d sy

mpt

oms

are

thos

e re

sulti

ng fr

om a

n ex

agge

ratio

nÖf t

hedr

ug's

kno

wn

phar

mac

oiog

ical

effe

cts,

i.e.

, dro

wsi

ness

, sed

atio

n, ta

chyc

ardi

a an

d hy

pten

sion

. Oth

er a

dver

seev

en,ts

, ',r

epor

ted"

si,n

c, e

rna

rket

intr

,od,

UC

,tiO

n w

hich

wer

e, te

mpo

rally

, (bu

t not

nec

essa

rily

caus

ally

) re

iat"

ed, t

oR

ISP

ER

DA

L"ov

erdo

se: i

nclu

de p

roio

nged

OT

inte

rval

,con

vuls

ions

, car

diop

ulm

onar

y ar

rest

, and

rar

e fa

talit

yas

s9ci

ated

with

mul

tiple

dru

g ov

erdo

se,.

Man

agem

ent o

f C

iver

cìi¡

sagè

:Jn

case

, of

acut

e ov

erdo

sage

, est

ablis

h an

d m

aìnt

ain

an a

irÝ

ay a

rid

ensu

read

equa

te o

xyge

natio

n an

d ve

ntila

tion.

Gas

tric

lava

ge (

afte

, r in

tuba

tion,

if p

atie

nt is

unc

onsc

ious

) 'a

ndad

min

istr

atio

n 9f

act

ivat

ed c

harc

oal,

toge

ther

with

a la

xativ

e sh

ould

be

cons

ider

ed. T

he p

ossi

bi(iW

of

obtu

ndat

ion,

sei

zure

s or

dys

toni

c re

actio

n of

the

head

and

nec

k fo

llow

ing

over

dose

may

cre

ate

a ris

k of

aspi

ratio

n w

ith in

duce

d em

esis

. Car

diov

ascU

larm

on~

orin

g sh

ould

com

men

ce im

med

iate

ly a

nd s

houl

d in

clud

eco

ntin

uous

ele

ctro

card

iogr

aphi

c m

onito

ring

to d

etec

t pos

sibl

e ar

rhyt

hmia

s. It

:ant

iarr

hyth

mic

ther

apy

isad

min

iste

red,

dis

opyr

amid

e, p

roca

inam

ide

and

quin

idin

e ca

rry

a th

eore

tical

haz

ard

of O

T-p

rolo

ngin

g ef

fect

sth

at m

ight

be

addi

tive

to th

ose

of r

lspe

rido

ne. S

imila

rly,

it is

rea

sona

ble

to'e

xpec

t tha

t ,th

e al

pha,

bloc

klng

prop

ertie

s of

bre

tyliu

ni m

ight

be

,add

itive

to th

ose,

of r

ispe

ridon

e, r

esul

ting

in p

robl

emat

ic h

ypot

ensi

on.

The

re I

s no

spe

cifc

ant

idot

eto

RiS

PER

DA

L".

The

refo

re a

ppro

pria

te s

uppo

rtiv

e m

easu

res

shou

ld b

e in

stitu

ted.

The

pos

sibi

lity

of m

ultip

le

drug

invo

lvem

ent s

houl

d be

con

side

red.

Hyp

oten

sion

and

circ

ulat

ory

colla

pse

shou

ldbe

trea

ted

w~

h ap

prop

riate

mea

sure

s su

ch

as in

trav

enou

s flu

ids

and/

or,

sym

path

omim

etic

age

nts

(epi

neph

rine

and

dopa

min

e sh

ould

not

be

used

, sin

ce b

eta

stim

ulat

ion

may

wor

sen

hypo

tens

ion

In th

e se

ttng

ofris

perid

one-

Indu

ced

alph

a bl

OC

kade

). In

cas

es

of s

ever

e ex

trap

yram

idal

sym

ptor

ns, a

ntic

holin

ergi

c m

edic

atio

nsh

ould

be

adm

inis

tere

d. C

lose

m

edic

al s

uper

visi

on a

nd m

onito

ring

shou

ld c

ontin

ue u

ntil

the

patie

nt r

ecov

ers,

DO

SA

GE

AN

D A

DM

INIS

TR

AT

ION

Usu

al

Initi

al D

ose:

,RIS

PER

DA

L"

(ris

peri

done

) ca

n be

adm

inis

tere

d on

eith

er a

BID

'or

a O

D s

ched

ule.

In

earl

ysh

ort-

term

clin

ical

tria

lS, R

ISP

ER

DA

L" w

as g

ener

ally

adm

inis

tere

d at

1 m

g B

ID in

itial

ly, w

ith in

crea

ses

inIn

crem

ents

ofl

mgB

ID o

nthe

;sec

ond

and

third

day

, as

tole

rate

d, to

a ta

rget

dos

e of

3 m

g B

ID b

y th

e th

ird

day.

Sub

sequ

ent s

hort

.term

con

trol

led

mal

s ha

ve In

dica

ted

that

tota

l dai

ly r

ispe

ridon

e do

ses

of u

p to

8 m

g on

a O

Dre

g, im

en, a

re a

lso,

s,af

e an

d ef

f"ec

tive.

In

a 10

, ng-

term

con

troi

ie,d

tria

l In

stab

le p

atie

nts;

-RIS

PER

DA

L"

was

adm

inis

tere

d ,O

n,a

OQ

sche

dule

at 1

mg

OD

initi

ally

, w~

h in

crea

ses

to 2

mgO

D o

n th

e se

cnd

day

and

to a

targ

etdo

se

of 4

mg

OD

on

the.

thil'

day

, How

ever

, reg

ardl

ess

of w

hich

reg

imen

is e

mpl

oyed

, in

som

e pa

tient

s a

slow

ertit

rati9

n m

ay b

e m

edic

ally

app

ropr

iate

. Fur

ther

dos

age

adju

stm

ents

, if i

ndic

ated

; sho

uld

gene

rally

occ

Ur

atin

terv

als

of n

ot le

ss th

an 1

wee

k, s

ince

ste

ady

stat

e fo

r th

e ac

tive

met

abol

ite w

ould

not

be

achi

eved

for

approximately liveek in the typical patient.When dosage adjustments are necessary,

smal

l dos

ein

crem

ents

/dec

rem

ents

of 1

-2 m

g ar

e re

com

men

ded.

Effi

cacy

'insc

hizo

phre

nia

was

demonstrated in a dose range of 4 to 16 mg/day in

shor

t-te

rm c

linic

al tr

ials

supp

ortin

g ef

fect

iven

ess,

of

RIS

PE

RD

AL"

, how

ever

, max

imal

.effe

ct w

as g

ener

ally

see

n in

a r

ange

of4

to 8

mglday. Doses above 6 mg/day forBID, dosing were not demonstrated to be

mor

e ef

ficac

ious

than

iow

erdo

ses,

wer

e as

soci

ated

with

mor

e ex

trap

yram

idal

sym

ptom

s an

d ot

her

adve

rse

effe

cts,

and

are

not

gene

rally

rec

omm

ende

d. In

a s

ingl

e st

Udy

sup

port

ing

OD

dos

ing,

the

effic

acy

resu

lts w

ere

gene

rally

str

onge

rfo

r 8

mgt

han

for

4 m

g. T

he.s

afet

y"of

dose

s ab

ove

16 m

glda

y ha

s no

t bee

n ev

alua

ted

in c

linic

al tr

ials

.M

aint

enan

ce T

hera

py:W

hile

:th'e

re is

no

body

of

evid

ence

ava

ilabl

e to

ans

wer

the

ques

tion

of h

ow lo

ng th

esc

hizo

phre

nic

patie

nt,tr

eate

d w

ithH

ISP

ER

DA

L" s

houl

d re

mai

n on

it, t

he e

ffect

iven

ess

of R

ISP

ER

DA

L"2

mg/

day:

to',8

m, g

lday

,atd

e,la

Yin

g re

laps

e w

as d

emon

stra

ted

in a

con

trol

led

tria

l~i ~

atle

nts

who

had

bee

ncl

iniC

all,y

sta

ble

lor

at le

ast

4.w

eeks

,a

nd,

we,

re

then

fO

Il0l

¡pr

a ~e

riqr

d on

i t .t

lear

s. I

n th

is tr

ial,

RIS

PER

DA

L"w

as a

dmin

iste

red

On

a O

D .s

ched

ule,

at 1

m' !

itial

lýÌ'w

~ in

cr, s

's to

2 m

g O

D o

n th

esecond day. and to'a target dose

of4

mg

OD

on

the

thi a

y (S

ee C

linic

al T

rials

, und

er C

LIN

ICA

LP

HA

RM

AC

OLO

GY

). N

ever

thel

ess,

pat

ient

s sh

ould

be

perio

dica

lly r

eass

esse

d to

det

erm

ine

the

need

for

mai

nten

ance

trea

tmen

t with

app

ropr

iate

. do

se.

Ped

iatr

ic U

se:

Saf

ety

and

effe

ctiv

enes

s'in

ped

iatr

ic p

atie

nts

have

not

bee

n es

tabl

ishe

d.D

osag

e in

Spe

cial

Pop

ulat

ions

:The

rec

onim

ende

d in

itial

dos

e is

0.5

mg

BID

in p

atie

nts

who

are

eld

erly

or

debi

liate

d, p

atie

nts

with

seve

r'l.I

enal

or

hepa

tic im

pair

men

t, an

d pa

tient

s ei

ther

pre

disp

osed

to h

ypot

ensi

onor

tor

who

m h

ypot

ensi

on w

ould

pos

e a

risk

. Dos

age

incr

ease

s in

thes

e pa

tient

s sh

ould

be

in in

crem

ents

of

no

mor

e th

an 0

.5 m

g B

ID.

Incr

ease

s to

dos

ages

abo

ve 1

.5 m

g B

ID s

houl

d ge

nera

lly o

ccur

at i

nter

vals

of a

tle

ast 1

wee

k. In

som

e pa

tient

s,

slow

er ti

trat

ion

may

be

med

ical

ly a

ppro

pria

te.

Eid

erly

or

pebi

ltate

d pa

i¡~nt

s" a

nd p

atie

nts

with

ren

al im

pairm

ent,

may

hav

e le

ss a

bilty

to e

limin

ate

RIS

PE

RD

AL"

,tha

n no

rmal

àdu

lts,.

Pat

ient

$ w

ith im

paire

d he

patic

func

tion

may

hav

e in

crea

ses

in th

e fr

eefr

actio

n of

.tber

ispe

ridon

e, p

ossi

bly

resu

lting

in a

n en

hanc

ed e

ffect

(S

ee C

liNIC

AL

PH

AR

MA

CO

LOG

Y).

Pat

ient

s w

ith a

pre

disp

ositi

on 1

0 hy

pote

nsiv

e re

actio

ns o

r fo

r w

hom

suc

h re

actio

ns w

ould

pos

e a

part

icul

arris

k Iik

ewi$

e ne

ed to

be.

tit

rate

d ca

utio

usiy

and

car

eful

ly m

onito

red

(See

PR

EC

AU

TIO

NS

). If

a o

nce-

a-da

ydo

sing

reg

imen

in th

e el

derly

or

debi

litat

ed p

atie

nt is

bei

ng c

onsi

dere

d, it

is r

ecom

men

ded

that

the

patie

nt b

e~

"''-

''''-~

-'';-

'''''ß

.~':~

_.."

"",=

-=,,,

..,,,,

,,,,-

!,,.,,

..r-.

~.'.

.."~

:,'::_

.":-

~ .~

~..~

.t~.~

.,=~

._~

~.!

_~'.!

Io!\"

'':..,

!!õ.':

~_

,l:,!~

~il.

~.h

.~$.

.to.~

. n!'c

;A~

::~d~

v_

.-.,.

...._

_~.._

_.__

=t"

.,,_.

,_.~

,__.

.,_..,

."'''.

....,'

,._...

.''.''

'''''J

..""~

..,-.

.,"";

a""'

'll~;

t~~~

''~d;

ræ:i!

aÆir

i;~~.

i~,:,

',~:"

,-",

,,~,_

,",_

titra

ted

on a

twic

e-a-

day

regi

men

for

2-3

day

s at

the

targ

et d

ose.

Sub

sequ

ent s

witc

hes

to a

onc

e-a-

day

dosi

ng r

egim

en c

an b

e do

ne th

ere'

atté

r.R

eini

tatio

n of

Tre

atm

ent i

n pa

tient

s Pr

evio

usly

Dis

cont

inue

d: A

lthou

gh th

ere

are

no d

ata

to s

peci

fica

llyad

dres

s re

initi

atio

n of

trea

tmen

t, it,

is r

ecom

men

ded

that

whe

n re

star

ting

patie

nts

who

hav

e ha

d an

inte

rval

off R

ISP

ER

DA

L ~

,the

initi

al ti

trat

ion

sche

dule

sho

uld

be fo

llow

ed.

Switc

hing

fro

m o

iiier

Ant

ipsy

chot

ics:

The

re a

re n

o sy

stem

atic

ally

col

lect

ed d

ata

to s

peci

fica

lly a

ddre

sssw

itchi

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APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

MEDICAL REVIEW(S)

CiÇLINICAL REVIEW/.... .

NDA 20-272/S-008Cross reference NDA 20-588/S-004

Clinical Review Cover Sheet

. Appears This WayOn Original

CLINICAL REVIEW,

Table of Contents

Tab I e of Co n tents ............ ... .... ...... ......... ........ .... ... ... ... ........... ... ....... ................. ....... 2

Ex ecutiv e Sum Mary . .... ... .... ... ... .... .... ...... ... ..... ......... ...... .............. ... ................. ....... 3

i. Reco m men dati 0 ns .............. ............................................................... ............ ........ 3

II. Summary of Clinical Findings ............................................................................. 3

C linI cal Revi ew .............................. .......................................................................... 5

i. Introduction and Background ............................................................................. 5

II. Clinically Relevant Findings From Chemistry, Animal Pharmacology and

Toxicology, Microbiology, Biopharmaceutics, Statistics and/or OtherCons ultan t Reviews.......... ................................... .................................... .............. 5

III. Description of Clinical Data and Sources ................................................. 6

v. Clinical Review Methods .ò.................................................................................... 7

VI. Integrated Review of Efficacy .............................................................................. 7

VI. Integrated Review of Safety ...............................................................................12

VIII. Dosing, Regimen, and Administration Issues ............................................18

IX. Conclusions and Recommendations ..................................................................19

XI. A P pen dix ................................................................................................ .............. 20

Page 2

,CLINICAL REVIEWExecutive Summary Section

Clinical Review forNDA 20-272/ 8-008

Executive Summarv

I. RecommendationsI recommend that the Division make an approvable action on supplement 008. I do not, however,agree,with some draft labeling proposals. C ..ì I( I1 , I

c: '". In place of this, I recommend that labeling state the

risperidone was superior to "rJactiveC J".

II. Summary of Clinical Findings

A. Brief Overview of Submission

This submission comprises a complete response to the Division's not-approved letter tosupplement 8 dated January 13, 1998. The sponsor proposes new labeling that describesrisperidone as being effective in the treatment of patients with schizophrenia L ..

C :Ifor up to ()-months.The sponsor submits one effcacy study RIS-USA-79 in support ofa claim of extended efficacy in the treatment of schizophreniai: J for upto (J-months. The sponsor also submits a pooled analysis of nine uncontrolled studies and apooled analysis ofRIS-USA-79 and RIS-INT-6.

B. EffcacyStudy USA-79 supports the claim that Risperdal is effective in maintaining a positive treatmentresponse for the symptoms of schizophrenia. D JC ~C .J It has been customary to allowclaims of extended efficacy based on the results of one positive, well designed, appropriately

red triaL. USA-79 meets this crteria; i:

J

J

Page 3

CLINICAL REVIEW..

Clinical Review Section

All diagnosesNumber (%) relapsed

Mean (SE) time to relapse

Relapse rate at 6 month a

Relapse rate at 1 year a

Relapse rate at end of trial a

SchizophreniaNumber relapsed

Relapse rate at 6 month a

Relapse rate at i year aRelapse rate at end oftrial a

RisperidoneN= 177

45 (25.4%)

452.2 (17.7)

19%

29%

34%

N= 14436 (25.0%)

19%

28%

34%

La: Kaplan-Meier estimates of relapse rate (probability of relapse).b: Stratified log-rank test controlling for investigator and sex.

i:

HaloperidolN= 188

75 (39.9%)

391. (21.8)

30%

45%

60%

N= 15662 (39.7%)

32%

47%

59%

p- value0.001 b

0.007 b

J:J

D. Effcacy ConclusionsStudy USA-79 supports the sponsor's claim that Risperdal is effective in maintaining treatmentresponse for schizophrenia. It has been customary to allow claims of extended efficacy based onthe results of one positive, well designed, appropriately controlled triaL. USA -79 meets thiscriteria; C J\ J~ JIn Study INT-6, a similarly designed study that was previously submitted, Risperdal wascompared to haloperidol and no treatment difference was observed. USA-79 had twice thenumber of patients in each group. This increase in statistical power is a possible explanation forthe difference between USA-79 being a positive study and INT-6 showing no difference.

VII. Integrated Review of Safety

Á. Brief Statement of Conclusions

These pooled long term controlled studies were not designed to establish long-term safety. Sinceboth INT -6 and USA-79 had haloperidol as an active control with no placebo comparator, long-term risperidone safety could only be compared to haloperidoL. Even then the studies were toosmall to detect differences of less than 1 %.

Page 12

CLINICAL REVIEW

Executive Summary Section

C. SafetyThis review focused on the long-term, controlled clinical trials. Risperdal has been on themarket in the US since 1993. The open label trials did not reveal uncommon, unexpected,unreported, serious adverse events that were likely to be drug related. Studies USA-79 and INT-6 were pooled for safety analysis. These studies were not designed to establish long-term safety.Since both INT-6 and USA-79 had haloperidol as an active control with no placebo comparator,long-term risperidone safety could only be compared to haloperidoL. Even then the pooledstudies were too small to detect differences of less than 1 %.

These two pooled studies detected only minimal differences between the two drugs' safetyprofies with the exception of the mean change in prolactin levels and weight gain. The meanprolactin level increased in the RIS group from 25.7 ng/ml at baseline to 40.2 ng/ml at end point,whereas it decreased in the HAL groups from 28.6 ng/ml to 22.6 ng/ml. Roughly twice thenumber of risperidone treated patients (58/241) gained? 7% of their baseline body weight whencompared to haloperidol treated patients (31/261).

,

I

1

D. DosingThe sponsor makes changes in the DOSAGE AND ADMINISTRA nON section of labeling thatreflect the dosing regimen in the long-term controlled trials USA-79 and INT-6. They areaccurate and acceptable from a clinical standpoint.

Appears This WayOn Original

Page 4

CLINICAL REVIEW


Clinical Review

I. Introduction and Background

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's

Proposed Indication(s), Dose, Regimens, Age GroupsThis submission comprises a complete response to the Division's not-approved letter datedJanuary 13, 1998.

RISPERDAUID (risperidone) is an antipsychotic agent belonging to the benzisoxazolederivatives. Risperdal(í (risperidone) tablets and oral solutions are approved for the managementof the manifestations of psychotic disorders in adults.

The clinical trials in which the effectiveness of risperidone was established primarily studiedadult patients with schizophrenia for up to 8 weeks. The safety and effectiveness of risperidonehas not been established in any pediatric patient population. Risperidone may be given in QD orBID dose schedules. Clinical trials initiated dosing at I-mg PO BID but subsequent trialsestablished 8-mg QD dosing as effective. The safety of doses exceeding 16-mg/day has not beenestablished.

The sponsor proposes new labeling that describes risperidone as being effective in the treatmentof patients with schizophreniaC ) for up to(J-months.

B. State of Armamentarium for Indication(s)

Risperidone is one of four approved drugs that are considered "atypical Antipsychotics". Othermembers of this class include clozapine, olanzapine, and ziprasidone. Atypical antipsychoticagents are so named for their 5HT2 and D2 antagonist effects. "Typical" antipsychotics arebelieved to exert their primary clinical effect through D2 blockade alone though neither of thesetheories of effcacy are established as fact.

C. Important Milestones in Product Development

Risperidone was first registered in the UK in December 1992 and launched in May 1993 for thetreatment of schizophrenia and other psychotic conditions. Risperidone was marketed in 1994 inthe United States and has been used widely since then. It is now licensed world-wide in morethan 90 countries.

II. Clinically Relevant Findings From Chemistry, Animal Pharmacology

and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or OtherConsultant ReviewsThere are no chemistry, animal pharmacology/toxicology, or biopharmaceutical issues in thissubmission.

Page 5

CLINICAL REVIEW


HI. Description of Clinical Data and Sources

A. Overall DataThe sponsor submits one effcacy study RIS-USA-79 in support of a claim of extended efficacyin the treatment of schizophrenia C J' for up to Cl-months. The sponsoralso submits a pooled analysis of nine uncontrolled studies and a pooled analysis ofRIS-USA-79and RIS-INT-6 in support of safety information in draft labeling. Additionally one uncontrolledstudy (RIS-INT-23) of elderly patients is summarized in the ISS.

B T bl L. t th cr. IT. I. a es IS mg e mica ria s

Trials Included in the ISS for NDA 20-2521Supplement 008

Trial Design Number of Subjects Doseffuation(RISIHAL)

USA-79 DB, HAL controlled, PO 192/203 RIS: 2-8 mgldayexcluding Site 8 HAL: 5-20 mg/day

177/188 Up to 2-yearsINT -6 DB, HAL controlled, PO 91/99 RIS and HAL 5-20 mglday; 1 yearUSA-5 Open-label 7 RIS 1-16 mglday; I-yearUSA-6 Open-label 265 RIS 2-16 mglday; 1- year

USA-7 Open-label 105 RIS 2-16 mglday; 34-months

USA-9 Open-label 107 RIS 2-16 mglday; 1 year

INT -4 Open-label 386 RIS 2-16 mglday; 57-weeks

INT -8 Open-label 264 RIS 2-20 mglday; I-yearNED-2 3 studies pooledBEL-17INT-12 Open-label 483 RIS 2-16 mglday; 7-months

INT23 Open-label 180 RIS 0.5-8 mg/day; I-yearElderly

C. Postmarketing ExperienceRisperidone has been extensively used for a number of years. In April 2001, Janssen estimatesthe cumulative exposure at c. .J treatment months, corresponding to more than C. J

t: Jpatient years. There have been nine periodic safety update reports on risperidone. During

the time period from June 1, 1993 to May 31,2000,2065 verified reports became available atJRF from various sources.

D. Literature ReviewThe sponsor provides a literature review that summarizes clinical data on the efficacy and safetyof risperidone long-term use in subjects with schizophrenia r: :: asreported in 116 articles identified in literature searches ~overing the period up to 25 January2001. Safety results ofrisperidone were reported in 79 articles. Most of the articles were casereports. The sponsor discovered three double-blind, reference-controlled and 11 reference-controlled, open studies emerged from this search. There were 32 open, non-controlled studies.The number of subjects comprised in these articles who received risperidone amounted to a totalof 4,053 subjects. There were no unexpected adverse events.

Page 6

CLINICAL REVIEW


V. Clinical Review Methods

A. How the Review was ConductedThis submission contained one effcacy study and a summary of multiple studies to review safetyparameters. Study USA-79 was the focus ofthe efficacy review. It has been customary in theDivision to allow claims of extended efficacy based on positive results in one well designed andadequately controlled study.

B. Overview of Materials Consulted in Review

Supplement 008 was an electronic submission. This submission represents a complete responseto a not approved action on supplement 008. No materials outside ofthe submission wereconsulted in this particular review;

C. Overview of Methods Used to Evaluate Data Quality and IntegrityRaw data was submitted to the Division of BiometrIcs via SAS transport files and analyzedaccording to the methods described in the sponsor's protocol. These results were compared tothe analyses in the submission. The submission was also examined for internal consistency.

D. Were Trials Conducted in Accordance with Accepted Ethical StandardsThe trial was performed in accordance with the declaration of Helsinki and its subsequentrevisions and the FDA Guideline 21 CFR Parts 50, 56, and 312.

E. Evaluation of Financial Disclosure

A financial disclosure and certification statement was included. This certified that JanssenResearch Foundation had not entered into any financial agreement with the clinical investigatorswhereby the value ofthe compensation would be effected by the outcome ofthe study.

VI. Integrated Review of Efficacy

A. Brief Statement of Conclusions

The data support the claim that Risperdal is effective in maintaining a positive treatmentresponse for the symptoms of schizophrenia. c: Ji: :: It has been customary to allow claims of extendedefficacy based on the results of one positive, well designed, appropriately controlled triaL. USA-79 meets this criteria; C :i

C JB. General Approach to Review of the Effcacy of the Drug

This submission contained one efficacy study and multiple studies to review safety parameters.Study USA-79 was the focus ofthe efficacy review. It has been customary to allow claims ofextended efficacy based on positive results in one well designed and adequately controlled study.

Page 7


C. Detailed Review of Trialsc. JStudy RIS-USA-79: A comparison of risperidone and haloperidol for prevention of relapsein subjects with schizophrenia and schizoaffective disorders- is submitted to support theindication of"C :ischizophreniaC 'Jlong-termC r -C-l Investigators and SitesA listing of the investigators and sites may be found in Table C-L in the appendix,

C-2 ObjectivesThe primary objective of the study was to evaluate the efficacy ofrisperidone and haloperidol inthe prevention of relapse during maintenance treatment of stable outpatients with schizophreniaor schizoaffective disorder by treating them with risperidone or haloperidol for a minimum of 1year.

C-3 Study PopulationThis was a trial in outpatient men and women aged 18-65 years with chronic schizophrenia orschizoaffective disorder classified by Diagnostic and Statistical Manual, Fourth Edition (DSM-IV). Patients were clinically stable (as judged by the investigator) for 1 month prior to enrollmentinto the triaL. Stable was defined as receiving the same dosage of antipsychotic medication for 30days and living in the same residence for 30 days. Inclusion and exclusion criteria may be foundin Table C-2. In the appendix

C-4 DesignThis was a one-year double-blind, active (haloperidol), parallel group study of stable medicallytreated outpatients. Double blind treatment began after stratification by sex and randomization.Patients discontinued their current antipsychotic medications gradually over the first 7 days ofdouble blind treatment. The trial used a parallel-group design with 2 treatment arms: risperidoneand haloperidoL. Trial medication was escalated over the first 3 days of double-blind treatment toa dosage of 4 mg/day risperidone or 10 mg/day haloperidoL. For the first month of therapy,assessments were made at I-week intervals to allow adjustment of medication to within the rangeof2 mg to 8 mg/day for risperidone and 5 mg to 20 mg/day for haloperidoL. Thereafter, trialvisits were scheduled every 4 weeks. Additional visits were to be scheduled as needed. Patientswere to be followed until the last patient enrolled into the trial had completed 1 year of double-blind treatment. After the initial I-year double blind treatment period, patients could continue ondouble blind treatment up to 112-weeks.

Relapse did not require discontinuation oftrial medication. Double-blind conditions remained forpatients who relapsed and continued trial medication. A relapsed patient could receive otherwisedisallowed psychotropic medication (e.g. neuroleptics other than risperidone and haloperidol,thymoleptics, or antidepressants) and were to have all routine assessments. A relapsed patientwho had continued on trial medication and relapsed a second time was to be discontinued. Everypatient who received trial medication and withdrew from the trial was to have a final set oftrialassessments. Patients who were withdrawn because of trial medication-related events were to befollowed unti the event resolved or was no longer considered clinically significant.

Page 8

CLINICAL REVIEW


C-5 AssessmentsThe primary efficacy parameter was the time to relapse. Relapse was defined as any 1 of thefollowing occurrences:

. psychiatric hospitalization,

. clinical judgment that an increase in level of care was necessary and increase in P ANSS

score of25% compared with Baseline, or an increase often points if the Baseline score was::40, (The increases in level of care and in P ANSS score had to occur within 2 weeks of eachother in order to qualify a patient's relapse.)

. deliberate self injury, in the investigator's opinion,

. emergence of clinically significant suicidal or homicidal ideation,

. violent behavior resulting in significant injury to another person or significant property

damage, in the investigator's opinion, or. significant clinical deterioration in the investigator's judgment (a CGI-C score of 6, "much

worse").. When the investigator rated the patient's CGI-C at 6, the patient was counted Analysis Plan

Secondary efficacy variables and safety assessments may be found in tables C-5.1 and C-5.2 inthe appendix.

C-6 Patient DispositionThe disposition of patients in study YSA-79 follows in table C-6.

Total number of patients discontinuedReason for discontinuation

Chose to discontinue 35 18.2 36 17,7Relapse 28 14.6 47 23.2Adverse event 24 12.5 30 14.8Lost to followup 10 5.2 10 4. 9Poor compliance 6 3. 1 15 7.4Administrative 6 3. 1 2 1. 0Other 3 1. 6 4 2. 0Inadequate response 2 1. 1 7 3, 4.Ineligible 0 0 3 1, 5Intercurrent ilness 0 0 2 1. 0Abnormal clinical laboratory result 0 0 1 0.5Upon visual inspection, one sees a disparity in the percentage of patients discontinuing due torelapse and poor compliance, but other reasons appear roughly equivalent. It is difficult toexplain the disparate numbers of patients who dropped out due to poor compliance since thedropout rate due to adverse events was only slightly higher in the haloperidol group. Poorantipsychotic medical compliance is linked to adverse treatment events. Since the primaryefficacy variable is time to relapse (a category of discontinuation) it appears that patients

Table C-6 Patient Disposition in Study USA-79RIS

N = 192

%59.4

nl14

HALN = 203n %

157 77.3

Page 9

¡CLINICAL REVIEW


discontinuing for other reasons did not skew the results in favor ofRisperdal for inappropriatereasons.

C-7 Baseline Demographics/Severity of IlnessThe distribution of age, race, sex weight and height were similar between treatment groups.

Table C-7.1 Patient Demographics in Study USA-79RIS HAL

N = 192 N = 203n % n 0/0

Sex Female 57 29.7 66 32.5Male 135 70.3 137 67.5

Race White 91 47.4 97 47.8Black 72 37.5 72 35.5

Hispanic 24 12.5 29 l4.3Other 3 1. 5 2 1. 0

Oriental 2 1. 0 3 1. 5Mean SD Mean SD

Age years 40.8 10.72 40.1 10.43. Weight kg 82.0 19.62 83.6 19.87

Height cm 171.3 11.75 171.3 10.1 8

The distribution of diagnostic types were also reasonably similar.

DSM- ivdiagnosisDiagnosistype

Table C-7.2 Distribution of Diagnoses by treatment groups for Study USA79RIS HAL

N = 192 N = 203n %) n 0/0155 80.7 l69 83.337 19.3 34 l6.794 49.0 1 l4 56.255 28.6 45 22.219 9.9 21 LO.318 9.4 13 6.45 2, 6 7 3. 41 O. 5 3 1. 5

SchizophreniaSchizoaffective disorderParanoidUndifferentiatedDepressiveBipolarResidualDisorganized

C-8 Concomitant Medications.Anti-Parkinson drugs were taken by 48% ofrisperidone patients versus 60% haloperidolpatients. This difference was mainly in patients using cogentin (risperidone group 38% versushaloperidol group 49%) while other anti-Parkinson drugs were used equally between the twogroups (e.g. akineton, artane, benztropine, kemadrin).

C-9 Effcacy Results

Two analyses were performed. During the audit ofRIS-USA-79, it was determined that the datafrom 1 site did not meet the Jansen Pharmaceutia quality standard. Therefore, the analyses wereperformed with and without Site #8. Time to relapse was the primary efficacy variable.

Page 10

CLINICAL REVIEWClinical Review Section

Percentage of patients experiencing relapse (by criteria definition and treatment group) are listedin table C-9.1.

Criteria for relapse

Entire TrialPsychiatric hospitalization

Significant clinical deterioration (a CGI- C score of6)Increase in level of care was nec.essar and increase inPANSS score of25% compared with Baseline, or anincrease of 10 points if the Baseline score was 40

Emergence of clinically significant suicidal orhomicidal ideationTOTALS

Table C-9.i Percentage of Patients Experiencing Relapse in Study USA-79RIS HALN=l77 N=188n % n 0/020 44. 4 36 48. 016 35.6 22 29.38 17.8 l4 18.7

2.2 3 4.0

45 75

Figure 1 displays the Kaplan-Meier survival probability plot o.ftime to relapse in USA-79.

Figure 1: Kaplan-Meier survival probabilty plot of time to relapse

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Time (in days)

RIS~USA-79

., -:.-.~ HALOPERIDOL "'- ~ -~ RISPERIDONE-- -o 3 6

o 0

Patients in the risperidone treatment group had a longer mean time to relapse (452.2 days) thanthe patients in the haloperidol treatment group (391.3 days). Among the patients with diagnosisof schizophrenia, there was a statistically significant difference between the two treatments, infavor ofrisperidone, in the survival curves (p = 0.007). In the risperidone group, the Kaplan-Meier estimates of relapse rates, i.e. the probability of relapse, were 19%,29%, and 34%, at 6months, 1 year and at the end ofthe trial, respectively.

Table C-9.2 Time to Relapse in Study USA-79 by Diagnosis

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These two pooled studies detected only minimal differences between the two drugs safetyprofies with the exception of the mean change in prolactin levels and weight gain. The meanprolactin level increased in the RIS group from 25.7 ng/ml at baseline to 40.2 ng/ml at end point,whereas it decreased in the HAL groups from 28.6 ng/ml to 22.6 ng/ml. Roughly twice thenumber ofrisperidone treated patients (58/241) gained ;;7% oftheir baseline body weight whencompared to haloperidol treated patients (31/261).

I

L

B. . Description of Patient Exposure

This review of safety focuses on the long-term controlled trials-USA-79 and INT-6. Thefollowing table reflects drug exposure in the long-term controlled studies.

Table VII-B.t Estimated Risperidone Exposure in Lon~-term Controlled TrialsDuration oftreatment (days) RIS .:4 mg RIS4-6mg RIS ::6 mg Total RISTotal no. of subjects 29 156 98 2831- 90 days, n (%) 1 i (37.9) 46 (29.5) 27 (27.6) 84 (29.7)91- 180 days, n (%) 5 (17. 2) 14 (9. 0) 10(10.2) 29 (10.2)181- 270 days, n (%) 2 (6.9) 10 (6. 4) 6 (6. I) 18 (6. 4)271- 360 days, n (%) 1 (3.4) 10 (6. 4) 8 (8.2) 19 (6. 7)::360 days, n (%) 10 (34.5) 76 (48.7) 47 (48.0) 133 (47.0)Mean duration of treatment (days) 269 (50.7) 328 (20.5) 290 (21.2) 309 (14.5)

Total duration of exposure (patient- years) 21 140 78 239

C. Methods and Specific Findings of Safety ReviewThis review focuses on the long-term, controlled clinical trials. Risperdal has been on the marketin the US since 1994. Open label experience is valuable as a screen for very rare, unreported,serious adverse events. Further open label experience did not reveal this type of newinformation.

D. Adequacy of Safety Testing

These studies were not designed to establish long-term safety. Since both INT-6 and USA-79had haloperidol as an active control with no placebo comparator, longer-term exposure torisperidone could only be compared to haloperidoL. The studies were too small to detectdifferences in events that occur at a rate of less than 1 %.

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There is a vast clinical experience with risperidone. The numbers of patients exposed in long-term controlled studies allowed for a reasonable estimate for an incidence rate for tardivedyskinesia of 1 % or greater. , r- :JL J

E. Summary of Critical Safety Findings and Limitations of Data

E-l Deaths in controlled trialsThere were two deaths in the risperidone treated patients and no deaths in the haloperidol treatedpatients. Neither risperidone treated patients' death was likely to be related to drug treatment.One patient completed suicide and the other died of multiple pulmonary emboli secondary todeep venous thrombosis of the both legs. Case summaries of these patients may be found in theappendix.

E-2 Serious Adverse EventsThere were no serious adverse events that were unexpected and considered likely to be drugrelated. The numbers and distribution of types of serious adverse events was roughly equalbetween the two treatment groups. Most of the serious adverse events were psychiatric in natureand likely to be related to the disease of schizophrenia as opposed to drug treatment. A table ofthe types of serious adverse events that occurred at least twice in one, or both treatment groups islisted in table E-2.1 in the appendix.

E-3 Discontinuations Due to Adverse EventsThe total number of discontinuations due to adverse events were greater in the haloperidoltreated patients versus risperidone treated patients. If one considers only adverse events that arelikely to be drug related as opposed to those that are likely to be incident to the disease, then thetwo treatment groups are less different. Nineteen versus 11 patients dropped out due to adverseevents that could be considered likely to be drug related. Hyperkinesia (potentially akathisia)occurred in 10 (3.3%) haloperidol treated patients versus 4 (1.4%) risperidone treated patients.The drop out rate for "extrapyramidal disorder" was slightly higher in the risperidone treatedpatients (5 (1.8%) risperidone versus 3(1.0% haloperidol)).

There are discrepancies between some tables of discontinuation data in the submission. There arediscrepancies in the total number of discontinuations due to adverse events between thesponsor's Table 4-3 and Table 4-9. The sponsor states that Table 4-3 is based on the trialtermination form and Table 4-9 is based on the adverse event form with action taken "permanentstop" regarding trial medication. In trial RIS-USA-79, a substantial number of subjects had"relapse" as reason for trial termination but also had an adverse event for which the treatmentwas permanently stopped. On the trial termination form, however, only "relapse" (which wasconverted into "insufficient response") was recorded. There are therefore more discontinuationsdue to adverse events than in the trial termination table. This coding difference does not appearto effect the rates at which patients dropped out due to adverse events.

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Sponsor's Table 4-3 Reasons for trial discontinuation -controlled long-term trialsReason for discontinuation, n (%) RIS ..4 mg RIS 4 - 6 mg RIS ~ 6 mg Total RIS HALTotal number of subjects 29 156 98 283 302Completed 6 (20, 7) 71 (45.5) 45 (45.9) 122 (43.1) 83 (27.5)Discontinued 23 (79.3) 85 (54,5) 53 (54.1) 161 (56.9) 219 (72.5)Discontinuation reason:_ Insuffcient response 3 (10.3) 23 (14.7) 22 (22.4) 48(17.0) 83 (27.5)

Adverse event 8 (27, 6) 17(10.9) 11 (11.2) 36 (12.7) 47 (15.6)

- Withdrawal of consent 10 (34.5) 21 (13.5) 4 (4.1) 35 (12.4) 36 (11.9)_ Non compliance 0 7 (4.5) 11 (11.2) 18 (6. 4) 27 (8. 9)_ Lost to followup 0 13 (8. 3) 0 13 (4.6) 17 (5, 6)

- Other 2 (6.9) 4 (2.6) 5 (5.1) 11 (3.9) 6 (2.0)_ Ineligibility 0 0 0 0 3 ( 1. 0)

The types and numbers of adverse events leading to discontinuation are listed in the followingsponsor's table 4-9. To be listed in the table at least two patients in one of the treatment groupshad to discontinue for that reason.

Appears This Way. On Original

Page 15


Sponsor's Table 4-9 Adverse events that led to treatment discontinuation in 0.5% of the totalRIS and HAL subjects - controlled long-term trials

WHO systeml organ class RIS .:4 mg RIS 4 - 6 RIS ;:6 mg Total RIS HALmg

WHO preferred tennTotal no. of subjects 29 156 98 283 302Total no. of discontinuations 9 (31. 0) 29 (18.6) 18 (18.4) 56 (19.8) 83 (27,5)due to AE , n (%) a)Psychiatric disorders 3 (10. 3) 21 (13.5) 14 (14.3) 38 (13.4) 56 (18.5)Psychosis 0 11 (7. 1) 3 (3.1) 14 (4. 9) 32 (10.6)Depression 1 (3.4) 4 (2.6) 4 (4.1) 9 (3.2) 4 (1.)Suicjde attempt 0 2 (1.) 4 (4.1) 6 (2.1) 2 (0.7)Hallucination 0 0 3 (3.1) 3 (1.) 1 (0.3)Agitation 0 0 0 0 4 (1. 3)Delusion 0 0 0 0 3 (1. 0)Somnolence 0 0 0 0 3 (1. 0)Anxiety 0 2 (1.) 0 2 (0.7) 3 (1.0)Schizophrenic reaction 0 1 (0.6) 1 (1.0) 2 (0.7) 2 (0.7)Nervousness 0 1 (0.6) 0 1 (0.4) 2 (0.7)Aggressive reaction 0 0 0 0 2 (0. 7)Central & peripheral 2 (6.9) 6 (3.8) 3 (3.1) 11 (3. 9) 19 (6. 3)nervous system disordersExtrapyramidal disorder 1 (3.4) 3 (1.9) 1 (1.0) 5 (1.8) 3 (1.0)Hyperkinesia 1 (3.4) 3 (1.9) 0 4 (1.4) 10 (3. 3)Dystonia 0 2 (1.) 0 2 (0.7) 1 (0.3)Tremor 0 0 2 (2.0) 2 (0.7) 2 (0.7)Oculogyric crisis 1 (3.4) 0 0 1 (0.4) 2 (0.7)Speech disorder 0 1 (0.6) 0 1 (0.4) 2 (0.7)Hypokinesia 0 0 0 0 2 (0. 7)Gastro- intestinal system 3 (10. 3) 0 0 3 (1.) 4 (1.3)disordersNausea 2 (6.9) 0 0 2 (0.7) 1 (0.3)Vomiting 2 (6.9) 0 0 2 (0.7) 1 (0.3)Body as a whole - general 0 1 (0.6) 0 1 (0.4) 9 (3.0)disordersAsthenia 0 0 0 0 2 (0. 7)Fatigue 0 0 0 0 2 (0. 7)Myo endo pericardial & 0 0 0 0 2 (0. 7)valve disordersMyocardial infarction 0 0 0 0 2 (0. 7)

Drop outs in the long-term studies reflected roughly the dropout rate from risperidone short termtrials in current labeling.

E-4 Adverse EventsCommon and drug related adverse events associated with long term use could not be elucidatedsince this was an active controlled triaL. In the ISS the sponsor suggests that the incidence rate ofcommon adverse events decreases with time. Whether this is actually representative of

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CLINICAL REVIEW.


individual patients feeling fewer or decreased intensity of adverse events or a reflection ofpatients dropping out who poorly tolerate the drug is difficult to telL. r- JC JE-5 LaboratoryCentral TendencyThe sponsor reported that mean laboratory values did not change over time with the exception ofprolactin The mean prolactin level increased in the RIS group from 25.7 ng/ml at baseline to 40.2ng/ml at end point, whereas it decreased in the HAL groups from 28.6 ng/ml to 22.6 ng/mL.Visual inspection ofthe mean change tables confirmed this assertion.

Outlier AnalysisUpon visual inspection there were not differences in the incidence of outliers betweenhaloperidol and risperidoi1e patients with potentially clinically significantly high or low clinicallaboratory values. Table E-5.1 in the appendix displays this data.

E-6 ECGThere were no relevant changes in ECG parameters. QTc mean values using four correctionmethods were unremarkable. The incidence of patients with QTc values increases wascomparable between treatment groups as seen in table E-6.1 where Bazett's (B) and Fridericia(F) corrections are displayed.

Table E-6.1 Distribution of corrected QTc increases at end point relative to baseline - controlled long-term trials

Corrected QTc RIS RIS RIS Total RIS HALincreases ..4mg 4 - 6 mg _ 6mgQTcB n/ N assessed (%)

0- 30 ms 22/ 26 (84.6) 112/128 (87.5) 75/88 (85.2) 209/242 (86.4) 231/ 263 (87.8)31- 60 ms 3/ 26 (11.) 13/128 (10.2) 10/88 (11.4) 26/242 (10.7) 25/263 (9.5)~60 ms 1/26 (3.8) 3/128 (2.3) 3/88 (3. 4) 7/ 242 (2.9) 7/263 (2.7)

QTcF0- 30 ms 24/26 (92.3) 114/128 (89.1) 76/88 (86.4) 214/242 (88.4) 241/ 263 (91.6)31- 60 ms 2/26 (7.7) 12/ 128 (9.4) 10/88 (11.4) 24/242 (9.9) 19/263 (7.2)~60 ms 0/26 (0) 2/ 128 (1.6) 2/88 (2. 3) 4/242 (1.7) 3/263 (1.)

E-7 Weight and Vital SignsThere were more risperidone patients who gained ~7% of their baseline body weight thanhaloperidol treated patients. There was, however, no dose dependency for risperidone withrespect to weight gain.

% change frombaseline at end point

Table E-7.1 Incidence of Body Weight Increase ;:7% at end point- controlled long-term trials

RIS RIS":4mg 4-6mg

Increase ~ 7% 11/25 31/ i 28

RIS;: 6mg

ni N assessed16/ 88

Total RIS HAL

58/241 31/ 26 i

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Mean weight change was significantly different from haloperidoL.Table E-7.2 Mean Weight Change in Controlled Clinical Trials

RIS HALn mean SE n mean SE p- value

Weight BL 166 82.48 182 84.20 0.590(kg) Year 1 99 2.49* 0.60 7l -0.20 0.89 0,016

Endpoint l66 2.36* 0.60 l82 -0.56 0,52 ~O.OOL

E-10 Special SearchesTardive Dyskinesia

The Extrapyramidal Symptom Rating Scale (ESRS) was used to determine the presence andseverity of tardive dyskinesia in Study USA-79. Emergence or worsening of dyskineticsymptoms were assessed using the following criteria: an increase from Baseline of~:3 points in 1item, or an increase of2 points in 2 or more items in the dyskinetic movement subscale on 2 ormore consecutive days. Patients were considered to have emergent or worsening dyskineticsymptoms ifthey met the criteria at any time during. the triaL. The existence of Baselinedyskinetic movement was also assessed with the following criteria: ~ 3 points in 1 item, or 2points in 2 items ofthe dyskinetic subscale for ESRS.

Eleven patients (3 RIS and 8 HAL) developed emergent or worsened tardive dyskinesia (TD)over the trial course. Ofthe patients with no symptoms at Baseline, 171 (98.3%) risperidonepatients and 177 (96.2%) haloperidol patients remained symptom-free throughout the triaL. Three

(1.7%) risperidone treatment group patients and 7 (3.8%) haloperidol treatment group patientsdeveloped emergent, persistent TD during the triaL. Of the 37 patients (18 RIS, 19 HAL), whohad dyskinetic symptoms at Baseline, 0 of the risperidone treatment group and 1 (5.3%) of thehaloperidol treatment group patients developed worsening symptoms by Endpoint.c ~c :i USA-79 produces an incidence of 1.7%(per year) ifone uses the mean duration of exposure (351 days) as the denominator.

The ISS reports that there were only 2 risperidone patients who developed tardive dyskinesia inthe controlled trial database. This number is manifestly smaller than the number reported for thesingle USA-79 triaL. C :iC -~VIII. Dosing, Regimen, and Administration IssuesThe sponsor makes changes in the DOSAGE AND ADMINISTRATION section oflabeling thatreflect the dosing regimen in the long-term controlled trials USA-79 and INT-6. They areaccurate and acceptable from a clinical standpoint.

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IX. Conclusions and Recommendations

A. ConclusionsStudy USA-79 supports the sponsor's claim that Risperdal is effective in maintaining treatmentresponse for schizophrenia. It has been customary to allow claims of extended efficacy based onthe results of one positive, well designed, appropriately controlled triaL. USA-79 meets thiscriteria CC

:i

r'i.C

:i.J

:J

In Study INT -6, a similarly designed study that was previously sui,mitted, Risperdal wascompared to haloperidol and no treatment difference was observed. USA-79 had twice thenumber of patients in each group. This increase in statistical power might explain the differencebetween USA -79 being a positive study and INT -6 showing no difference.

These studies were not designed to establish long-term safety. Since both INT-6 and USA-79had haloperidol as an active control with no placebo comparator, long-term risperidone safetycould only be compared to haloperidoL. Even then the studies were too small to detect adverseevents that occurred at a rate of less than 1 %.

These two pooled studies detected only minimal differences between the two drugs safetyprofies' with the exception ofthe mean change in prolactin levels and weight gain. The meanprolactin level increased in the RIS group from 25.7 ng/ml at baseline to 40.2 ng/ml at end point,whereas it decreased in the HAL groups from 28.6 ng/ml to 22.6 ng/ml. Roughly twice thenumber ofrisperidone treated patients (58/241) gained ?7% of their l:mseline body weight whencompared to haloperidol treated patients (31/261).L ~r: J USA-79 produces an incidence of 1.7%(per year) if one uses the mean duration of exposure (351 days) as the denominator. The ISSreports that there were only 2 risperidone patients who developed tardive dyskinesia in thecontrolled trial database. This number is manifestly smaller than the number reported for thesingle USA-79 triaL. i: JC -J

B. RecommendationsI recommend that the Division make an approvable action on supplement 008. t: J

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CLINICAL REVIEW


c.the risperidone was superior to "rJactiveC- J".

.J i recommend that labeling state

Paul J. Andreason, MDClinical Reviewer, HFD-120

XI. AppendixTable C-l Listing of Investigators Sites for

USA-79Investigator Site

Site #02Ronald Brenner, M. D.St. John's EpiscopalHospital327 Beach 19th StreetFar Rockaway, NY i 1691

Site# 03David Brown, M. D.

441 1 Medical Parkway DriveAustin, TX 78756

Site #04Wayne K. Goodman, MD/Matthew Byerly, M, D,Department of PsychiatryUniversity of FloridaPSB 11- 4301600 SW Archer RoadGainesvile, FL 32610- 0256

Site #06James Chou, M. D.

Room 20N 1 1Department of PsychiatryBellevue Hospital Center550 First A venueNew York, NY 10016

Site #07Bar Cole, M. D./ Michael De

Priest, MDSouthern Nevada AdultMental Health Services6161 W. Charleston Blvd.Las Vegas, NY 89102

No. of Patients

Entered =33Randomized 30

Entered 15

Randomized= 15

Entered= 10

Randomized= 8

Entered= 24Randomized= 19

Entered= l7Randomized- l4

Page 20


Table C-L Listing of Investigators Sites forUSA-79

Investigator Site

Site #08Cal Cohn, M. D.The Cohn Center,Psychiatr7777 SW FreewaySuite 1036Houston, TX 77074

Site #09John Csernansky, M, D.Washington University4940 Children's PlaceBox 8134

St. Louis, MO 63110

Site # 10John Davis, M, D.1601 West Taylor StreetChicago, IL 60612

Site # 11

Lawrence A. Dunn, M. D.Durham VA MedicalHospital508 Fulton

Durham, NC 27705

Site # 12Alan Green, M, D.David A. Klegon, MDCommonwealth ResearchCenterHarard Medical Center

74 Fenwood RoadBoston, MA 02 i 15

Site # 13

Alex Kopelowicz, M. D. (PI)15535 San FernandoMission Blvd.Mission Hils, CA 91345

No. of Patients

Entered= 35

Randomized= 30

Entered= 17

Randomized= 13

Entered= 0

Randomized= 0

Entered= 4

Randomized= 4

Entered= 9

Randomized= 9

Entered= 27

Randomized= 27

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CLINICAL REVIEW



Investigator Site

Site # 15Mark Hamer, M. D.VAMC - 116ADepartment of Psychiatr109 Bee StreetCharleston, SC 29401

Site # 16

Harold Harsch, M. D.General Hospital,Psychiatr - 175

8700 W. Wisconsin AveMilwaukee, WI 53226

Site # 17Federico Adan, M, DDominion Tower (D- 79)1400 NW 10 th AvenueSuite 307AMiami, FL 33136

Site #18George G. Jaskiw, M. D.Chief, Schizophrenia SectionPsychiatr Services 116- A (B)

Cleveland V AMC10,000 Brecksvile RoadBrecksvile, OH 44141

Site # 19Banole Johnon, M. D.The Mental Sciences Institute1300 MoursundHouston, TX 77030

Site # 20Ari Kiev, M. D.Social Psychiatry ResearchInstitute75 Booth AvenueEnglewood, NJ 07063

Site # 21

No. of PatientsEntered= 9

Randomized= 7

Entered= 8

Randomized= 7

Entered= 9

Randomized= 7

Entered= 8

Randomized= 6


Entered= 13

Randomized= 9

Entered= 1 8

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...CLINICAL REVIEW



Investigator Site

Mar Ann Knesevich, M. D.St. Paul Medical CenterSouthwestern Medical Center

5959 Har Hines Suite 924Dallas, TX 75235

Site # 22Douglas Levinson, M, D.Medical College of

Pennsylvania & HahnemannUniv. Hospital3200 Henr AvenueRoom 206APhiladelphia, P A 19129

Site 23H. E. Logue, M. D.Birmingham PsychiatryPharaceutical Studies, Inc.3490 Independence Drive

Birmingham, AL 35209

Site #24Robert M. Hamer Ph. D (PI)Matthew Menza, M. D.( CO- PI)RWJ Medical School675 Hoes LanePiscataway, NJ 08854

Site #26Raj Naka, M. D.16216 Baxter RoadChesterfield, MO 63017

Site # 28Charles Nemeroff, M. D.Emory University School ofMedicinel639 Pierce DriveSuite 4000Atlanta GA 30322

Site # 29

No. of PatientsRandomized= 10

Entered= 8

Randomized= 6


Entered= 5

Randomized= 5


Entered= 1

Randomized= 0

Entered= 2

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.,,:C,,_,_' -"" ",._'._'CLINICAL REVIEWiJ



Investigator Site

Vemon Neppe, M. D.NorthWest Outpatient Med, Ctr.l0330 Meridian Ave.Seattle, WA 98133Budgetl Contract:6808 44th Avenue, NESeattle, W A 98 i 15

Site # 30Sheldon Preskom, M. D,1 LOO N. St. Francis .

Suite 200Wichita, KS 672 1 4- 2878

Site #31Michael Plopper, M. D.Mesa Vista Hospital7850 Vista Hil AvenueSan Diego, CA 92 1 23

Site # 33George Simpson, M, D.Professor of PsychiatryUSC School of Medicine1937 Hospital Place

Grad HallLos Angeles, CA 90033

Site # 34Stephen Strakowski, M. D.Department of PsychiatryUniversity of CincinnatiML 559231 Bethesda AvenueCincinnati, OH 45267- 0559

Site # 35Marshall Thomas, M. D.University of Colorado4455 E. 12th AvenueDenver, CO 80220

Site # 36


Entered= 16

RandoIDized= 13


Entered= 2

Randomized= 1

Entered= 7

Randomized= 5

Entered= 3

Randomized= 2

Entered= 16

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CLINICAL REVIEW



Investigator Site

Jose Yaryra- Tobias, M. D.

Institute for Bio- BehavioralTherapy and Research935 Northern Blvd.

Great Neck, NY 1 1021

Site # 39Scott A. West, M. D.Psychiatric Institute ofFlorida, P A77 W. Underwood Street3rd FloorOrlando, FL 32806

Site # 40Iring S. Kolin, M. D.

1065 Morse Blvd.Suite 202Winter Park, FL 32789

Site # 42Marin J. Miler, M. D. .Larue Carter Hospital2601 Cold Springs RoadIndianapolis, IN 46222

Site # 43George Pahl, M. D.13301 North Meridian

Suite 101

Oklahoma City, OK 73120

Site # 44Tai P. Yoo, MDMercy Hospital BehavioralMedicine Services5555 ConnerDetroit, MI 48213


Entered= 1 1

Randomized= 9

Entered= 4

Randomized= 4

Entered= 1

Randomized= 1

Entered= 1 1

Randomiz;ed= 16

Entered= 5

Randomized= 5

Table C-2 Inclusion and Exclusion Criteria for Study USA-79INCLUSION CRITERIPatients who met the following criteria were eligible for this trial:

patient or legal guardian signed an approved informed consent

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CLINICAL REVIEW/Clinical Review Section

- male or female between 18 and 65 years of age- met DSM-IV criteria of schizophrenia or schizoaffective disorder- had a documented I-year history of schizophrenia or schizoaffective disorder since the firstpharmacological treatment for psychotic symptoms- within the past 24 months was discharged from an inpatient psychiatric unit, had a partialhospitalization, completed crisis management intervention, or stayed in a psychiatric hospitalemergency room holding area for at least 12 hours- received a stable dosage of antipsychotic medication for the 30 days prior to entering the trial(Stable was calculated by dividing the minimum dosage by the maximum dosage and defined asa ratio ~ 0.75,)- domiciled at the same address for at least 30 days preceding trial entry- was able to discontinue current antipsychotic medication, in the opinion ofthe investigator- was clinically stable, in the opinion ofthe investigator- had negative urine drug screens for cocaine, opiates, barbiturates, amphetamines,phencyclidine, lysergic diethylamide acid, and methadone- females had a negative pregnancy test

agreed to refrain from using ilicit drugs and abusing alcohol

EXCLUSION CRITERIPatients who met 1 or more ofthe following criteria were not eligible for this trial:- females who were pregnant or nursing- had another current DSM-IV Axis-I diagnosis (except caffeine or nicotine dependence) orAxis-II diagnosis of borderline personality disorder or antisocial personality disorder (A historyof substance dependence or substance abuse must be in remission for at least 3 months at thetime of Screening.)

- had clinically significant neurological disorder or other condition with neurologicalmanifestations, with the exception ofDSM-IV defined medication-induced movement disorders- had history or the presence of gastrointestinal, liver, or kidney diseases, or other conditions ofsufficient severity to interfere with the absorption, distribution, metabolism, or excretion of trialmedication- had clinically significant medical disease which would prohibit treatment with risperidone orhaloperidol- had unstable medical ilness, ie, unstable angina, labile hypertension, poorly controlled diabetes- received concomitant medication, other than OTC medications or antibiotics, for fewer than 14days at the time of Screening (Doses of concomitant medications should be stable for 14 days,that is, minor variations of up to 25% are permitted.)

had carcinoma during the previous 5 years (History of treated basal cell skin carcinoma isallowed.)was HIV -positive

- received current treatment with the antipsychotic clozapine or known 0 be refractory toantipsychotics- was acutely psychotic and showed no response or minimal response to risperidone at dosages:;8 mg/day or haloperidol at a dosage of:;20 g/day when given for 4 weeks minimum- was currently being treated with :;10 mg/day risperidone or :;25 mg/day haloperidol

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CLINICAL REVIEW


- required treatment with antidepressants, lithium, carbamazepine, or valproic acid within the 30days preceding trial entry- had history of neuroleptic malignant syndrome- had known hypersensitivity to risperidone or haloperidol- had history of seizures requiring medication- received depot neur~leptic injections within 1 treatment cycle of Screening- received an investigational medication within 30 days before Screening- had history of attempted suicide in the previous 6 months or current suicidal ideation

was currently at risk for violent behavior against otherswas considered by the investigator as potentially noncompliant

Table C-5.1 Secondary Effcacy Variables in Study USA-79. relapse rates, I-year and Endpoint

. total and subscales ofPANSS,

. I-year relapse rate,

. clinical improvement measured by a 20% decline in total P ANSS score,

. CGI and CGI-C,

· QOLI,. Drug Attitude Inventory,

. cognitive function tests (Wechsler Memory Scale, California VerbalLearning Test,

Continuous Performance Task, Verbal Fluency, Digit Symbol, and Wisconsin Card Sort),and

. Health Care Resource Utilization

Table C-5.2 Safety Assessments in Study USA-79. adverse events

. clinical laboratory tests: blood chemistry profie: sodium, potassium, chloride, bicarbonate,

glucose, urea nitrogen, creatinine, calcium, phosphorus, uric acid, total bilirubin, alkalinephosphatase, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase,gamma glutamyl transpeptidase, lactic dehydrogenase, total serum protein, albumin, andprolactin complete blood count with differential and platelet count urinalysis by dip stick; ifabnormal, a microscopic examination urine drug screen serum pregnancy test (females ofchildbearing potential)

. ECG

. vital signs: pulse, respiration, temperature, blood pressure

. physical examination

. ESRS

Summaries of Deaths in Lone:-term Controlled Trials that were not Considered Drue:RelatedSubject 0152, a 41-year old Caucasian male in RIS-USA-79, was taking RIS 4 mg and wasadmitted to hospital on Day 97 ofthe trial for dyspnea and chest pain. The physician felt that thesymptoms were due to chest inflammation. One day later the subject was seen again by thephysician for the same symptoms and he recovered the same day. Eight days later the subject

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. .. .. ......CLINICAL REVIEW'.


complained of difficulty breathing and pain in his left arm. He became pale, diaphoretic andcollapsed. He was pronounced dead when the emergency squad arrived. Autopsy revealed thecause of death as bilateral deep vein thrombosis with multiple pulmonary emboli. Theinvestigator considered this event unrelated to the trial medication.

Subject 435, a 39-year old Caucasian female who was taking RIS 12.5 mg in trial RIS-INT-6.Twenty-five days after the start of treatment, she committed suicide. There was no relation to thetrial medication according to the investigator. Listing AEA gives details about the events leadingto death.

Table E-2.1 Serious adverse events in:: 0.5% of the total RIS and HAL subjects-controlled long-term trials

WHO organ system class RIS RIS RIS Total RIS HALWHO preferred term ~4mg 4 - 6 mg ~ 6mgTotal no. of subjects 29 156 98 283 302No. of subjects with SAE, 4 (13.8) 38 (24. 4) 18(18.4) 60 (21. 2) 69 (22. 8)n(%)Psychiatric disorders 3 (10.3) 24 (15. 4) 13 (13. 3) 40 (14. 1) 52 (17. 2)Psychosis 0 1 8 (1 1. 5) 9 (9. 2) 27 (9.5) 38 (12. 6)Suicide attempt 0 3 (1. 9) 4(4.1) 7 (2. 5) 4 (1. 3)Depression 1 (3. 4) 2 (1. 3) 2 (2. 0) 5 (1. 8) 0Hallucination 1 (3,4) 0 2 (2. 0) 3 (1. 1) 1 (0. 3)Agitation 0 1 (0. 6) 1 (1. 0) 2 (0. 7) 5 (1. 7)Drug abuse 1 (3. 4) 1 (0. 6) 0 2 (0, 7) 1 (0. 3)Paranoid reaction 0 1 (0. 6) i (1. 0) 2 (0. 7) 0Schizophrenic reaction 0 1 (0. 6) 1 (1. 0) 2 (0. 7) 3 (1. 0)Aggressive reaction 0 0 0 0 2 (0. 7)Anxiety 0 0 0 0 3 (1. 0)Delusion 0 0 0 0 3 (1. 0)Body as a whole - general 0 6 (3. 8) 3 (3. 1) 9 (3. 2) 15 (5. 0)disordersInjury 0 2 (1. 3) 2 (2. 0) 4 (1. 4) 4 (1. 3)Chest pain 0 2 (1. 3) 1 (1. 0) 3 (1. l) 1 (0. 3)Syncope 0 1 (0. 6) 0 1 (0.4) 2 (0. 7)Therapeutic response 0 1 (0. 6) 0 1 (0. 4) 3 (1. 0)increasedCondition aggravated 0 0 0 0 2 (0. 7)Metabolic and nutritional 1 (3. 4) 2 (1. 3) 1 (1. 0) 4 (1. 4) 5 (1. 7)disordersDehydration 1 (3. 4) 0 1 (1. 0) 2 (0, 7) 0Diabetes melltus 0 2 (1. 3) 0 2 (0. 7) 1 (0. 3)Hyponatraemia 0 0 0 0 2 (0. 7)Central & peripheral 0 2 (1. 3) 1 (1. 0) 3 (1. 1) 4 (1. 3)nervous system disordersConvulsions 0 0 0 0 2 (0. 7)Myo endo pericardial & 0 0 0 0 2 (0. 7)valve disordersMyocardial infarction 0 0 0 0 2 (0. 7)

Page 28

......CLINICAL REVIEW).....


Table E-5.1 Laboratory value changes beyond the predefined limits in :;2% ofthe total RIS and HAL subjectswith normal baseline values - controlled long-term trials

RIS RIS RIS Total RIS HALVariable -C4mg 4 - 6 mg :;6mgHematology ni N assessed (%)Hematocrit_ Abnormally low 0/22 (0) 31 1 l5 (2.6) 0/38 (0) 3/l75(1.7) 1/ 188 (0.5)_ Abnormally high 0/22 (0) 1/ 115 (0.9) 0/38 (0) 1/l75 (0.6) 4/188 (2.1)WBC_ Abnormally high 012 (0) 01 25 (0) .3/55 (5. 5) 3/82 (3. 7) 1/85 (1. 2)Blood chemistry ni N assessed (%)Chloride_ Abnormally low 01 25 (0) 21 iis (1.7) 2/38 (5. 3) 41 178 (2.2) 3/187 (1.6)_ Abnormally high 01 25 (0) 1/ 115 (0.9) 0/38 (0) 1/ 178 (0.6) 2/187 (1.)

GGT_ Abnormally high 1/26 (3. 8) 41 137 (2.9) 2/91 (2.2) 7/254 (2.8) 7/263 (2.7)Glucose_ Abnormally low 0/27 (0) II 141 (0,7) 01 92 (0) 1/260 (0.4) 01 272 (0)

_ Abnormally high 0/27 (0) 9/141 (6.4) 0192 (0) 9/260 (3,5) 81 272 (2.9)

SGPT (ALT)_ Abnormally high 1/26 (3. 8) 41 140 (2.9) 0192 (0) 5/258 (1.9) 61 270 (2.2)

Total protein_ Abnormally low 01 26 (0) 01 137 (0) 01 89 (0) 0/252 (0) 0/270 (0)_ Abnormally high 01 26 (0) 1/137 (0,7) 01 89 (0) 1/252 (0.4) 61 270 (2.2)


Page 29


/s/Paul Andreason11/5/01 03: 16: 17 PMMEDICAL OFFICER

Thomas Laughren12/15/01 11: 55: 03 AMMEDICAL OFFICERI agree that this supplement is approvable i see memoto file for more detailed comments. - -TPL

MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH

DATE: December 15,2001

FROM: Thomas P. Laughren, M.D.Team Leader, Psychiatric Drug ProductsDivision of Neuropharmacological Drug ProductsHFD-120

SUBJECT: Recommendation for approvable action forRisperdal tablets and solution (risperidone) for the longer-term treatment of schizophrenia

TO: File NDA 20-272/S-008 & NDA 20-588/S-004

(Note: This overview should be fied with the 7-25-01

original submission.)

1.0 BACKGROUN

Risperdal is currently approved and marketed for the treatment of schizophrenia, in an immediate releasetablet (NA 20-272) and in an oral solution (NA 20-588). These supplements provide data in supportof a new claim for these same formulations in the longer-term treatment of schizophrenia, in a dose rage

of ( :i mg/day.

These supplements were originally submitted 3-12-97, and a nonapproval letter was issued 1-13-98. The3-12-97 submission included effcacy date from 4 trals, only 1 of which was a controlled tral (! -6), and

that study, a 1 year comparson of risperidone and haloperidol, demonstrated no difference between these2 active drugs in relapse, and thus, was considered uninterpretable. We also considered longer-term safetydata submitted in 3-12-97 to be uninterpretable. However, we did invite the sponsor to submit labelinglanguage to note the apparent lack of a 2D6 inhibitory effect for risperidone, as demonstrated in datasubmitted with these original supplements. We also, in the 1-13-98 letter, asked the sponsor to addlanguage in labeling to describe the results of a cross-fostering stdy that showed a direct toxic effect onthe fetus, and supported, in our view, the continuation of a Category C for pregnancy. Both of thesechanges were finally approved in a 7-19-01 letter.

1

Since the proposal is to use the currently approved Risperdal formulations for this expanded indication,there was no need for chemistr, pharacology, or biopharmaceutic reviews ofthis supplement. The focuswas on clinical data. The primary review ofthe efficacy and safety data was done by Paul Andreason,M.D., from the clinical group. Yeh-Fong Chen, Ph.D., from the Division of Biometrcs, also reviewed theefficacy data.

The study supporting this supplement was conducted under IN 31,931. The original supplements for thisexpanded indication (S-008 & S-004) were submitted 7-25-01.

We decided not to take these supplements to the Psychopharmacological Drugs Advisory Committee

(PDAC).

2.0 CHEMISTRY

As Risperdal tablets and solution are already marketed, there were no CMC issues requiring review forthis supplement.

3.0 PHARMCOLOGY

As Risperdal tablets and solution are already marketed, there were no phartox issues requiring reviewfor this supplement.

4.0 BIOPHARACEUTICS

As Risperdal tablets and solution are already marketed, there were no biopharmaceutics issues requiringreview for this supplement.

5.0 CLINICAL DATA

5.1 Effcacy Data

5.1.1 Overview of Study 79

Results from study 79 were submitted in support ofthis claim for the longer-term efficacy ofRisperdal inschizophrenia. This 35 center, US, outpatient, parallel group study enrolled patients with eitherschizophrenia or schizoaffective disorder (DSM-IV) who were judged to be stable by the investigator forat least 1 month prior to radomiztion. "Stable" was defied as receiving the same dosage of antipsychotic

2

medication and living in the same residence for 30 days. Patients meeting these criteria were radomized

(n=395) to either risperidone 4 mg/day (n= 192) or haloperidol 10 mg/day (n=203) for a minimum periodof i year, during which time they were observed for relapse. Medication was titrated up to these initialtarget doses over the first 3 days. During the first month of the trial, adjustments in medication could bemade weekly, within a range of2 to 8 mg/day for risperidone and 5 to 20 mg/day for haloperidoL.Thereafter, patients were seen monthly, some for periods of up to 2 years. The study ended when the lastrandomized patient reached the 1 year point.Relapse was defined as any 1 ofthe following:-psychiatric hospitalization-clinical judgement that an increase in level of care was necessary and an increase in P ANSS total scoreof25% compared to baseline, or an increase of i 0 if the baseline score was .: 40 (both had to occur withina 2 week period)-deliberate self injury-emergence of clinically significant suicidal or homicidal ideation-violent behavior resulting in significant injury to another person or significant property damage-CGI-C score of 6 or 7

The primary outcome was time to relapse. Secondary outcomes included relapse rate, and P ANSS totaland subscales, among others.

The primary analysis was the log-rank test for time to relapse,

Patients in study 79 were roughly 2/3 male, roughly Yz Caucasian and 1/3 Afrcan American, and the meanage was roughly 41 years. Roughly 82% of patients were schizophrenic.

Forty-one % ofrisperidone patients completed to 1 year, compared to 23% of haloperidol patients.Patients in the risperidone group had a longer mean time to relapse (452 days) than patients in thehaloperidol group (391 days), p=O.OO 1. Risperidone also was superior to haloperidol on this measure in

the subgroup with schizophrenia (p0.007), i: Jc. J However, the effect sizes were similar to those for the schizophrenic patientsL JC. .J The crude relapse risks at 1 year were23% for risperidone and 35% for haloperidol (p.009). The cumulative relapse rates at 1 year were 29%for risperidone and 45% for haloperidoL.

Dr. Chen did an analysis considering all censored patients as treatment failures, and this analysis alsofavored Risperdal over placebo (p=0.008).

Dr. Chen conducted subgroup analyses based on gender and race. This analysis showed a superiority ofrisperidone over haloperidol only for the male subgroup, however, the effect sizes were similar for bothsubgroups. Analyses based on race showed a superiority risperidone over haloperidol for both Caucasianand African American subgroups.

3

Comment: Both Drs. Andreason and Chen considered this a positive study supporting a claim oflonger-term effcacy for Risperdal in the treatment of schizophrenia, and I agree. I also agree with Dr. Andreaonthat labeling should J c: :ic: .. mention thatsuperiority was established over an active comparator in this triaL.5.1.2 Conclusions Regarding Effcacy Data

Study 79 demonstrated a benefit of risperidone over haloperidol for the maintenance of stability, or delayof relapse, in patients with schizophrenia who were stble at trial entr and were then observed for relapseduring a 1 to 2 year followup period.

5.2 Safety Data

Dr. Andreason's safety review of this supplement was based on 283 patients who received Risperdal ina pool of2 controlled long-term studies (Study 79 and INT -6). Dosing was according to the currentlyrecommended dose range for RisperdaL. There were no unexpected safety findings among these patients,and no basis for changes in the labeling for Risperdal from the standpoint of safety, C. :i

5.3 Clinical Sections of Labeling

We have modified the language in the 4 sections oflabeling in which the sponsor has proposed changes,i.e., Clinical Trials, Indications, Adverse Reactions, and Dosage and Administrtion. We have also addedlanguage changig the focus of the claim for this drg from "management of the manifesttions of psychosis"to "schizophrenia," as part of a class action for the antipsychotic drugs.

6.0 WORLD LITERATURE

4

Dr. Andreason reviewed the sponsor's report on a total of 116 published papers pertining to the longer-term use ofRisperdal in schizophrenia. He concluded that there were no unexpected adverse events

reported that would impact on Risperdal labeling.

7.0 FOREIGN REGULATORY ACTIONS

To my knowledge, Risperdal is not approved for the longer-term treatment of schizophrenia anywhere atthis time.

8.0 PSYCHOPHARMCOLOGICAL DRUGS ADVISORY COMMITTEE (pDAC)MEETING

As noted, we did not take this supplement to the Psychopharmacological Drugs Advisory Committee

(PDAC).

9.0 DSI INSPECTIONS

DSI did not, to my knowledge, inspect investigative sites for this supplement.

10.0 LABELING AN APPROV ABLE LETTER

10.1 Labeling Attached to Approvable Package

Our proposed labeling for this new claim is included in the approvable letter.

10.2 Foreign Labeling

To my knowledge, Risperdal is not approved for the longer-term treatment of shizophrenia anywhere atthis time.

10.3 Approvable Letter

The approvable letter includes our proposed labeling for this supplement.

11.0 CONCLUSIONS AN RECOMMENDATIONS

5

I believe that Janssen has submitted suffcient data to support the conclusion that Risperdal is effective andacceptably safe in the longer-term treatment of schizophrenia, I recommend that we issue the attched

approvable letter with our proposed labeling language for this expanded claim.


cc:Orig NDAs 20-272/S-008 & NDA 20-588/S-004HFD-120HFD-120/TLaughren/Ratz/P Andreason/SHardeman

DOC: MMSCZLT.AEI

6


7


Thomas Laughren12/15/01 12: 11 :47 PMMEDICAL OFFICER

MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AN RESEARCH

DATE: February 14,2001

FROM: Thomas P. Laughren, M.D.Team Leader, Psychiatric Drug ProductsDivision of Neuropharmacological Drug ProductsHFD-120

SUBJECT: Recommendation for approval action forRisperdal tablets and solution (risperidone) for the longer-term treatment of schizophrenia

TO: Pile NDA 20-272/S-008 & NDA 20-588/S-004

(Note: This overview should be fied with the 1-28-02 response to our 1-11-02

approvable letter.)

We issued an approvable letter for these supplements on 1-11-02, with proposed modifications to labeling.There were no issues other than labeling that needed resolution prior to tag a final approval action. The

sponsor has in fact accepted our proposed changes verbatim. They have also made changes throughoutlabeling to shift the focus ofthe claim from "psychosis" to "schizophrenia." as we had requested in a 9-25-00 letter.

There are only two issues that require further comment:

r-

-In the cover letter to their i -28-02 response, the sponsor has raised a question about a statementregardingi: :: we had included within a bracketed comment to them in our proposed

labeling. They express a concern about this sttement but they do not, in my view, ariculate any questionthat needs a response at this time. r. .:

1

CJ however, I thin they need to give us a more definitive question before we can provide a meaningfulresponse, Therefore, I recommend that we not respond to this vague inquiry at this time.

In summar, we have reached agreement with the sponsor on final labeling and I recommend that weapprove these supplements, with the agreed upon final labeling.

~lhlsWay0I Otigit

cc:Orig NDAs 20-272/S-008 & NDA 20-588/S-004HFD.:120HFD-120/TLaughren/Ratz/P Andreason/SHardeman

DOC: MEMSCZL T.API

2


/s/Thomas Laughren2/14/02 02: 07: 53 PMMEDICAL OFFICER

CENTER FOR DRUG EV ALUA TION ANDRESEARCH

APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

STATISTICAL REVIEW(S)

"

DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICEFOOD AND DRUG ADMINISTRTIONCENTER FOR DRUG EV ALUA TION AND RESEARCH

STATISTICAL REVIEW AND EVALUATION

Medical Division: Division of Neuropharmacological Drug Products (HFD-120)Biometrics Division: Division of Biometrics I (HFD-710)

NDA NUMBER/SERIL NUMBER: 20-272/S-008 & 20-588/S-004

DATE RECEIVED BY CENTER: 7/25/01

DRUG NAME: RISPERDALiI (risperidone)

INICATION: Schizophrenia C- .:SPONSOR: Janssen Research Foundation

STATISTICAL REVIEWER: Yeh-Fong Chen, Ph.D.

STATISTICAL TEAM LEADER: Kun Jin, Ph.D.

BIOMETRICS DIVISION DIRCTOR: George Chi, Ph.D.

CLINICAL REVIEWER: Paul Andreason, M.D.

PROJECT MANAGER: Steve Hardeman, M.D.

I. TABLE OF CONTENTS

1. Introduction and Background-------------------------------------------------------------------------------------- 22. Summary ofthe Sponsor's Results and Conclusions for Study RlS-USA-79 --------------------------------- 2

3. Description of the Sponsor's Studies and Statistical Methodologies-----------------~---------------------------- 3

3.1 Study RlS-USA -79----------------------------------------------------------------------------------------------------- 33.1.1 Trial Objectives--------------------------------------------------------------------------------------------------- 33.1.2 Trial Design------------------------------------------------------------------------------------------------------ 33 . 1 .3 E ffi cacy------------------------------------------------------------------------------------------------------------ 33.1.4 Statistical Methods and Analyses Planned----------------------------------------------------------------- 4

3.2 Study Rl S-!NT -6------------------------------------------------------------------------------------------------------- 63 .2. 1 Effi cacy Assessments---------------------------------------------------------------------------------------"----- 6

3 .2.2 Statisti cal Analyses----------------------------------------------------------------------------------------------- 7

4. Detailed Review of the Sponsor's Individual Study ResuIts-------------------------------------------------- 7

4. 1 Study Rl S- USA - 7 9----------------------------------------------------------------------------------------------------- 7

4.1,1 Subject Disposition----------------------------------------------------------------------------------------------- 74.1.2 Premature Discontinuations------------------------------------------------------------------------------------- 84.1.3 Demographics and Baseline Characteristics---------------------------------------------------------------- 84.1.4 Primar Efficacy Parameter-------------------------------------------------------------------------------- 94.1.5 Secondary Efficacy Parameters--------------------------------------------------------------------------- 11

4.1.6 Sponsor's Effcacy Conclusion---------------------------------------------------------------------------- 154.2 Study Rl S- INT -6-------------------------------------------------------------------------------------------------------- 16

4.2. 1 S ubj ect Dispositi on---------------------------------------------------------------------------------------------- 1 6

4.2.2 Premature Discontinuations------------------------------------------------------------------------------------- 164.2.3 Demographics and Baseline Characteristics---------------------------------------------------------------- 164.2.4 Primary Eff cacy Param eter------------------------------------------------------------------------------------ 164.2.5 Secondary Effcacy Parameters--------------------------------------------------------------------------- 164.2.6 Sponsor's E ffi cacy Concl usi on-------------------------------------~---------------------------------------- 1 8

5. Statistical Reviewer's Findings and Comments----------------------------------------------------------------------- 18

II. EXECUTIVE SUMMARY OF STATISTICAL REVIEWER'SFINDINGS

. This reviewer did not have any inconsistent findings on the values of the sponsor's statisticalanalysis results.

. C. J the sponsor had statistically significant test results shown on the primary and some

secondary effcacy endpoints for the whole study population on Study RIS-USA-79C. JC ~C ~. Except for two diagnosis groups, the sponsor did not perform any other subgroup analysis.

According to this reviewer's subgroup analysis results, the risperidone was shownsignificantly more effective than haloperidol for male patients but not for female patients. Forboth white and black patient groups, there existed statistically significant differences betweenthe risperidone and haloperidol treatments.

. After reversing the values for censoring variables in the early discontinued study patients, the

robustness ofthe test result for the primary endpoint was confirmed.

III. STATISTICAL REVIEW AND EVALUATION OF EVIDENCE

1. Introduction and Background

In response to the FDA's not approvable letter dated January 13, 1998, the sponsor submittedthis amendment to the supplement S-008 to provide for the long-term treatment of patients withschizophrenia C .:

According to the sponsor's submission, efficacy data supporting this amendment were derivedfrom clinical studies RIS-USA-79 and RIS-INT-6. The long-term efficacy ofrisperidone indelaying onset to relapse of schizophrenia c. :i was established by an indepth review of data from RIS-USA-79 in which an established agent, haloperidol was used as areference neuroleptic agent. Data from the earlier study, RIS-INT-6, comparing long-termtreatment with risperidone and haloperidol in the treatment of subjects with chronic schizopreniawere used to support the findings ofRIS-USA-79. Since Study RIS-INT-6 was reviewed before,this review wil be only focusing on the statistical evaluation for Study RIS-USA-79 but wilreport the sponsor's study outlnes and statistical results for both studies.

2. Summary of the Sponsor's Results and Conclusions for Study RIS-USA-79

The primary efficacy endpoint for Study RIS-USA-79 was time to relapse in stable outpatientswith chronic schizophrenia or schizoaffective disorder who received risperidone or haloperidolas maintenance treatment for at least I year. The secondary efficacy endpoints included relapserates at I-year and at endpoint, total and sub scales ofPANSS, CGI severity, CGI-relative tochange from the baseline assessment, cognitive function, quality of life, drug attitude inventoryand health care resource utilization. Table 1 shows a summary ofthe sponsor's efficacy resultsfor the primary and some important secondary endpoints.

Table 1. Summary of Efficacy ResultsEffcacy Risperidone Haloperidol p-value

Primary Variable N=I77 N=188. Time to Relapse (days) 452.23 (SE 17.68) 391.3 (SE 21.83) 0.001Secondary Variables. Number of patients with Psychotic Relapse

---- at 1 year 41 (23.2%) 65 (34.6%) 0.009_n_ at Endpoint 45 (25.4%) 75 (39,9%) 0.002

. P ANSS, change from Baseline to Endpoint BL mean change BL mean change---- Total PANSS score 65.06 -3.15 67.38 1.79 pO:O.OOl

---- Positive symptoms 18,58 -1.6 19.15 -0,24 0.005---- Negative symptoms 16.98 -0.53 17.80 0.77 0,004---- Disorganized thoughts 14,97 -0.79 15.38 0.17 0.014m_ Uncontrolled hostility/excitement 1.04 0.29 6.26 0.73 0.076---- Anxiety/depression factor 1.45 -0.52 8.76 0.24 0.005

. CGI-C, change from Baseline to Endpoint---- Very much improvement 12 (6.9%) 8 (4.3%) 0:0.001

---- Much improvement 41 (23.7%) 25 (13.4%)

---- Minimum improvement 50 (28,9%) 35 (18.7%)

---- Unchanged 35 (20.2%) 59 (31.6%)

2

According to the sponsor's test results shown on Table 1, they concluded that risperidOrie wasstatistically significantly more effective than haloperidol in maintaining clinical efficacy over a1- to 2- year period in stable subjects with schizophrenia or schizoaffective disorder. Log-termtreatment with risperidone was associated with superior symptom improvement includingstatistically significantly superior efficacy against haloperidol on positive, negative and affectivesymptoms.

3. Description of the Sponsor's Studies and Statistical Methodologies

3.1 Study RIS-USA-79

3.1.1 Trial Objectives

The primary objective of this double-blind study is to compare the time to relapse in stableoutpatient schizophrenics and subjects with schizoaffective disorder receiving risperidone orhaloperidol for at least 1 year.

Secondary objectives include comparing the effects of these two drugs on the incidence ofrelapse, symptom measures (P ANSS, CGI), extrapyramidal side effects (ESRS), compliance,cognitive function (6 item test battery), subject satisfaction, quality of life and resource use.

3,1.2 Trial Design

This was a double-blind trial in outpatients with chronic schizophrenia or schizoaffectivedisorder classified by Diagnostic and Statistical Manual, Fourth Edition (DSM-N). Patientswere judged by the investigator to be clinically stable for 1 month prior to enrollment into thetrial, discontinued their current antipsychotic medications, and were assigned to treatment usinga randomization scheme that 'Yas stratified by sex. Stable was defined as receiving the samedosage of antipsychotic medication for 30 days and living in the same residence for 30 days.

The trial used a parallel-group design with 2 treatment arms: risperidone and haloperidoL. Trialmedication was escalated over the first 3 days of double-blind treatment to a dosage for 4 mg/dayrisperidone or 10 mg/day haloperidoL. For the first month oftherapy, assessments were made atI-week intervals to allow adjustment of medication to within the range of2 mg to 8 mg/day forrisperidone and 5 mg to 20 mg/day for haloperidoL. Thereafter, trial visits were scheduled every4 weeks. Additional visits were to be scheduled as needed. Patients were to be followed until thelast patient enrolled into the trial had completed 1 year of double-blind treatment. Patients whorelapsed a second time were to be discontinued from the triaL.

3.1.3 Effcacy

Several parameters were used to evaluate the efficacy of risperidone for maintenance treatmentof patients with stable schizophrenia or schizoaffective disorder.

3

3. I .3.1 Primary Efficacy Parameter

The primary efficacy parameter was the time to relapse. Relapse was defined as anyone of thefollowing occurrences:

· psychiatric hospitalization,· clinical judgment that an increase in level of care was necessary and increase in P ANSS

score of25% compared with Baseline, or an increase often points if the baseline score was::40, (The increases in level of care and in P ANSS score had to occur within 2 weeks of eachother in order to qualifY a patient's relapse.)

· deliberate self injury, in the investigator's opinion,· emergence of clinically significant suicidal or homicidal ideation,· violent behavior resulting in significant injury to another person or significant propert

damage, in the investigator's opinion, or· significant clinical deterioration in the investigator's judgment (a CGI-C score of6, "much

worse").

When the investigator rated the patient's CGI-C at 6, the patient was counted as relapsed even ifthe investigator did not indicate relapse.

3.1.3.2 Secondary Efficacy Parameters

The secondary efficacy parameters were:· Relapse rates at I-year and at Endpoint· Total PANSS

· P ANSS subscale scores· Clinical improvement measured by a 20% decline in total P ANSS score· CGI and CGI-C

· Quality oflife (the Delight-Terrible (D-T) scales in the brief Quality of Life Interview)· Cognitive function tests· Drug Attitude Inventory and,· Health Care Resource Utilization

3.1.4 Statistical Methods and Analyses Planned

Assume that a projected relapse rate over a I-year period of25% in the risperidone group and40% in the haloperidol group, 165 patients per treatment, or a total of 330 patients were reqiredto achieve the power of 0.8. To adjust for patient discontinuations resulting from reasons otherthan disease relapse, the protocol specified the randomization of 414 patients from 40 sites. Allstatistical tests were interpreted at the 5% 2-tailed significance level, unless otherwise noted.

Trial sites were sorted by the number of patients enrolled. Iftoo few patients were entered at asite, the site was grouped with another site accordingly by size. Sites with the fewest patientswere pooled with the next smallest site; If the number of patients was not ¿ 12 after pooling, the

4

next smallest site was included in the pool. The process was repeated until all-sites had aminimum of 12 patients.

Two populations of patients were defined for purposes of analyses:1. All randomized patients who received trial medication were counted in the population for

safety analyses;2. All randomized patients who received trial medication and who had at least 1 post-Baseline

assessment were counted in the intent-to-treat population for the analyses of changes fromBaseline.

There were 4 weekly visits numbered 3 through 6 (Week 1 to Week 4) starting the double-blindtreatment. Visits could continue through 27 months oftreatment and were numbered 7 through33 (Week 8 through Week 112). Visits 3 through 6 were to be performed on specified days plusor minus 1 day (i.e., Visit 3 could be made on trial days 7,8 or 9). Visit 7 through 33 were to bemade on the specified day plus or minus 4 days from the previous visit (i.e., Visit 7 could bemade on trial days 53 through 61). Any deviation from this schedule was considered a violationof the protocol.

3.1.4.1 For Baseline Demographic Characteristics

Demographic information was summarized statistically for age, with mean values, standarddeviations, standard errors, median values, and minimum and maximum values provided. Forpatient sex and race, frequency counts were provided by treatment group. Inter-group differenceswere evaluated with a 2-way ANOV A model with treatment and investigator as factors. Forcategorical data, the Cochran-Mantel-Haenszel (CMH) test, adjusting for investigator, was used.

3.1.4.2 For Primary Parameter- Time to Relapse

Kaplan-Meier survival curves were generated for each treatment group. Between treatmentdifferences were assessed using a stratified log-rank test controlling for investigator and sex.

Relapse rate at 6 month, 1 year, and at end ofthe trial, were estimated by using Kaplan-Meiermethod.

Secondary analyses were performed on the subsets of patients who had diagnosis ofschizophrenia or schizoaffective in order to assess the consistency in treatment effects acrossthese subgroups. Whereas a similar statistical method, a stratified log-rank test controllng forinvestigator and sex, was applied in the analysis of the schizophrenia subgroup. For the

schizoaffective subgroup, a non-stratified log-rank was used due to the small sample size.

3.1.4.3 For the Secondary Parameters

3.1.4.3.1 Relapse Rate

One-year relapse rate frequency tables were generated and CMH tests were applied controllngfor investigator and sex. A similar analysis was performed for the endpoint data.

5

The differences in relapse rates between the two treatment groups were assessed for the subsetsof patients who had diagnosis of schizophrenia or schizoaffective at baseline. Similar to theanalysis on the time to relapse data, due to the small sample size, the between treatmentcomparison for the schizoaffective subgroup was based on the chi-square test without controllngfor the investigator and sex effects.

3.1.4.3.2 Positive and Negative Symdrome Scale (P ANSS)

The changes from baseline in total P ANSS score and sub scale scores were calculated at eachassessment time point. Within-group differences were calculated using the paired t-test and inter-group comparisons were performed using an ANCOV A model with investigator, treatment, andsex as factors, and the baseline value as a covariate.

3.1.4.3.3 Cognitive Assessments

Treatment differences in each ofthe cognitive assessment tests were analyzed using ANCOV Awith investigator, sex, and treatment as factors, and the baseline value as a covariate.

3.1.4.3.4 Drug Attitude Inventory (DAI)

Between treatment differences were evaluated with the CMH test controllng for investigator andsex. For total DAI, the sum of all items was calculated, and inter-treatment differences in thechanges from baseline were analyzed using the ANOV A model with factors of treatment, sex,

and investigator.

3.1.4.3.5 Quality of Life Interview (QOLI)

Descriptive statistics for the observed changes from baseline were provided for the Delight-Terrible (D- T) scales, which were added together, with total calculated scores. Treatmentdifferences in D- T scales were examined using ANCOV A with factors for treatment, sex andinvestigator as factors, and baseline scores as covariates.

3.2 Study RIS-INT-6

RIS-INT-6 was the first long-term study with risperidone to be conducted under double-blindconditions. The trial was of a multicenter, multinational, double-blind, randomized designcomparing the efficacy of risperidone and haloperidol over 1 year in patients with an acuteexacerbation of chronic shcizophrenia at selection.

3.2.1 Effcacy Assessments

3.2.1.1 Primary Efficacy Parameter

The primary efficacy parameter was the time to discontinuation as a result of adverse events orclinical relapse. Relapse was defined as a deterioration in the subject's clinical condition thatcould not be managed satisfactorily after adjustment of dosage within protocol limits

6

3.2.1.2 Secondary Efficacy Parameters

The secondary efficacy parameters were:. Total PANSS

· PANSS subscale scores (positive, negative, and psychopathology scales)· CGI. Quality of life

. Patient compliance

3.2.2 Planned Statistical Analyses

Sample size determination was based on a projected I-year relapse rate of 25% in the risperidonegroup and of 55% in the haloperidol group. It was estimated that 80 subjects per treatment group,or a total of 160 subjects were would provide 90% power to detect statistically significantdifference in the relapse rates at a two-tailed significance level of 0.05. To account for patientdiscontinuations for reasons other than disease relapse, a total of 180 subjects across 40 centerswere randomized.

The primary efficacy parameter (the time to discontinuation because of adverse events orpsychotic relapse) was estimated by the Kaplan-Meier product-limit method and comparedbetween treatment groups by means of the Gehan' s generalized Wilcoxon test, stratified forcountr.

Changes from baseline to endpoint in P ANSS total and subscale scores were subjected to a two-way analysis of covariance (ANCOY A) model with factors for baseline score, treatment, andcountry. A clinical response was defined as a 50% or greater reduction in P ANSS score. Thenumber of responders and the CGI scores in each treatment group was compared using theCochran-Mantel-Haenszel tests for general association. The compliance rating scale scores ineach group were compared using the Yan Eletern test.

4. Detailed Review of the Sponsor's Individual Study Results

4.1 Study RIS-USA-79

4.1.1 Subject Disposition

In total, 397 subjects were enrolled into RIS-USA-79 from 32 sites in the USA: 395 subjectreceived trial medication (192 risperidone and 203 haloperidol). At the time of stopping the trial,78 subjects were stil being treated with risperidone and 46 were stil receiving haloperidoL.

During the audit ofRIS-USA-79, the sponsor determined that the data from Site #8 did not meetthe Janssen Pharmaceutical quality standards, so the analyses were performed with and withoutSite #8. Since the sponsor mentioned that the results from the analyses with or without this sitewere found generally consistent. In the sponsor's study report for efficacy analyses, the efficacydata without Site #8 were presented but with brief summaries of the all site population analyses.

7

After excluding data from Site #8, there were total 365 subjects in the efficacy analyses. Thegroups of risperidone and haloperidol had 177 subjects and 188 subjects, respectively.

4.1.2 Premature Discontinuations

As shown in Table 2, more subjects discontinued treatment with haloperidol (77.3%) than wasthe case for risperidone (59.4%). This was principally due to a higher rate of relapse in thehaloperidol group (23.2%) than in the risperidone group (14.6%).

Table 2. Summary of Reasons for Premature DiscontinuationReasons for Discontinuation Risperidone Haloperidol

N=192 N=203

n % n %Chose to discontinue 35 18.2 36 17.7Relapse 28 14.6 47 23.2Adverse event 24 12.5 30 14.8Lost to follow-up 10 5.2 10 4.9Poor compliance 6 3.1 is 7.4Administrative 6 3.1 2 1.0Other 3 1.6 4 2.0Inadequate response 2 1.0 7 3.4Ineligible 0 0 3 1.Intercurrent ilness 0 0 2 1.0Abnormal c1inicallaboratorv result 0 0 1 0.5Total Number ofSubiects Discontinued 114 59.4 157 77.3

4.1.3 Demographics and Baseline Characteristics

The demographic characteristics were well balanced between the treatment groups. Overall31.1 % of the patients were female; 47.6% were white and 36.5% were black. Their meanage:!SD was 40.5:!1 0.56 years old (median age 39 years and range 20 years to 65 years old).Their mean weight:SD was 82.8:!19.74 kg and their mean height:SD was 171.3:!lO.96 cm.Table 3 provides a by treatment summary of the demographic and Baseline characteristics for the395 patients who were randomized and received trial medication.

Table 3. Baseline Dèmographic Characteristics including data from Site #8Demographic Data Risperidone Haloperidol

N=192 N=203

n % N %Sex Female 57 29.7 66 32.5

Male 135 70.3 137 67.5Race White 91 47.4 97 47.8

Black 72 37.5 72 35.5Hispanic 24 12.5 29 14.3Other 3 1.5 2 1.0Oriental 2 1.0 3 1.5

8

Mean SD Mean SDAge (years) 40.8 10.72 40.1 10.43Weight (kg) 82.0 19.62 83.6 19.87Height (cm) 171.3 11.75 171.3 10.18

The without Site #8 baseline demographic characteristics by treatment groups were shown inTable 3.1. Overall 30.1% of the patients were female; 47.7% were white and 35.6% were black.The mean age:SD was 40.2::10.51 years old. Their mean weight:SD was 82.8::19.11 kg andmean height:SD was 171.3::11.01 cm and.

Table 3.1. Baseline Demographic Characteristics without data from Site #8Demographic Data Risperidone Haloperidol

N=I77 N=188

n % N %Sex Female 50 28.2 60 31.9

Male 127 71.8 128 68.1Race White 81 45.8 93 49.5

Black 67 37.9 63 33.5Hispanic 24 13.6 27 14.4Other 3 1.7 2 1.0Oriental 2 1.1 3 1.6

Mean SD Mean SDAge (years) 40.3 10.62 40.1 10.43Weight (kg) 82.8 19.21 82.8 19.06Height (em) 171.5 11.87 171.2 10.16

4.1.4 Primary Efficacy Parameter

Since the sponsor determined that the data from Site #8 did not meet the Janssen Pharmaceuticalquality standards, they only presented the data analyses for the primary and secondary efficacyvariable excluding data provided by this site in their study report.

According to the sponsor's study report, subjects in the risperidone treatment group had a longermean time to relapse (452.2::17.7 days) than the subjects in the haloperidol treatment group

(391.3::21.8 days). However, as the last observations for both treatment groups were censored,the mean time to relapse may be underestimated.

The 25th percentile for time to relapse was 292 days for the risperidone treatment group and 113days for the haloperidol treatment group. Median time to relapse was 406 days for subjects onhaloperidol, but there were too few relapsing subjects in the risperidone group to determine amedian time to relapse. There were insufficient numbers of relapse subjects in either treatmentgroup to calculate the 75th percentile relapse rates.

9

Using the stratified logrank test, there was a statistically significant difference, in favor ofrisperidone, between the survival distribution ofthe 2 treatment groups (p=O.OOI). The Kaplan-Meier survival probability plot of time to relapse is shown in Figure 1.

Figure 1. Kaplan-Meier Survival Probabilty plot of time to relapse

(Note: The upper curve is for Risperidone group and the lower curveis for Haloperidol group)

q

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1LQ)inD-II to

16 ci0:Olc:

ëii!D

Õ ''

~ ci

:eII.J0è: N

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0ci

0 200 400 600 800

Time (days)

The one year relapse rate (probabilty of relapse), based on the Kaplan-Meier estimates, were29% and 45% for the risperidone and haloperidol groups, respectively. The Kaplan-Meierestimates for the relapse rates were consistently lower in the risperidone group than in thehaloperidol group at 6 month (19% versus 30%), 1 year (29% versus 45%), and at the end of thetrial timepoints (34% versus 60%).

In order to verify the results for subjects with C :J for those withschizophrenia, the analyses were repeated in each diagnosis of the population. These results areshown in Table 4.

Among the patients with diagnosis of schizophrenia (n=200), there was a statistically significantdifference between the two treatments, in favor ofrisperidone, in the survival curves (p=0.007).In the risperidone group, the Kaplan-Meier estimates of relapse rates, i.e., the probability ofrelapse, was 19%,28% and 34%, at 6 months, 1 year and at the end of the trial, respectively.These rates were consistently lower than those in the haloperidol group (32%, 47% and 59%respectively)

c .=i

10

~ JC. J Nonetheless, th~-Kaplan-M~ier estimates of

relapse ratesat 6 months, 1 year and at the end ofthe trial were 19%,34%, and 34%, in the risperidone group,which were consisetntly lower than the corresponding rates in the haloperidol group (21 %, 37%and 62%, respectively).

Table 4. Analysis of Time to Relapse in Patients with Schizophrenia and SchizoaffectiveDisorders

Risperidone Haloperidol P-valueAll diaenoses N=I77 N=188 0.001 b

Number (%) relapsed 45 (25.4%) 75 (39.9%)Mean (SE) time to relapse* 452.2 (17.7) 391.3 (21.8)Relapse rate at 6 montha 19% 30%Relapse rate at 1 yeara 29% 45%Relapse rate at end of triaia 34% 60%25% Quartile (days) 292.0 113.050% Quartile (days) ---- 406Schizophrenia N=144 N=156 0.007°Number relapsed 36 (25.0%) 62 (39.7%)Relapse rate at 6 montha 19% 32%Relapse rate at 1 yeara 28% 47%Relapse rate at end of triaia 34% 59%25% Quartile (days) 293.0 109.050% Quartile (days) ---- 385

L ~- -

*The estimated means were biased, since the last observations were censored."Kaplan-Meier estimates of relapse rate (probabilty of relapse).bStratified log-rank test controllng for investigator and sex.C ~4,1.5 Secondary Effcacy Parameters

4.1.5.1 Relapse Rates (The Crude Rates)

Of365 patients in the trial, 41 patients (23.2%) in the risperidone treatment group and 65patients (34.6%) in the haloperidol treatment group relapsed by the end ofthe first year(p=0.009). At Endpoint, 45 patients (25.4%) on risperidone treatment and 75 patients (39.9%) onhaloperidol had relapsed (p=0.002).

Similar significant differences (p=O.OII) were apparent in subgroup analyses of patients withschizophrenia. C. .J11

c =lTable 5. Relapse Rates in Subjects with Schizophrenia and Schizoaffective Disorders

Relapse Rates Risperidone Haloperidol P-value

n I % N I %All diagnoses N=I77 N=1881 Year 41

I

23.2 65

I34.6 0,009

Endpoint 45 25.4 75 39.9 0.002

Schizophrenia N=144 N=1561 Year 32

I

22.2 56

I

35.9 0.016Endpoint 36 25.0 62 39.7 0.011

C ,~

As it was shown in Table 6, most ofthe patient relapses were due to the psychiatrichospitalization and clinical deterioration.

Table 6. Summary of the Number of Subjects Discontinuing due to Relapse by Criteria ofR ie apse

Criteria for Relapse Risperidone HaloperidolEntire Trial N=I77 N=188

n % n %Psychiatric hospitalization 20 44.4 36 48.0Significant clinical deterioration (a CGI-C score of 6) 16 35.6 22 29.3Increase in level of care was necessar and increase in P ANSS 8 17.8 14 18.7score of 25% compared with Baseline, or an increase of 10points if the Baseline score was 0(40

Emergence of clinically significant suicidal or homicidal 1 2.2 3 4.0ideationTotals 45 75

4.1.5.2 Positive and Negative Symptom Scale (PANSS)

There was no significant difference in baseline measures of positive, negative or affectivesymptoms on the PANSS (see Table 7).

The mean shift from baseline on the P ANSS total score at endpoint was better in the risperidonetreatment group (-3.15), compared to + 1.79 in the haloperidol treatment group. At endpoint,there was a significant difference in favor of risperidone over haloperidol for the total P ANSSscore (p..O.OOl) and for both the positive (p=0.005) and negative (p=0.004) subscales. A similaradvantage for risperidone was also seen on the anxiety/depression (p=0.005) and disorganizedthoughts (p=0.014) subscales ofthe PANSS. The between treatment difference for uncontrolledhostility/excitement was on the borderline of significance (p=0.076).

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Table 7. PANSS results - data from Site 8 were excludedP ANSS Risperidone Haloperidol P-value

N Mean SE N Mean SE

Total PANSSBaseline 170 65.06 184 67.38 0.162Year 1 91 -7.13 1.40 69 -5.74 1.99 0.261

Endpoint 170 -3.15 1.42 184 1.79 1.28 .-0.001

Positive SymptomsBaseline 171 18.58 186 19.15 0.364Year 1 92 -2.77 0.56 69 -1.71 0.79 0.212Endpoint 171 -1.56 0.49 186 -0.24 0.46 0.005

Negative SymPtomsBaseline 172 16.98 186 17,80 0.172Year 1 92 - 1.59 0.54 69 -1.55 0.73 0.835Endpoint 172 -0.53 0.41 186 0.77 0.46 0.004

DisorganizedThoughts 171 14.97 184 15.38 0.478

Baseline 93 -1.47 0.34 69 -1.26 0.48 0.322Year 1 171 -0.79 0.36 184 0.17 0.35 0.014Endpoint

UncontrolledHostilitvÆxcitementBaseline 172 6.04 186 6.26 0.321

Year 1 93 -0.43 0.22 69 -0.38 0.29 0.655Endpoint 172 0.24 0.23 186 0.73 0.20 0.076

Anxietv/DepressionBaseline 172 8.45 186 8.76 0.425Year 1 93 -0.96 0.26 69 -0.84 0.40 0.167Endpoint 172 -0.52 0.29 186 0.24 0.24 0.005

Note: 1. Mean values at Baseline are the mean score, all other means are the mean change from Baseline,non-imputed.

2. p-value determined by an analysis of covariance model with Baseline as a covariate and treatment,investigator, and sex as factors.

Table 8 shows us the test results for different diagnosis groups. As it was observed in Table 8,the test results obtained in the subgroup of patients diagnosed as having schizophrenia give usthe same conclusions as those described for the population as a whole except the item ofdisorganized thoughts. The treatment of risperidone showed significantly more effective thanhaloperidol at reducing total PANSS scores as well as those relating to positive symptoms,negative symptoms and anxlety/depression.L ~c :i risperidone was found to be significantly more effectivethan haloperidol at reducing the total P ANSS score as well the subscale scores relating tonegative symptoms and disorganized thought in this subgroup analyses.

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Table 8, P ANSS results in subjects with schizophrenia 1: JPANSS Mean change at endpoint versus baseline

Schizophrenia ,

Risperidone Haloperidol p-valueN=144 N=156

Total PANSS -3.01 2.22 0.004(n=139) (n=152)

Positive -1.56 0.05 0.008Symptoms (n=140) (n=154)

Negative -0.51 0.73 0.026Symptoms (n=141) (n=154)

Disorganized -0.61 0.17 0.146Thoughts (n=140) (n=152) /UncontrolledHostilty/ 0.41 0.77 0.251Excitement (n=141) (n=154)

Anxiety/ -0.75 0.36 ~0.001Depression (n=141) (n=154) -Note: 1. N denotes the total number of patients in the group but n denotes the number of patients used to compute

the mean change from Baseline to the endpoint.2. p-values were from the analysis of covariance test of no difference between treatment groups with baseline

score as covariate.

4.1.5.3 Clinical Global Impression (CGI/CGI-C)

The CGI ratings at Baseline were comparable in both groups, however, during double-bltndtreatment, symptoms decreased more with risperidone treatment than with haloperidol treatment.Table 9 shows that the overall CGI ratings at endpoint were significantly better with risperidonethan with halopericdol (p~O.OOI), with 59.5% ofrisperidone-treated subjects compared with36.4% of the haloperidol group being minimum improved, much improved or very muchimproved.

T bl 9 CGI C fr B l Y 1 dEd .a e - om ase me to ear an n lpomtRisperidone Haloperidol p-valuen % n %

Year 1 N=93 N=70Very much improvement 7 7.5 4 5.7 0.006Much improvement 28 30.1 14 20.0Minimum improvement 27 29.0 19 27.1Unchanged 28 30.1 27 38.6 ,

Endpoint N=173 N=187Very much improvement 12 6.9 8 4.3 ~0.001Much improvement 41 23.7 25 13.4Minimum improvement 50 28.9 35 18.7Unchanged 35 20.2 59 31.6

14

4.1.5.4 Cognitive Assessments

There were no statistically significant differences between treatment groups and no significantcha~ge from Baseline for any of the cognitive assessment scales.

4.1.5.5 Drug Attitude Inventory

The items 'Good things about medication outweigh the bad' (p=0.033) and 'medications makeme feel more relaxed' (p=0.037) were statistically significantly favorable to risperidone atendpoint.

At Weeks 2 and 4, and at endpoint, statistically significantly (p=0.038, 0.044, and 0.001,respectively) greater number of haloperidol subjects rated their medication as causing 'weird likea zombie' symptoms. At the same visits, significantly more subjects receiving haloperidol thanrisperidone (p=0.04, -:0.001, and -:0.001, respectively) stated that their medication caused'tired/sluggish' feelings:

4.1.5.6 Quality of Life

The Delight-Terrible scales of the QOLI showed a trend in favor ofrisperidone (p:S0.10) atEdpoint on the majority of scales. There were statistically significant differences betweenrisperidone and haloperidol in 'general satisfaction,' 'daily activity and functioning,' 'family,'and 'social relationship' categories (Table 10).

Table 10. Changes in Quality of Life AssessmentsQuality of Life Mean change from baseline to endpoint

Risperidone Haloperidol P-value.N=I77 N=188

General satisfaction 0.28 -0.11 0.011Daily activity and functioning 0.93 -0.29 0.018Family relationships 0.39 -0.50 0.005Social relationships 0.54 -0.37 0.002

4.1.5.7 Health Care Resource Utilization

The majority of parameter were significantly different from Baseline at mose assessments. But,no comparison between treatment groups was performed.

4.1.6 Sponsor's Efficacy Conclusion

Risperidone was statistically significantly more effective than haloperidol in maintaining clinicaleffcacy over a 1- to 2-year period in stable subjects with schizophrenia or schizoaffectivedisorder. Long-term treatment with risperidone was associated with superior symptomimprovement, including statistically significantly superior efficacy against haloperidol onpositive, negative, and affective symptoms.

15

The finding that risperidone is superior to haloperidol, which has itself been shown to beeffective in preventing relapses, indicates that risperidone has an important role to play in thelong-term treatment of schizophrenia.

4.2 Study RIS-INT-6

4.2.1 Subject Disposition

A total of 190 subjects were recruited into the study from 48 centers in seven countries: 91

subjects were assigned to treatment with risperidone and 99 received haloperidoL.

4.2.2 Premature Discontinuations

A significantly greater proportion of subjects discontinued treatment with haloperidol (62subjects; 63%) than was the case with risperidone (47 subjects; 52%; p=0.04 CMH test).

The primary reason for discontinuing therapy was insufficient efficacy (including psychoticrelapse) which accounted for 20 subjects (22%) in the risperidone group and 32 subjects (32%)in the haloperidol group.

4.2.3 Demographics and Baseline Characteristics

The subjects in the risperidone group comprised 57 male and 34 female patients with a medianage of33 year (range: 18 to 65 years). The haloperidol group included 58 male and 41 femalepatients with a median age of34 years (range: 18 to 65 years).

4.2.4 Primary Efficacy Parameter: Withdrawal for Adverse Events and/or Psychotic Relapse

In total 25 subjects (27%) withdrew from risperidone and 26 (26%) withdrew from haloperidolbecause of adverse events and/or psychotic relapse. Regarding the time to discontinuation, 25%of the subjects in the risperidone group dropped out by Day 141 (lower 95% CI: Day 78)whereas 25% of the subjects in the haloperidol group had done so by Day 100 (lower 95% CI;Day 36). The difference between the groups was not statistically significant (p=0.457, Gehan'sgeneralized Wilcoxon test stratified for country).

4.2,5 Secondary Efficacy Parameters

4.2.5.1 PANSS Scores

Baseline P ANSS scores were found to be comparable in the two groups of subjects. However,subjects treated with risperidone tended to have a significantly greater change in total PANSSscore at end point (-24.6) than those receiving haloperidol (-18.9; p=0.059 ANOV A). Thecorresponding changes in the total P ANSS-derived BPRS scores were -14.0 for risperidone and-10.8 for haloperidol (p=0.061).

16

As shown in Table i 1, the mean changes in total P ANSS scores were progressive throughout the52 week evaluation period in both groups of subjects,

Table 11. P ANSS resultsPANSS Risperidone Haloperidol p-value

N Mean SE N Mean SETotal P ANSS

Baseline 91 95.8 1.91 99 96.8 1.91 0.059Year 1 45 -39.0 3.90 36 -38.3 4.26Endpoint 91 -24.6 3.08 99 -18.9 2.89

Positive SubscaleBaseline 91 22.8 0.67 99 23.5 0.72 0.082Year 1 45 -11.7 1.21 36 -11.9 1.37Endpoint 91 -7.9 0.92 99 -6.6 0.94

Negative Subscale

Baseline 91 26.0 0.76 99 26.5 0.76 0.103Year 1 45 -8.7 1.19 36 -8.1 1.43Endpoint 91 -5.9 0.87 99 -4.6 0.77

Thoughts DisturbancesBaseline 91 13.4 0.43 99 14.2 0.42 0.1 05Year 1 45 -6.7 0.71 36 -6.9 0.75Endpoint 91 -4.6 0.54 99 -4.2 0.52

HostilityBaseline 91 8.5 0.32 99 8.7 0.33 0.410Year 1 45 -3.9 0.47 36 -3.8 0.71Endpoint 91 -2.2 0.43 99 -1.7 0.47

Anxiety/DepressionBaseline 91 11.6 0.34 99 11.1 0.39 0.291Year 1 45 -4.7 0.60 36 -4.5 0.54Endpoint 91 -2.5 0.47 99 -1.6 i 0.45

Note: Mean values at Baseline are the mean score, all other means are the mean change from Baseline.

4.2.5.1 Clinical Global Improvement (CGI)

The mean baseline values ofthe CGI were 5.0 for risperidone and 5.1 for haloperidoL. Thecorresponding mean scores at end point, were 3.8 and 4.1, respectively (p=0.103, CMH test).

The mean overall CGI change score versus baseline were also comparable in the two treatmentgroups at endpoint (3.1 for risperidone and 3.2 for haloperidol, p=0.357).

4.2.5.2 Quality of Life

The mean total Quality of Life score at baseline was 47.0 for risperidone and 45.4 withhaloperidoL. There was a significantly greater improvement in the risperidone group for the

17

cluster 'instrumental role functioning' (+2.3) than was apparent in the haloperidol group (+ 1.0;p=0.037). The changes from baseline to end point on the other subscales were similar in the twotreatment groups.

4.2.5.3 Compliance Rating Scale

The majority of patients in both groups (77%) had 'good' or 'very good' scores on thecompliance rating scale at endpoint. There was no significant between-group difference at anytime point during the study.

4.2.6 Sponsor's Efficacy Conclusions

Because of the choice of comparator, as well as other design considerations, the conclusions thatcan be drawn from the results ofRIS-INT-6 are somewhat limited. Nonetheless, the findings arenot inconsistent with those of RIS- USA -79, and support the conclusion that risperidone is aneffective antipsychotic for the long-term treatment of schizophr~nia.

5. Statistical Reviewer's Findings and Comments

1. When the sponsor's study RIS-USA-79 was evaluated, this reviewer did not find anyinconsistent test results with the sponsor's. For the primary endpoint and the secondaryendpoints, this reviewer was able to exactly duplicate the sponsor's results.

2. £. :i the sponsor had statistically significant test results shown on the primary and some

secondary efficacy endpoints in the whole study population (i.e, patients with eitherschizophrenia or schizoaffective disorder) for Study RIS-USA-79C- JC _ JC :J. Table 12 shows thesummary of p-values for all study patients, only schizophrenia patients r: JC .:

Table 12. Summary ofp-values for the Whole Study Population and Sub-populationsEffcacy variables All Diagnoses Schizophrenia 'r- --

(N=365) (N=300) , =Primary Variable. Time to Relapse (days) 0.001 0.007 -Secondary Variables. NuIIber of patients with Psychotic Relapse

---- at 1 year 0,009 0.016---- at Endpoint 0.002 0.011

. P ANSS, change from Baseline to Endpoint---- Total PANSS score ~0.001 0.004---- Positive symptoms 0.005 0.008--- Negative symptoms 0,004 0.026---- Disorganized thoughts 0.014 0.146---- Uncontrolled hostility/excitement 0.076 0.251---- Anxiety/depression factor 0,005 ~0.001 '- -

18

3. Except for two diagnosis groups, the sponsor did not perform any other subgroup analysis.

They did mention in the protocol that" Ifthe size ofthe study permits, relevant demographicor baseline value-defined subgroups wil be examined for unusually large or small responses,e.g., comparison of effects by age, sex, and race." However, it is not clear what they mean'permits' .

Since there are reasonable number of patients in both female and male groups as well aswhite and black race groups, it would be interested to know the analysis results among thesesubgroups. This reviewer performed subgroup analyses similar to what were shown inTable 4 and summarized results in Tables 13 and 14.

As we can observe in Table 13, the risperidone was shown statistically significantly moreeffective than haloperidol for male patients but not for female patients. Since the risperidonetreatment group did have smaller relapse rates than the haloperidol treatment group forfemale patients, the lack of ability to detect differences between these two groups may be dueto the insufficient sample size.

According to Table 14, there existed statistically significant difference between therisperidone and haloperidol treatment groups on both white and black patient groups.

Table 13. Subgroup Analyses for GenderRisperidone Haloperidol P-value*

Female Patients N=50 N=60 0.1280Number relapsed 12 (24%) 22 (36.7%)Relapse rate at 6 montha 11% 24%Relapse rate at 1 yeara 32% 38%Relapse rate at end of triaia 32% 58%25% Quartile (days) 292 20050% Quartile (days) ---- 590Male Patients N=127 N=128 0.0012Number relapsed 33 (26%) 53 (41.4%)Relapse rate at 6 montha 22% 33%Relapse rate at 1 yeara 28% 49%Relapse rate at end of triaia 34% 61%25% Quartile (days) 282 10750% Quartile (days) ---- 375* p-values were obtained from the log-rank test without any stratification,

19

Table 14. Subgroup Analyses for Race of White and BlackRisperidone Haloperidol P-value*

White Patients N=81 N=93 0.0133Number relapsed 25 (30.9%) 39 (41.9%)Relapse rate at 6 montha 27% 39%Relapse rate at 1 yeara 35% 59%Relapse rate at end of triaia 41% 70%25% Quartile (days) 154 7950% Quartile (days) ---- 278Black Patients N=67 N=63 0.0333Number relapsed 13 (19.4%) 23 (36.5%)Relapse rate at 6 montha 12% 17%Relapse rate at 1 yeara 26% 35%Relapse rate at end of trial

a 26% 55%25% Quartile (days) 348 22550% Quartile (days) ---- 582*p-values were obtained from the log-rank test without any stratification,

4. To check ifthe early discontinued patients influence the test results for the primary endpoint,time to relapse, this reviewer treated them as failures by reversing their censoring variablesand reran the analyses. The p-value shows .0008. So, it assures us the robustness ofthe testresult for the primary endpoint. The Kaplan-Meier Survival curves for this case is shown inthe following figure.

Figure 2. Kaplan-Meier Survival Probability plot of time to relapse after reversing censoringvariables for the early discontinued patients. (Note: The upper curve is forRisperidone group and the lower curve is for Haloperidol group)

C!

coQ) cii!u.Q).,0.m lD~ c:Clcë¡¡mÕ ."~ ci:em.con. N

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oci

a 200 400

Time (days)

600 800

20

Yeh-Fong Chen, Ph.D.Mathematical Statistician

Concurrence:

Dr. Jin Dr. Chi

cc: NDA 20-272 (S-008)HFD-120/Dr. KatzHFD-120/Dr. Laughren

HFD-120/Dr. Andreason

HFD-120/Mr. Hardeman

HFD-700/Dr. AnelloHFD-710/Dr. Chi

HFD-710/Dr. JinHFD-710/Dr. Chen

This review consists of21 pages. MS Word: C:/yfchen/nda20272_s008/review,doc

21


/s/Yeh- Fang Chen12/20/01 10: 03: 07 AMBIOMETRICS

Kun Jin12/20/01 11:21:05 AMBIOMETRICS

George Chi12/21/01 11:44:39 AMBIOMETRICS


APPLICATION NUMBER:

NDA 20-272/8-008 & 20-588/8-004

ADMINISTRATIVE and CORRESPONDENCEDOCUMENTS

EXCLUSIVITY SUMRY for NDA # 20-272 SE8-008 & 20-588 SE8-004Trade Name Risperdal Generic Name risperidoneApplicant Name: Johnson & Johnson Pharmaceutical Research &DevelopmentHFD- 120Approval Date 3/3/02PART I: IS AN EXCLUSIVITY DETERMINATION NEEDED?

1. An exclusivity determination will be made for all originalapplications, but only for certain supplements. CompleteParts II and III of this Exclusivity Summary only if youanswer "YES" to one or more of the following questions aboutthe submission.

a) Is it an original NDA? YES/ / NO /i/

b) Is it an effectiveness supplement? YES / ~/ NO / /

If yes, what type (SEl, SE2, etc.)? SE8

c) Did it require the review of clinical data other than tosupport a safety claim or change in labeling related tosafety? (If it required review only of bioavailabilityor bioequivalence data, answer "NO.")

YES / ~/ NO / /If your answer is "no" because you believe the study is abioavailability study and, therefore, not eligible forexclusivity, EXPLAIN why it is a bioavailability study,including your reasons for disagreeing with any argumentsmade by the applicant that the study was not simply abioavailability study.

If it is a supplement requiring the review of clinicaldata but it is not an effectiveness supplement, describethe change or claim that is supported by the clinicaldata:

Page 1

d) Did the applicant request exclusivity?

YES / / NO /~/

If the answer to (d) is "yes," how many years ofexclusi vi ty did the applicant request?

e) Has pediatric exclusivity been granted for this ActiveMoiety?

YES / / NO /~/

IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GODIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.

2. Has a product with the same active ingredient (s), dosage form,strength, route of administration, and dosing schedulepreviously been approved by FDA for the same use? (Rx to OTe)Switches should be answered No - Please indicate as such).

YES / / NO /~/

If yes, NDA # Drug Name

IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THESIGNATURE BLOCKS ON Page 9.

3. Is this drug product or indication a DESI upgrade?

YES / / NO /--/

IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THESIGNATURE BLOCKS ON Page 9 (even if a study was required for theupgrade) .

Page 2

PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES(Answer either #1 or #2, as appropriate)

1. Single active ingredient product.

Has FDA previously approved under section 505 of the Act anydrug product containing the same active moiety as the drugunder consideration? Answer "yes" if the active moiety(including other esterified forms, salts, complexes, chelatesor clathrates) has been previously approved, but thisparticular form of the active moiety, e.g., this particularester or salt (including salts with hydrogen or coordinationbonding) or other non-covalent derivative (such as a complex,chelate, or clathrate) has not been approved. Answer "no" ifthe compound requires metabolic conversion (other thandeesterification of an esterified form of the drug) to producean already approved active moiety.

YES / ~/ NO / /

If "yes," identify the approved drug product (s) containing theactive moiety, and, if known, the NDA # (s) .

NDA # 20-272 Risperdal tablets

NDA # Risperdal oral soln20-588

NDA #

2. Combination product.

If the product contains more than one active moiety (asdefined in Part II, #1), has FDA previously approved anapplication under section 505 containing anyone of the activemoieties in the drug product? If, for example, thecombination contains one never-before-approved active moietyand one previously approved active moiety, answer "yes." (Anactive moiety that is marketed under an OTC monograph, butthat was never approved under an NDA, is considered notpreviously approved.)

YES / / NO / /

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If "yes/" identify the approved drug product (s) containing theactive moietyi andi if known i the NDA # (s) .

NDA #

NDA #

NDA #

IF THE ANSWER TO QUESTION i OR 2 UNER PART II is II NO i II GODIRECTLY TO THE SIGNATURE BLOCKS ON Page 9. IF "YES1 II GO TO PARTIII.

PART III: THREE-YEAR EXCLUSIVITY FOR NDA i S AN SUPPLEMENTS

To qualify for three years of exclusivity i an application orsupplement must contain "reports of new clinical investigations(other than bioavailability studies) essential to the approval ofthe application and conducted or sponsored by the applicant."This section should be completed only if the answer to PART II iQuestion i. or 2 i was "yes."

i. Does the application contain reports of clinicalinvestigations? (The Agency interprets "clinicalinvestigations" to mean investigations conducted on humansother than bioavailability studies.) If the applicationcontains clinical investigations only by virtue of a right ofreference to clinical investigations in another applicationianswer "yes i" then skip to question 3 (a). If the answer to3 (a) is "yes" for any investigation referred to in anotherapplication, do not complete remainder of summary for thatinvestigation.

YES I ~I NO I_I

IF II NO i II GO DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.

2. A clinical investigation is "essential to the approval" if theAgency could not have approved the application or supplementwi thout relying on that investigation. Thus, theinvestigation is not essential to the approval if i) noclinical investigation is necessary to support the supplementor application in light of previously approved applications(i.e., information other than clinical trials, such asbioavailability data, would be sufficient to provide a basis

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for approval as an ANDA or 505 (b) (2) application because ofwhat is already known about a previously approved product), or2) there are published reports of studies (other than thoseconducted or sponsored by the applicant) or other publiclyavailable data that independently would have .been sufficientto support approval of the application, without reference tothe clinical investigation submitted in the application.

For the purposes of this section, studies comparing twoproducts with the same ingredient (s) are considered to bebioavailability studies.

(a) In light of previously approved appiications, is aclinical investigation (either conducted by theapplicant or available from some other source,including the published literature) necessary tosupport approval of the application or supplement?

YES / ~/ NO /__/

If "no," state the basis for your conclusion that aclinical trial is not necessary for approval AN GODIRECTLY TO SIGNATURE BLOCK ON Page 9:

(b) Did the applicant submit a list of published studiesrelevant to the safety and effectiveness of this drugproduct and a statement that the publicly availabledata would not independently support approval of theapplication?

YES / ~/ NO / /(1) If the answer to 2 (b) is "yes," do you personally

know of any reason to disagree with the applicant'sconclusion? If not applicable, answer NO.

YES / / NO /~/

If yes, explain:

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(2) If the answer to 2 (b) is "no," are you aware ofpublished studies not conducted or sponsored by theapplicant or other publicly available data that couldindependently demonstrate the safety and effectivenessof this drug product?

YES I I NO ILl.

If yes, explain:

(c) If the answers to (b) (1) and (b) (2) were both "no,"identify the clinical investigations submitted in theapplication that are essential to the approval:

Investigation #1, Study # RIS-USA-79

Investigation #2, Study #

Investigation #3, Study #

3. In addition to being essential, investigations must be "new"to support exclusivity. The agency interprets "new clinicalinvestiga.tion" to mean an investigation that 1) has not beenrelied on by the agency to demonstrate the effectiveness of apreviously approved drug for any indication and 2) does notduplicate the results of another investigation that was reliedon by the agency to demonstrate the effectiveness of apreviously approved drug product, i. e., does not redemonstratesomething the agency considers to have been demonstrated in analready approved application.

(a) For each investigation identified as "essential to theapproval," has the investigation been relied on by theagency to demonstrate the effectiveness of a previouslyapproved drug product? (If the investigation was reliedon only to support the safety of a previously approveddrug, answer "no.")

Investigation #1 YES I

YES I

I

I

I

NO I

NO I

I

I

NO ILI

Investigation #2

Investigation #3 YES I

If you have answered lIyes" for one or moreinvestigations, identify each such investigation and theNDA in which each was relied upon:

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NDA #NDA #NDA #

Study #Study #Study #

(b) For each investigation identified as "essential to theapproval," does the investigation duplicate the resultsof another investigation that was relied on by the agencyto support the effectiveness of a previously approveddrug product?

Investigation #1 YES /

YES /

/

/

/

NO / /

/

NO /~/

Investigation #2

Investigation #3 YES / NO /

If you have answered "yes" for one or moreinvestigations, identify the NDA in which a similarinvestigation was relied on:

NDA # Study #

NDA # Study #

NDA # Study #

(c) If the answers to 3 (a) and 3 (b) are no, identify each"new" investigation in the application or supplement thatis essential to the approval (i. e., the investigationslisted in #2 (c), less any that are not "new") :

Investigation #-l, Study # RIS-USA-79

Investigation # , Study #

Investigation # , Study #

4. To be eligible for exclusi vi ty, a new investigation that isessential to approval must also have been conducted orsponsored by the applicant. An investigation was "conductedor sponsored by" the applicant if, before or during theconduct of the investigation, 1) the applicant was the sponsorof the IND named in the form FDA 1571 filed with the Agency,or 2) the appl icant (or its predecessor in interest) providedsubstantial support for the study. Ordinarily, substantialsupport will mean providing 50 percent or more of the cost ofthe study.

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(a) For each investigation identified in response toquestion 3 (c): if the investigation was carried outunder an IND, was the applicant identified on the FDA1571 as the sponsor?

Investigation #1

IND # 31-931 YES / ~/ NO / / Explain:

Investigation #2

IND # YES / / NO / / Explain:

(b) For each investigation not carried out under an IND orfor which the applicant was .not identified as thesponsor, did the applicant certify that it or theapplicant i s predecessor in interest providedsubstantial support for the study?

Investigation #1

YES / __I Explain NO / __I Explain

Investigation #2

YES / / Explain NO / / Explain

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(c) Notwithstanding an answer of "yes" to (a) or (b), are. there other reasons to believe that the applicantshould not be credited with having "conducted orsponsored" the study? (Purchased studies may not beused as the basis for exclusivity. However, if allrights to the drug are purchased (not just studies onthe drug), the applicant may be considered to havesponsored or conducted the studies sponsored orconducted by its predecessor in interest.)

YES /__/ NO /~/

If yes, explain:

Steven D. Hardeman, R. Ph. 3-21-02

Signature of PreparerTitle: Senior Regulatory Proj ect Manager

Date

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Steve Hardeman3/21/02 11:45:06 AMSigned for Dr. Katz

...,è'~ ".V1:.

( -l~~~,::~t-DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Serviæ

Food and Drug AdministrationRockvile, MD 20857

NDA 20-272\S-008NDA 20-588\S-004

Johnson & Johnson Pharmaceutical Research & Development L.L.CAttention: Susan J. MerchantManager, Regulatory Affairs1125 Trenton-Harbourton RoadTitusvile, New Jersey 08560-0200

Dear Ms. Merchant:

We acknowledge receipt of your April 22, 2002 submission containing final printed labeling inresponse to our March 3, 2002 letter approving your supplemental new drug applications forRisperdal(I (risperidone) Tablets and Oral Solution.

We have reviewed the labeling that you submitted in accordance with our March 3, 2002 letterand we find it acceptable.

However, we note that under CLINICAL TRILS section, "short-term efficacy" subheading ismissing and it needs to be added at the next printing.

If you have any questions, call Ms. Melaine Shin R.Ph., Regulatory Management Officer, at 301-594-5793.

Sincerely,


Russell Katz, M.D.DirectorDivision of Neuropharmacological Drug ProductsOffice of Drug Evaluation ODE ICenter for Drug Evaluation and Research


/s/Russell Katz1/14/03 08: 50: 41 AM

Division of Neuropharmacological Drug Products

REGULATORY PROJECT MANAGER REVIEW

Application Number: NDA 20-272/SE8-008NDA 20-588/SE8-004

Name of Drug: RisperdalCI (risperidone) Tablets and Oral Solution

Applicant: Johnson & Johnson Pharmaceutical Research & Development L.L.C.

Material Reviewed:

· NDA 20-272/SE8-008 (FA): April 22, 2002· NDA 20-588/SE8-004 (FA): April 22, 2002· AP letter based on submitted labeling text: March 3,2002

Baclmround and Summary:

NDA 20-272/S-008 and NDA 20-588/S-004 were approved on March 3, 2002 whichincorporated the addition of safety and efficacy information in the long-term treatment ofschizophrenia. The sponsor submitted the FPL on April 22, 2002.

Review:

1. Under CLINICAL TRILS section, subsection heading "short-term effcacy" is missing.

2. Under STORAGE AND HANDLING section, the following were added:

7503220Ds Patent 4,804,663February 2002~J anssen 2000

RISPERDALCI tablets are manufactured by:JOLLC, Gurabo, Puerto Rico orJanssen-Cilag, SpA, Latina, Italy

RISPERDALCI oral solution is manufactured by:Janssen Pharmaceutica N.V,Beerse, Belgium

NDA 20-272/S-008 & NDA 20-588/S-004 page 2

RISPERDALQD tablets and oral solution are distributed by:Janssen Pharmaceutica Products, L.P.Titusvile, NJ 08560

Conclusions:

Upon discussion with the Clinical Team Leader, Dr. Thomas Laughren, I recommend that weissue an Acknowledge & Retain letter and ask the sponsor to provide the corrected version(addition of "short-term efficacy" subheading) ofFPL at the next printing.

Melaine Shin, RPh.Regulatory Management Officer

Robbin Nighswander, R.Ph.Supervisory Regulatory Health Project Manager

This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.-------------------------------------------------------------------------------------------------------~-------------/s/

Melaine Shin12/19/02 11:26:52 AMCSO

Robbin Nighswander1/2/03 10: 22: 56 AMCSO

/'''-~~ .øl,:::ir- DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug AdministrationRockville, MD 20857

NDA 20-272

Janssen Research FoundationAttention: EDWARD G. BRANN1125 TRNTON-HARBOURTON ROADP.O.Box 200

TITUSVILLE, NJ 08560

Dear MR. BRANN:

We refer to your new drug application (NDA) submitted under section 505(b) of theFederal Food, Drug, and Cosmetic Act for RiSPERDAL (RISPERIDONE) TABLETS. .

We have received your submission of May 11, 2000, reporting on your postmarketingstudy commitment to assess the long-term safety and efficacy of risperidone.

We conclude that study RIS-USA-79, entitled "A Comparison of Risperidone andHaloperidol for Prevention of Relapse in Subjects with Schizophrenia and

Schizoaffective Disorders" fulfills the above postmarketing study commitment.

This completes all of your postmarketing study commitments acknowledged in our letterof December 29, 1993.

We encourage you to propose labeling changes based on the results of study RIS- USA -79in a prior approval NDA supplement.

If you have any questions, call Steven D. Hardeman, RPh., Senior Regulatory ProjectManager, at (301) 594-5525.

Sincerely,

RUSSELL KATZ, M.D.

DIRECTOR

DIVISON OF NEUROPHARMACOLOGICAL

DRUG PRODUCTS

OFFICE OF DRUG Ev ALUA nON I

CENTER FOR DRUG Ev ALUA nON AND RESEARCH

/s/Russell Katz3/28/01 03: 25: 34 PM

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