—___fl
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -346
`
`MEDICAL REVIEW
`
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`1
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`age
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`ALKERMES Exh. 2019
`
`Luye V. Alkermes
`IPR2016-1096
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`REVIEW AND EVALUATION OF CLINICAL DATA
`
`Application Information
`
`NDA:
`Sponsor:
`Clock Date:
`
`21-346
`Janssen
`8/31/01
`
`Drug Name
`
`Generic Name
`Trade Name
`
`Risperidone Long Acting Injection
`Risperdal CONSTA
`
`Drug Characterization
`
`Pharmacological Category: Benzisoxazole derivative
`Proposed Indication:
`Schizophrenia
`NDA Classification:
`3-S
`Dosage Forms, Strengths, and Routes of Administration:
`Injection 25mg, 37.5mg and
`50mg
`
`Reviewer Information
`Clinical Reviewer: Earl D. Hearst, M.D.
`Review Completion Date: 10/01/03
`
`,.u
`mi
`
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`
`—
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`EXECUTIVE SUMMARY: ................................................................................... .. 3
`BACKGROUND ................................................................................................. .. 3
`ORGANIZATION OF THE RESPONSE TO THE ACTION LETTER .................. .. 4
`J&JPRD STUDIES ........................................................................................... .. 13
`CLINICAL STUDIES ........................................................................................ .. 14
`ESTIMATE OF EXPOSURE TO RISPERDAL CONSTA ................................. .. 14
`COMPLETED CLINICAL STUDIES DATA ....................................................... .. 16
`ONGOING EXTENSION CLINICAL STUDIES ................................................. .. 22
`OTHER NON-IND CLINICAL RESEARCH STUDIES ...................................... .. 31
`
`POSTMARKETING EXPERIENCE .................. U. ............................................ .. 36
`OVERVIEW OF THE LITERATURE SEARCH ................................................. .. 43
`LITERATURE SAFETY RESULTS .................................................................. .. 43
`SUMMARY OF EVENTS OF INTEREST ......................................................... .. 43
`SUMMARY AND CONCLUSION ..................................................................... .. 44
`APPENDIX .....................................................
`................................................ .. 45
`TABLE OF STUDIES ....................................................................................... .. 46
`REFERENCES FOR EFFICACY ..................................................................... .. 48
`
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`EXECUTIVE SUMMARY:
`
`. _ _
`
`The sponsor has previded a summary of published and unpublished literature
`that makes a persuasive case for the usefulness and need of Risperdal Consta.
`The safety data updated in this submission is similar to that of the original NDA
`for Risperdal Consta. No new pattern of events was uncovered that would alter
`the risk/benefit profile of Risperdal Consta as pesented in the original NDA. From
`a clinical viewpoint | recommend that Risperdai Consta be approved.
`
`I . REVIEW:
`
`BACKGROUND
`
`Johnson & Johnson Pharmaceutical Research 8. Development (JaJPRD),
`submitted a New Drug Application for RlSPERDAL CONSTA (NDA 21-346). a
`long-acting injection formulation of risperidone, in the treatment of schizophrenia
`On August 31, 2001.
`
`The Division of Neuropharmacological Drug Products (DNDP) notified
`J&JPRD on June 28, 2002 that the application for RlSPERDAL CONSTA
`was not approvable under Section 505(d) of the Act and 21 CFR 314.125(b).
`Three Pharmacology/Toxicology deficiencies were cited in the letter as the
`primary factors influencing the decision by the Division to not approve NDA 21-
`346: (1) differences in the tumor profiles in the 24-month carcinogenicity studies
`with RlSPERDAL CONSTA and RlSPERDAL tablets; (2) no reproductive
`toxicology studies with RlSPERDAL CONSTA; and (3) no data to support that
`impurities
`“
`were qualified in the oral nonclinical studies.
`The Division elaborated further by concluding. “These findings would preclude
`approval of this application in the absence of any demonstration of a ciinical
`advantage of this product".
`
`J&JPRD met with DNDP on July 26. 2002 to discuss plans to address each
`of the pharmacology/toxicology issues cited in the Action Letter and to
`initiate discussion regarding the clinicai benefit of RISPERDAL CONSTA
`J&JPRD again met with DNDP on February 25, 2003 to discuss plans for the
`complete response to the Action Letter. Three main topics were discussed at
`the meeting: (1) the potentia! clinical benefit of a long-acting intramuscular (IM)
`formulation of an atypical antipsychotic; (2) nonclinical studies that would be
`submitted in the complete response to address pharmacology/toxicology issues
`raised in the Action Letter; and (3) plans to conduct an embryofetal toxicity study
`with RlSPERDAL CONSTA.
`
`Following a presentation of the potential clinical benefit of RlSPERDAL
`CONSTA, the Division agreed that there is a potential clinical benefit of a
`depot atypical antipsychotic and suggested that the complete response should
`contain a detailed review 6f the existing data for IM depot and oral
`formulations that make a compelling argument for improved compliance and
`
`3
`
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`decreased relapse of psychotic symptoms with depot antipsychotics. The
`Division further agreed to consider approving RISPERDAL CONSTA
`without a complete resolution of the carcinogenicity findings in rat if the
`data demonstrate that the M depot formulation provides clinical benefit.
`J&JPRD provided alist of nonclinicai studies that would be included in the
`complete response to address the pharmacology/toxicology deficiencies cited
`in the Action Letter. In addition to these studies. the Division requested
`summary and individual data listings for the incidence of adrenomedullary
`findings (including adrenal pheochromocytoma) from the oral
`carcinogenicity study in rat. The Division noted that if J&JPRD proposed
`strain or substrain differences as an explanation for the differences in tumor
`profiles between the oral and IM depot studies, it would be important to
`provide data by which to compare the relevance of each strain or substrain
`for assessing human risk.
`
`At the February 25, 2003 meeting, the Division stated their position that the
`complete study report for the IM depot embryofetal developmental toxicity
`study should be submitted to NBA 21-346 prior to approval. However, the
`Division agreed to consider the potential for a clinical benefit when making a
`decision as to the need for the embryofetal developmental toxicity study
`prior to approval. The Division further agreed to continue discussions related
`to the design of the embryofetal toxicity study at a later time.
`
`At a teleconference held on March 25, 2003 with J&JPRD and Dr. Lois
`Freed. Pharmacology/'l'oxicoiogy Reviewer for DNDP, the following
`agreements were reached on the design of the embryofetal toxicity study:
`
`-Dr. Freed agreed that the 80 mglkg dose was too high because it
`impairs mating, and suggested that J&JPRD consider a dose
`between 20 mglkg and 80 mg/kg. An additional dose-ranging
`study will be conducted to evaluate possible higher doses than
`20 mg/kg.
`‘
`
`-A third dose (below 20 mg/kg) group will be added to the study.
`
`-An oral treatment group is required to provide a reference to the
`previous study with RISPERDAL. tablets (NDA 20-272). in addition to
`agreements reached on the design of the study. J&JPRD agreed to include a
`proposal in the complete response regarding the timing of the submission of the
`embryofetal toxicity study.
`
`Organization of the Response to the Action Letter‘
`
`This document contains the responses from J&JPRD to issues identified by
`DNDP in the Action LetterLgated June 29, 2002, for RISPERDAL
`CONSTA, (NDA 21-346, submitted August 31 ,' 2001). The organization
`
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`and content of the response reflect recommendations made by the Division at
`meeting held on February 25, 2003 and at a teleconference held on March 25,
`2003.
`
`Clinical response:
`
`We have previously acknowledged a clinical need for a long acting injectable
`form of risperidone. We asked the sponsor to summarize and provide
`documentation to support this belief. The sponsor supplies 64 research papers
`supporting their position. There are reference links to refer the reader to the
`literature papers that supportthe following points.
`l have included the references
`in the appendix to this review. Several papers are summarized below.
`
`Mentschel, Leucht, and Kane have recently completed an unpublished meta-
`analysis involving studies of at least 10 months in duration comparing long-acting
`v5 oral antipsychotics. Overall relapse rates on oral medications were 45%
`compared with 30% on depots, with an absolute risk reduction of 14% and a
`relative risk reductEOn of 32% (p=0.002). See studies beiow:
`
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`

`Reviews of adherence suggest nonadherence rates of 26% with depot
`medication and nonadherence rates of 40 to 50% with oral medication. The use
`
`of long-acting injectable antipsychotics appears to increase adherence by
`between 10 and 40%. See below.
`
`Young, Zonana and Shepier, Bull Am Acad Psy Law 1986 This paper compared
`5 studies with depot medication to 23 studies of oral meds regarding adherence.
`
`John L. Young, MD; thwart! V. 20mm. MD; and Lynn Shaping, fl!)
`
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`

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`Remington and Adams, Can. J. Psy, 1995 See below.
`
`Conduslons
`
`Our undersiznding of depot neuralepfitcs has pmgressed
`cmsiderably over the years. and a number of conclusions
`embedmwn m theamentbodyol’evidenee.
`i. Depot neurolepucs represent an attentive but likely
`underutillud alternative to oral agents. parfitatlarly in the
`United States.
`2. Depot Demolepiics offer distinct afivmmges associated
`with unavailability and titration of action. Yet, they also
`have disadvmtages such as dose titration.
`3. Relapse rates are diminished with depot as compared to
`oral neurolcptlca. but not In the extent that might be
`antleipaled.
`d. Depoteeumleptlcsaremtapam'lheydoemenm
`compliance. although they do permit belle:-
`documentation ofnoncempllance in a way that can help
`distinguish it from treatment resistance.
`5. Depots appear equally effective in terms of clinical
`Immense. and they do not appear to have a mate: risk of
`side-effects.
`
`6. The conversion from oral to depot neurolepfics is not
`well established fur any of the depot nanoleptiu. and is
`Influenced, at least in part, by the recent trend towmls
`lower Wellness.
`7. Plasma lewls for depots correlate better with dose than
`with clinical response or sideeeffeets.
`In the face of dimielshing health cue dollars.
`deinsfixmionalizan‘on and greater emphasis on outpatient
`programs. depot neuroleptics are likely to take on a more
`important mic in the long-term autumn: of schizopleenia.
`To this end, we need In expand our knowledge of depot
`ncumlepties. particularly in terms of pharmacokinetlcs.
`dosing and clinical demographics. In light of the
`development of newer oral neurolepties with atypical
`features. it will also be important to pursue the developmnl
`of depoxs which can offer these same clinical advamages.
`
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`Cramer and Rosenheck, Psychiatric Services 1998
`
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`A recent unpublished meta-analysis found a 23% risk of relapse with first-
`generation medications compared with a 15% risk with second- generation
`medications (p=0.0001), Kane, JM et al
`
`Abstract:
`
`Objective: The objective was in perform a systematic review and meta-analysis of the
`
`pmnlial of the new generalion antipch drugs (NA) to improve adherence and
`
`decrease relapse was in patients with schizophrenia.
`
`Mm Randomizul, controlled trials comparing NA with placebo end/or conventional
`
`antipsychotics were identified. Dam on relapse. general We! failure and drop-outs
`
`due to adverse events were extracted, and combined in a meta-analysis. Mg; Pew
`
`trials were availabie for each individual drug. therefore NA were analyzed as a group in
`
`an exploitative manner. The panalysis of six pimebo comparisons. involving a total of 983
`
`patients. clearly demnstrated that NA are effective for relapse prevention. Eleven studies
`
`with a total of 2032 patients provided comparative data on mlapsduemmm failure for
`
`new and conventions: anlipnychnties. The analysis revealed a modest but slalisiicaliy
`
`significam reduction in relapse rates and overall nutrient failure with the new drugs.
`
`Whether this advantage was partly mediated by improved adherence no treatment remains
`
`unclear. No significant superiority in mm; of fewer dropouts due to adverse events was
`
`found. Funhcmiom. a number of methodological problems were identified. Conciusions:
`
`Overall, the currently available data suggest a potenlial for the new drugs to reduce
`
`relapse rates. Methodological issues to be addressed in future trials include the choice of
`
`comparator. appropriate dosage, the application of clinically-relevant relapse criteria.
`
`monitoring of adherence, and the minimization of drop-outs.
`
`10
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`Correll, Leucht, and Kane have recently completed an unpublished meta-
`analysis indicating a clinically and statistically significant reduction in the risk of
`TD utilizing second-generation as compared with first-generation antipsychotics.
`Mean annual risk of TD for SGA==.91% vs. 6.2% for Haldol used as comparator in
`3 studies. See below.
`
`Abstract
`
`Background: Boscd on lower rates of acme cxtrapyramidat side effects compared to first
`
`genmatim antipsychotks (FGAS) and preliminary data. second generation antipsychotics ($6M) an:
`
`expected to also cause less tan-1hr: dyskinuia (TD). Methods: Systematic review of audits with SGAs
`
`tasting at year and reporting on new use: nl'TD nrdysldnesitt Results: In aim studies. MOS patients
`
`received mum: with ritperidtme (3 studies. infill). champion (1 studies 1.2610). quetinpino {2
`
`studies. 1:386), amisulpride (1 study. F331) or zipnsidone (1 study. 11:25?) for a weighted mean of 269
`
`days. Study designs were double-blind and mm (rial). opera-label extensions of double-blind
`
`morde trials (tr-ill. and openvlahel (11:2). (lithe four trials that trad a comparator (sit in dultr with
`
`schizophrenia—spectmm disorders). three used halnperidol (1:403) and on: placebo (11:71). PM: shards
`
`included adult: (n=t4l9. Imam age: 3'? years). one a mixed population (nzztl'i. mum age: 50 years). and
`
`tltrnt: exclusively patients 254 ycars (M479: mu age: 78 years). Th: weighted moan annual
`
`of
`
`T1) for 86A: was 0.91% (range: 0-2.l%) in adults. 6.8% in the mixed population. and 5.8% (range: 2.6-
`
`l3.4%) in tit: elderly. compared to 5.3% (range: 4.144%) in adults titrated with lmlopcridol.
`
`Conclusions: Results from nine tongqcnn studies support the notion that 36A: have a reduced risk for
`
`TD compared to FGAS. However. more carefully designed studies. Meally beyond one year and
`
`comparing dificmnl 50A; in KIA-naive paticnts. are needed to estimate tit: true rink. It would not. itme
`
`pmmattrr: for clinicians to considcr thcsc findings in making lot-ism maintain dtClSiGns.
`
`11
`
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`
`
`l have reviewed all the papers and agree that the following sponsor supplied
`conclusions are a fair presentation of the literature.
`
`Relapse in schizophrenia is serious. Relapse is characterized not only
`by decreased social and vocational functioning and increased
`caregiver burden, but also by homelessness, self-harm (including
`suicide), and aggressive or violent behavior. Moreover, patients with
`frequent relapse may accumulate morbidity in the form of residual or
`persistent symptoms and decrements in function from their
`premorbid status.
`
`60% to 75% of patients with schizophrenia relapse within 1 to 2
`years without antipsychotic medication. The nonadherence rate with
`oral medications in schizophrenia is on average 42%.
`
`Continuous medication reduces the risk of relapse to 20 to 30%.
`
`Patients without gaps in medication therapy have 2 to 4 times less
`risk of rehospitalization.
`
`Patients with a :30-day gap in medication therapy have >4 times the
`risk of suicide attempts.
`
`Depot antipsychotic treatment, a method of attaining continuous
`medication, has been shown to reduce relapse rates and
`rehospitalization to a significant degree compared with treatment
`using oral antipsychotics.
`
`Only first-generation antipsychotics (haloperidol and fluphenazine)
`are available in depot formulations for those patients who can benefit
`from treatment with a long-acting injectable antipsychotic.
`
`Risperidone long-acting injectable has been shown to be an effective
`and well-tolerated antipsychotic medication in both short— and long-term
`heahnent
`
`They conclude that Risperidone is the only second-generation antipsychotic with
`a long-acting injectable form in late—stage development, and therefore represents
`a unique and significant addition to the treatment armamentarium of
`schizophrenia and an important means for improving treatment outcomes.
`
`It is my belief that Risperdal Consta would be a useful addition for the treatment
`of schizophrenia and persuasive data has been provided by the sponsor;
`
`12
`
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`SAFETY DATA:
`
`This submission reports safety infomation for RISPERDAL CONSTA from
`15 May 2001 to 18 March 2003, as requested by the Division of
`Neuropharmacological Drug Products in a communication on 18 March 2003.
`
`ORGANIZATION AND DATA SOURCES
`
`Johnson and Johnson Pharmaceutical Research and Development (J&JPRD)
`provides the requested safety information in this submission. The information is
`organized as follows (i.e., completed J&JPRD clinical studies and ongoing
`J&JPRD sponsored clinical studies, other clinical research studies
`[medical affairs and others], postmarketing experience, and worldwide literature.
`The studies and other source information that contribute to this safety response
`are shown in Table 1 along with the number of patients exposed to RISPERDAL
`CONSTA and the design of the study, if applicable.
`
`Table 1: Sources ofSafgy [formation
`Study Nttmber
`Destgn
`
`Coplesed IMPRD Studies
`
`Number of
`RISPERDAL CONSTA
`«rated Patiems
`
`Randomized, open-label comparison in
`oiannpineu year treatment (3-month
`amiysis endpoint)
`Opal-label, switching from on?
`nemlepuccit month treatment
`Open-labs}. switching from typical depot
`neuroleplic; 3 momh treatment
`
`Open label extension of RESJ‘Nr-él and
`RlS-TNT-S'I
`Open label extension ethSthT-fiz and
`RlS-IN’F-SS
`Open label estimation of RISMSA-IZI
`Open tabs] extemisn uleS-USA-259
`
`309
`
`141
`
`[66
`
`806 '
`212 “
`
`fits-{N162
`
`RES-US$259
`
`luS-INT-BS
`
`Ongoing JJtJPRD Studies
`“3m”
`RJS-INT-SO
`
`242'
`RIS-USA-I96
`:5“
`RtS-USA-265
`1664‘
`Tom! Mann) Studies
`NA
`one: Clinical Resend: Stufllu ‘* Vaned
`NA
`Postmarkfllag Population
`NA
`
`NA\Vortdwldc Literature NA
`
`‘ Dan fiat RIS—IN’T—G} and IUS-USA-l‘h m.- cun'ulrnive from the clinical “than 3: of E3 Match 2003
`’ Dan for RisJNT—SO and RIS—USA»365 are wrtltlniv: fi-om firch databases as of l5 March 2003
`” Sum of”:an in le—lNr-hl. RIS-INT-b}. RJS-INT-ai RIS—USAJ96. and RES-USAA259. Paints in MS-
`INT-W and Rl3-USA-265 ttxe firefly imhtfld In the RISINTéZ, RIS-lNT-SS. and R]S~USA-259 MESS.
`" Spnmmd by Janna-Giza Mum: Am amps. 1mm Ham; Median Afi‘sin USA, mi 00m
`
`J&JPRD studies
`
`The safety information provided in this document from the J&JPRD clinical
`
`13
`
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`
`

`

`
`
`studies completed after the 4—month Safety Update Report was derived from
`the finalized/locked clinical databases.
`
`The safety information for the ongoing extension studies came from the
`phannacovigilance database (CiOMS Narrative/line listings) for RISPERDAL
`CONSTA up to 25 March 2003. In addition, some specific analyses (i.e.,
`exposure and discontinuations due to adverse events) for the ongoing extension
`studies were determined from the unlocked clinical databases as of 16-18 March
`
`2003 to provide the requested information. Therefore. the safety information from
`the ongoing studies is limited as of the cutoff date and as these studies are not
`finalized, is subject to potential future alterations.
`
`Other non-IND clinical research studies
`
`The safety data for this section was derived from a search of the
`phannacovigilance database that excluded all J&JPRD studies and all events
`unrelated to a clinical study. The majority of these studies were sponsored by
`Janssen-Cilag Medical Affairs Europe and Janssen Pharmaceutica, Medical
`Affairs Division in USA. As with all pharmacovigilance data, this information
`might be subject to change and is not as complete as the data derived from
`locked clinical databases. Exposure calculations included these types of studies
`as well as two J&JPRD sponsored studies (RlS-JPN-16 and RlS-SlV-101) that
`are being conducted in Japan.
`
`Clinical studies
`
`Since the submission of the 4-month Safety Update Report of 4 December,
`2001 (cutoff date 15 May 2001 ), three Phase 3 clinical studies were completed
`(RIS—lNT-85, RlS-USA-259 and RlS-lNT-BZ). in addition, 4 Phase 3 open-label
`extension studies (RlS—lNT-63, RlS-USA—196, RlS-INT~80, and RIS»USA-
`265) are ongoing and provide up to 3 years of clinical safety information.
`Two of the ongoing studies are extensions of the Phase 3 studies described in
`NBA 21-346 submission for RISPERDAL CONSTA. Study RlS—USA—1 96
`is the extension of RlS-USA—121; RlS-lNT-63 is the extension of RlS-lNT-61,
`and RlS-lNT-57. Data from these two open-label extension studies until the
`cutoff date of 15 May 2001 were presented in the 4-month Safety Update.
`
`Estimate of Exposure to RISPERDAL CONSTA
`(Clinical Studies)
`
`Table 14 summarizes patient-years of exposure in the studies conducted since
`the ISS plus the ongoing extension studies. In total, 1664 patients have been
`treated with RISPERDAL CONSTA in these studies for a total exposure of
`749456 days or 2053.30 patient-years.
`
`14
`
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`

`

`
`
`Table 14: Patient-yams ofExposure on RISPERDAL CONSTA:
`gaig Smdies or Studies Completed after 15 Max 2001
`Number
`Total
`
`Study
`All studies '
`mm
`rams-3°
`
`1117.80“
`INT-85
`USA-196‘
`USA-259
`
`Of
`Patients
`1664'
`309
`13116
`
`212
`166
`242
`141
`
`Biposure,
`Days
`749456
`79851
`5431779
`
`411096
`11221
`52889
`8823
`
`Patiem—yeam
`arExpesure
`2115330
`2111,77
`1439.31
`
`169.85
`3D.76
`144.90
`24.17
`
`35.04
`12791
`14
`USA-265“
`"
`INT~62, INT—85. and USA-259 are emulated studies. INT-53, INT—
`so, USAJ 96, and USA-265 are ongoing,
`” INT-3!) is the extension study ommsz and INT-85. USA-265 is
`the extension study of USA-259,
`fl Data for INT-63 and USAvl96 mcumulativc from the clinical
`databases as of 18 March 2003
`* Data tbr INT~80 and usmes are cumulative from 11:: clinical
`databasas as of HS March 2003
`‘ Sum ofpatienls in INT-62, TNT—63, INT-85, USA-196, and USA-
`259. Patients in INT-80 and USA-2155 are already included in 111a
`INT-62, INT-85. Md USA-259 tom's:
`
`Total exposure in the pooled, multiple-dose studies included in the ISS was
`230546 patient-days or 631.63 patient—years in 1499 patients. The multiple-dose
`studies included in the lSS were: RES-USA-121, RlS-INT-61, RIS—lNT-57, RIS-
`INT-31, RIS-lNT-32, RIS-SWE-17. RlS-lNT—63 is the extension study of RIS-INT-
`61 and RIS-lNT-57. RIS-USA-196 is the extension study of RiS-USA-121.
`The total number of patients treated with RISPERDAL CONSTA in clinical
`studies can be determined by adding the following to 1499:
`
`-The number of RISPERDAL CONSTA—treated patients in INT-62, INT-85,
`and USA-259 (309 + 166 + 141 = 616).
`
`-The number of patients in the placebo arm of USA-121 who entered USA—196
`(59).
`
`-The number of patients in the RISPERDAL oral arm of INT—61 who entered
`INT-63 (203).
`
`15
`
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`

`

`This gives a total of 1499 + 616 + 59 +203 = 2377 RISPERDAL CONSTA-treated
`patients with 230546 + 749456 = 980002 total days of exposure or 2684.94
`patient-years of exposure to RISPERDAL CONSTA based on
`clinical study databases as of 18 March 2003.
`
`Completed Clinical Studies Data
`
`Deaths (Completed Clinical Studies)
`
`There were 2 patients who died in the completed RISPERDAL CONSTA
`clinical studies since the 4-month Safety Update Report (Table 2). Both deaths
`occurred in the RISPERDAL CONSTA group in the one year comparative
`study RIS—lNT—62. In this study 6 patients died in the comparative olanzapine
`group. Only the RISPERDAL CONSTA treated patients will be described
`here.
`
`Study
`
`Table 2: Patients Who Died During the Completed Clinical Studlw
`l [US-IN'T-GZz lllS_-l.}S.1|’p259I RISJNT-BS !
`Placebo
`draw!
`—
`.-
`-
`u
`—
`
`RISPERDAL CONSTA
`MN [361
`2.309 (0.6)
`0309" (0)
`on.“ (o;
`once (a)
`0:615 (0)
`
`RlS—INT-62 “ (1 year)
`RJS-INT-tSZ ('3 months)
`Rls-USA—zso
`mums:
`Total (3 months)
`Pooled NBA completed
`studies‘ (3 months)
`' Include, warns over the entire 31mm
`’ Mum] numbczofpatiznm (309) chasm! haclnda 9 pmleamwtxo were onlde with final
`rispardnne and who discontinued during the tun-in period. Those 9 panama did m min
`RISPERDAL CONSTA“.
`‘ The completed reputed-1km stmbutnmgudglnalNDAdaatwmpmkd them 346mb
`emllpuinx {mum-:22. RS-mT-S‘L RIS‘N'LEL RBJNT.31, RIB-3W3”. ills-N132)
`
`"1071 L0)
`
`611499 (0A9
`
`Neither of the deaths in the RISPERDAL CONSTA group were considered
`related to study medication (Table 3) nor did they occur by the 3-month
`endpoint (Table 2). No patients died in either RIS-USA-259 or RIS-INT-85.
`Both patients, who died in RIS-INT—62, were women. One patient (CRF ID
`A30074, 50-years-old). who had been administered RISPERDAL CONSTA
`50 mg/biweekly with 21 injections, was hospitatized for “weight loss” and
`“dysphagia”, and was diagnosed with “esophageal carcinoma". She
`
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`
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`

`subSequently died from the esophageal cancer. Patient CRF ID A30074 (55—
`years-old), who had received 16 injections of 50 mg/biweekly RISPERDAL
`CONSTA died ("accident") in a fire. Both causes of death were considered
`by the investigator not to be related to study medication.
`
`Table 3: Cause and Rtean ofDeaths in the Committed Sundias
`{IRIS-NLthi RES-US$259: RIS-tNT-SS!
`Age
`Cause of Death
`
`Patient it)
`
`Relatedness‘
`
`Not related
`
`Nam refitted
`
`55
`
`A30074
`
`RIS-INT-fiz
`
`Esophageal
`F Esle
`cancer
`carcinoma
`Accident
`Death
`F
`50
`RIS—INT—él
`M0775
`“ Rcimedncss as reported by the investigtortmd confirmed hytha sputum:
`
`Serious Adverse Events (Completed Clinical
`Studies)
`There was a similar incidence of serious adverse events reported with
`RISPERDAL CONSTA in the Phase 3 completed clinical studies compared
`to that reported with RISPERDAL CONSTA and placebo treatment in the
`ISS of the NDA (Table 4). SAEs are mainly psychiatric in nature with no unusual
`pattern to the occasional medical SAE.
`
`Table 4: l’atiems With Serious Adverse Events During the Completed Clinical Studies
`(RlS-NT-EQ, RIS-USA-259, RlS—lNT-ssi
`
`Study
`
`'
`
`RiS-lNT-t'fl ( I yenr)‘
`
`RlS-lNT-él {3 maths)
`RJS-USA-ZIS‘)
`
`RlS—iNT-SS
`Total (3 months)
`
`Placebo
`
`MIN {‘55)
`
`-—
`
`—
`-
`
`—
`-
`
`RISPERDAL CONSTA
`
`NN [93)
`
`73/309 (25.2)
`
`4189.9” (133)
`22,841 (15.6)
`
`14! 166 (8.4)
`77f616 {12.5)
`
`E" (I?
`
`Pooled Nil-t completed
`511mm: (3 month 5)
`includes ewuls over the min: period
`‘
`the mini sunburn-I:pr (309)du¢smm:lu§e 5| pattierttsahnaummly mudwithrxal
`’
`rispemlum and wins dis-matinee! (hinting mar-B: yet-ind. Times 9 palitmisdifl not receive
`RISPERDAL CONSTA“!
`ND». that mm pooled fin.- the 3-month endpoint
`‘ The mpll'led reputed-dune nukes m the
`(RJS'U'MAZI, RPS-[N L57, Euerr-6I, RIS-iNT-Bl, RM\\‘E-l?, ins—mum
`
`“TIN” (1 L8)
`
`17
`
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`

`
`
`A higher incidence of SAEs in the psychiatric disorder category was noted in the
`RIS-INT- 62. Two patients (RlS—iNT~62) died due to a serious adverse event and
`12 patients discontinued treatment due to a serious adverse event. in addition,
`narratives for all serious adverse events for these studies are provided and i
`have reviewed these.
`
`Table 5: Serious Adverse Events in 2 or More Patients in any Stud: (Eggplant Clinical Studies)
`RISPERDAL
`REPERDAL
`RISPERDAL
`CONSTA
`comm
`CONSTA
`RIS—iNT-SS
`Ins-USA4593
`RiS—INT-éll
`(N =- 309)
`{N =~ 165)
`(N r- Hi)
`um (96)
`NM (96)
`MN (93)
`
`Adverse event
`Preferred term
`
`78 {25.2)
`
`14 (8.4)
`
`22 (15‘s)
`
`9{ 6,4)
`
`9 (5-4)
`1 (0.6)
`1 {0.6)
`
`o a
`
`2 (1.2)
`
`44 {142)
`17 (5.5)
`7 (13)
`6 {1.9)
`4 1 LS)
`3 l 1.0)
`3 {1.0)
`2 {0.15)
`2 (0,6)
`2 (0.1?!
`2 (0.6}
`2 (076)
`2 (0,6)
`
`Any Serious Adverse Event
`Psychiatric disorders
`Psychosis
`Suicide all-erupt
`Anxiety
`injury
`Drug abuse
`Agitation
`Depression
`Alcohol problem
`Depression aggravated
`immnia
`Manic martian
`Medication error
`Paranoid reaction
`
`3 includes events era that crttin: smdypuiod
`
`Serious Adverse Events of Potential Clinical interest
`RlS-INT-62
`
`in RIS—lNT-BZ, the serious adverse events of potential clinical interests were
`tardive dyskinesia (1), hyperglycaemia (2), convulsions (1). and myocardial
`
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`
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`

`

`
`
`infarction (1). These events are briefly summarized here by the sponsor. None of
`these patients died as a consequence of the serious adverse event.
`
`Tardive Dyskinesia
`Patient CRF ID A3031? [age 44 yrs]. had the serious adverse event of
`“dyskinesia tardive". She had a known history of experiencing tardive
`dyskinesia. Her starting study dose was RiSPERDAL CONSTA 25 mg
`biweekly and she completed the study on a dose of RISPERDAL CONSTA
`50 mg biweekly. The event was considered severe by the investigator and
`reported as doubtfully related to study medication. The event resolved without
`change to the trial medication and she