`
`Efects 0f the Clozapme Nanonal
`
`Ae’stry System on ' eldence of
`Deaths Related to Agr
`
`
`0 Gilbert Honigfeld, l’h.D.
`
`This material may be protected by Copyright law (Title 17 US. Code)
`
`Obiectioe:Clozapine is the only medication distributed in. the U.S through a
`national patient registry system that provides the medication only ifres‘ults of
`patients. weelIly blood tests show no evidence of significant white--blood cell
`suppression, an ell'ect that can be fatal if it progresses to advanced: agranulo-
`cytosis. This study assessed morbidity and mortality related to agmuulocyto-
`_ sis during the first five years of the national registry system. Mediorlsf Data
`hoIn-the national registry database maintained by the US. manufacturer of
`clozapi'ne was used to determine the level of treating systems adherenceto
`the mandated program of weekly white blood cell caunts, number of?In-
`stances in which clozapine treatment was denied becauseof-prio'r'dcterm1-
`nation of white blood cell suppression, and number ofeases oFaUr-Inuloeyto—
`sisanddeaths related to agrunulocytosis among treated: patlentsfromFebru-
`ary l990, when clmapine was mmmercia‘lly int:odnc’ed.m'the U.S.-through
`December 1994. The actual numbers of cases of agamflocytnsis andrelated
`deaths were compared with expected outcomes based on clinical.research
`done before the drug became available commercially. lie__'.s___ults: Approximate—
`ly 97 percent oftreating systems had a high overalllev'cl of adherenceto the
`registry protocol. [n 28 instances, the pretreatment authorization require
`ment resultedm denial of clozapine; after. additional data were considered,'
`15 of the patients were cleared for treatment. The actual inCidenccs: of332 I
`cases of agranulocytosis and 12 related deaths were lower than theexpectcd -
`995 cases and 149 deaths. Lodgings; The clozapine nanonalIregisnrysystem
`fostered early detection of white blood Cell suppression, prevented oc'l'real-
`ment withclozapine of- patients who had previously developedwhite blood
`cell suppression, and brought about lower than expectedratesofagranulocy—
`tosis and associated deaths. (Psycldatn'c Services 47:52—56, 1996)
`
`sideIn the Uoiled States They repre-
`sent potential candidates for treat-
`ment with clozapinc, an atvpical an—
`fipsychotic meditation indicated tor
`the treatment-resistant patient. As of
`December 31, 1994, a total of 99,502
`patients in the US. bad’heen exposed
`lochrmpine, andmorc than half of
`them remained'on the medication at
`that time.
`increased public interest in clum-
`pine and . enhanced Familiagiity of
`physicians with the medication V make
`it likely tlmt’therapwtic use ’or cl'oza-
`pinc will become more com-mun in
`"the coming ycaIs. However, clow—_
`pine use is associated with risk of
`,agmnulocytosis, a potentially fatal
`bleed disoId'er that
`is usually r1.
`vomible if detected early enough.
`Quotations-in social and medicalsup-
`port networks Fer persons with severe
`mental
`illness. underscore the need
`for lnoeechneslto help safeguaId this
`vulnerablepatient group From such
`udvcmc side effects.
`in keeping with genem‘l principles
`developed by the Food and Dung-Ada
`ministration. current procedunis lbr
`distribution of clozapine stipulate
`that the.mcdimtion'15 available"In the
`U. S. only through healment systems
`mgistercd with the national registry
`developed and maintained by the -
`U.S. mnufitenirer of clozapine. The I
`. purpose ofthe registry :is tel-enhance
`:paLier‘nt's-af‘éty by. facilitating» early dc-r
`faction. ofzpot'entially dangerous white
`blood- CCll suppression, ,diSpensing.
`the medication only to patients with
`current blood tests, delineating ra-
`
`Dr. Hmigfeld-is asmiate professor in the
`depamnem of psychiatry at the Robert
`Wumljohnwn Medical School of the Unit
`varsity of Medicine and Dentistry of New
`jersey, 675 Hoes Lane. Piscatatroy, New
`jersey 08854: He served as consultant to
`Samlu: Pharmaceuticals Corporation at
`theptime ofthe study.
`
`52
`
`AMN1011
`IPR 0fU.S. Patent No. 7,765,106
`
`n 1990,, approximately 5 million
`persons in the Uhitec'lStates'snfi
`feted frouI severe "mental disor-
`rlers. Of those, more than half, about
`2.5 million had Schizophrenia (1).
`Among persons with schizophrenia,
`between [0 and 30 percent do not re-
`spond adequatelv- to standard anti-
`psychotic agents because the: agents
`have suboptimal efficacy or: intolera-
`ble advexse ell'eeLs{2) Thus between
`250000 and 750000 treatment—rans-
`lanl persons with schizophrenia» to:
`
`Wm mm 0 January 1996 van No.1
`
`
`
`
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`Sponsihilities for patient monitoring,
`and eliminating as candidates for
`therapy anyone with a history of
`clozapine-relatcd white blood cell
`suppression.
`All potential candidates lbr the
`medication must. be cleared through
`the martian] registry to identify per-
`sons who have had signifiwnt clow—
`pine-related white blood cell
`sup—
`pression in the past and who should
`not receive the medication again be-
`cause of markedly increased risk of
`agranulOCYESis. White blood cell
`counts are normally 5.000 per cubic
`millimeter or greater. A white blood
`ml! count below 3,500 per cubic mil-
`limeter indicates leukopenin, a condi-
`[ion of mild white blood cell suppres-
`sion that is generally reversible upon
`intcrruption of clozapine therapy.
`Agnmulocytosis, a potentially fatal
`complication, is~indicated by a white
`blood cell count below 2,000 and de-
`
`fined by an absolute neutrophil count
`below 500 per cubic millimeter. Dis-
`continuation of clozapinc is mandato-
`ry for patients with agranulocytnsis
`because they are at high risk of dead:
`sectmdaiy to a wide range ol'oppor—
`tunisiic infections.
`
`The registry system requires all pa..-
`ticnts to have a baseline white blood
`
`cell count and weekly white blood
`cell counts throughout
`treatment
`with cloupiac and 161' four weeks af-
`‘ter treahneni ends. The medication. is
`dispensed weekly only to patients for
`whom data on current white blood
`
`cell counts are available. The registry
`system also outliucs thc I'csponsibilir
`ties of physicians, pharmacies, pa.-
`tients, and the medication} manufac—
`tutor and wholesale distributors in
`
`ensuring proper use of the medica-
`tion. Distribution of the medication is
`a.
`limited to registered pharmacies,
`which agree to follmv the
`no
`blood—no drug" guidelines.
`'li‘eahnent-systcms that fail to Fulfill
`their obligations to report results of
`weekly monitoring of patients white
`blood cell counts are contacted by na-
`tional registry stall; who explain the
`risksof clozupine therapy and the re.-
`quirements for weekly monitming.
`Subsequently, national registry stall
`Follow up with the physicians and
`pharmacists involved to verify that
`the-problems have been corrected.
`
`This paper discusses cliniml prac—
`tice related 'to the clovapinc national
`registry system, reports on the inci—
`dence of agrunuloqtttisis and agitatin-
`locytosis-related deaths from Febru-
`my. 1990, when clozapine was. first
`distributed commercially in the (3.5.,
`to. December 1994; andwnigraros this
`clinical experience with expectations
`based on premarlret clinical research
`projedtions.
`'
`This study does not addressldimct-
`ly the issue of optimizing the fre-
`quency and patternof white. blood
`cell
`testing, although the study's
`prospective analyses of rates ol'iagrau-
`ulocytosis and related deaths may
`have some bearing on this issue. ”the
`issue of whether formal alterations in
`
`the current requirement of weekly
`blood tests will result ingan incwpt—
`uhlc” increase in-rislr-is the firms of
`
`separate epidemiologic studies and
`will not be considered here. This
`
`study specifically addressed- current.
`quality assurance Emotions and
`sought
`to answer» the question of
`whether the month single, national
`registry ofall-‘clmapincuS-crs in the
`United States ‘liaslgenlmnced patient
`safety and contributed» to the savingof
`lives.
`I
`
`Methods
`
`Tbenaliorlqt wish-y
`All data aiming; to ' the clozapine, . na-
`tional' registry are cuiwrcdrintosan in—
`tcgrat'ed,
`computerized} database-
`maintainedby the manufactur’cn Pa-
`ticuts' computing records-arc- estab-
`‘lished during the initial phone ans
`made by physrcrans who arcsecli-ing
`clearance toi-stuitaspecific patient on
`cl’ozapine‘g The roan-HS include the
`patients identi J'iinig' code number
`mid initials, the physicians identifier-
`tion,
`the pharmacy’s identifiattion,
`daily dosage of clozupine in mil-
`ligmms,_ and white blond cell test
`dates-and results; '
`_
`These data are retained perma-
`nently, and .ndditional data are added
`each Week. As more than-60,090. pa-
`tients. ouri‘ently. rec-elite elorapimé,
`more than 500,090 separate fieldsof
`data- arc- ant tip-"die inauul'aiFItuer’s
`national registry each-.nrmk lln. addi-
`tion; separate . dstabdsm ,nrc ringin—
`tained in track all reported adherse
`reactions- Allsda'iu analyzed in thisire-
`
`PSYOIIAWMS o jamury 1996 W147 No.1
`IPR ofU.S. Patent No. 7,765,106
`
`port were drawn, from those sources
`and were provided by the inanulhc-
`turei;
`.
`We used these data to examine two
`process variables related to functions
`of the national registry system over
`the first five years ochinmercjal dis-
`tribution ofthe medication: level of
`
`adherence to the. registry protocol
`and denial of clinically inappmpriate
`retreatment. We also examined 'two
`outcome varial‘ilcs—nitc of agranulo—
`cy'tosis and rate of deaths related to
`agmmulocytosis—and compared those
`rates with the rates that wereprmlict—
`ed in analyses conchicted before the
`medication was conuncrcially distrib-
`uted in the US.
`
`Results and discussion
`Adherence to registry protocol
`The manufiicturer's educational and
`
`servicing activities, plus the potential
`threat of disciplinary action such- as
`dercgistmfiou as a clozapine treat-
`mcut system,,appmr to have resulted
`in generally high levels of adherence
`to weekly ‘n-ionitoring; Over the first
`five years of commercial distribution,
`of'clnmpine, more than 97"perceut of
`treating physicians and pharmacists
`managed their patients on clozapiuc
`it high overall levels of, adherence to
`the requirements'of the. product. 121-
`beling. The remaining 3-porceut have
`been clumcterized- by varying levels
`of pmtomloo‘mplianoe. National rog-
`istry data‘show thatu small percent:
`age ol'lreatruentxsystems periodically
`relax adherence to monitoring guide—
`lines.
`
`. Of themore than 10,000 physicians
`and plummcists currently involved in
`dis‘pcnsing‘clompinc, about 700 are
`contacted annually because of poor
`compliance in reporting data to the.
`natioual
`registry. National registry
`stall institute corrective actions. in-
`cluding ulucutimn clinical manage-
`ment training, and i nten‘sified-rcvicw.
`As new trcauncnt systems are added,
`and older one; only become large or
`complacent,
`this iterative process
`continues.
`
`.
`
`Between 1990 and 1992, analyses
`were performed to determine il'cor-
`rcctive actions by national-7 registry
`stall were associated with improved
`reporting of white blood cell count;
`In Mattll 1992 registry staff identi-
`
`53
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`Figure I
`
`Cumidative number of actual and predicted (ases of agmnulocytosis muting-pa-
`tients receiving clamping, 19904994l
`
`1,000
`
`800
`
`400
`
`5 z
`
`200 -
`
`0
`
`
`
`
`
`1990
`
`___
`1991
`
`
`1994 ..
`' Cumulnlive numbers nfmflmtsreceiving clamping were 9.807In 1990, 24.11.12In 199I. 4t246in I992.
`7-1,“?m was and 99,‘592m 1994. qulimd number ofcamwas calculated usinga conservative asu-
`matr: nl'n l mutant mu. nl'agmnnlocytosis, basalmmmrkct clinicalItsearch
`
`I 992
`
`1993
`
`i i i i r
`
`.
`
`f
`
`canto? the required records of white
`blood 'ccll counts._ One year later, in
`April. 1993, despite the addition of
`more than 400 patients. to the case-
`loads of these 100 physicians, for a to-
`tal $2.767 patients. the percentage of
`acceptable reports ofwhite blood cell
`counts by that: physicianshad- im-
`proved-to til percent.
`
`Denial of mmmmcnz
`Patients who have dismntinued “$6
`of clamping due to amnuloc'ytosis
`are at increased n's'lc ofdeveloping the
`rcactiwi again, generally earlier in
`therapy and in a more aggressive
`form, if Cl07apine is reinstituted (3).
`file-national registry clears each p0-
`tgn-h‘al candidate for clozapine Hiera-
`py to reduce the chances of reexpo-
`sure. to the mcdi'catiun by persons at
`increased risk of developingagmnu-
`locleIsis.
`l‘l‘elween- February 1-990 and Dc-
`ccmbcr 1994, them, were 28 instances
`in which Intential-cmididates. for the
`medication weredenied reheaunent.
`Nine inshutces involved eight pa-
`tients who had confirmed histories of
`white blood cell counts helow 2.000
`or absolute ncumehil counts below
`1.000. The nine instances included—
`two attempts to obtain retreatnmnt
`clearance for one patient In'four oth-
`er instances the regisby was tested-by
`the mmlaclurcr uSing idoxitification
`numbers of nun-reh-mmhle patients
`to assure that the system 'fimctioned
`appropriately. In the other 15 in-
`stances, retreahnent was denied until.
`closer - inspection revealed errors in
`data; these patients were Subsequent—
`1y cleared lot retreatmcnt.
`
`Rate of agramdocytosis
`Between February 1990' and Decom-
`her 1994, a total of 99,502 patients
`were exposed to clamping in the {1-5;
`and .had records (if more than One
`white blood cell count. During the
`first (silcndar year in thestudy period
`(February tluOugh Decemlicr 1990),
`9,807 patients wen: exposed to clum-
`pine. The cumulative total had in-
`creased to 24,112 patients by the end
`ofcalendar year 1991-, to 47246'at the
`e'nd of 1992, to 7'4,345 at the end of
`1993, and to 99,502 by. the end of
`1994.
`.
`Among the total (if-99,502‘patieuts
`
`fled physicians who had mare'tha‘n six
`patients for whom more than 10 pgr-
`cent of the required reports of white.
`blood cell counts in the latest three
`months were Itlissiug; 'meI-his list,
`the 100 physicians with the highest
`percentage of patients for Whom
`
`men: than 1.0 percent of the tepgrts
`were-misging were identified' At that
`time,those 100- physicians were re-
`sponsih'le for. 2,343:patients.
`Beforethe intervention by naIiOnal
`registry stafi; 582pcrccnt. 9591ng pa—
`tients-were missingmore than, 10pm;
`
`
`'Figure 2.
`
`Cumulative number of actual and predicteddeaths relatedto complications of
`agnmuloeytosis amendDpatic‘uls rmci‘ving clumping 1990—1994'
`160
`
`Npatients
`
`140
`
`
`
`1333
`
`
`' Cumulative iuunhc-s ofpaiienls lauvmgdtmmmr \Vlfl‘t‘ 9897 in:1990..24.1}2Eill“)9! 473-1671“ l$2..
`m.was cachIlaled using normative esti—
`74.34?“in 1993. and 99,502m 19.91Must-xi 'niinah‘er.‘
`trunks Ola lput-lucid rule ufngmnulmsfmsisand aI5.malt rat'c oFass'ociatcdmortality.'li'asal on pre-
`marluct.clinical research.
`
`54
`
`AMN10 1 1
`IPR ofU.S. Patent No. 7,765,106 -
`
`WTRICSERVICBS 6 January [996 “31.47 No.1
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`maze I
`Efl'ect’s ofactual and hylmthciic‘al rates oi'conipliance. ina'epoitirig ofwhiteblood
`cell counts on incidence nfagranulocytosis and related deaths among patients re-
` ceiving clamping
`
`figranulocytosis
`
`Rate of compliuum (96)
`
`Rate (%)1
`
`Ncases
`
`Death
`
`.
`Bate (fir?
`
`p
`. N cases
`
`' N pre-
`veritable
`deaths"
`
`Actual
`9010 100'
`30:90- 455 -
`Hmmflicflcal
`75 “I 90 ;,
`
`43 to 50
`
`38
`m.
`
`m
`
`L.m
`
`382
`l G
`
`597
`
`995
`
`3.!
`50.0
`
`in
`10.9
`l5.0
`
`1?.
`8
`
`'30
`30
`I49
`
`_
`-—
`
`m
`G8
`L37
`
`:‘x':
`
`l _\- use: among 99502 patients. the cumulative number of-patimits- imimlorl' in the national registry” from
`Feln'"nary 1990 through December 1994
`:-Ndeaths among N- cases: ofagranuloq-tosis
`3 (km-[ureawithN dad“ at 90 In 100 percent Lunlpflam’e'n1reporting
`4 Elle nmg99509. cases includedIn the xntionalregistw from Fdirmnv 1990 through ”member mil-1
`5‘ lutuumong patients treated when donpine was Em distributed commercially in Ftniandin i973
`
`duringthe. study: period, there were
`2,931 cases uf-leukopenia (crude inci—
`dence. rate. of 29.5 vporcen t),. 382 cases
`of agranulncvtosrs (38 percent), and
`£12 deadis associzitedwith agmnulocy-
`The rate , of
`iosis {lit-f2 percent).
`leuktpenia unriiirmsquilc closely to
`’ predictions based on prémarlret clini-
`cal researdui'approximately 2.5 to 3
`percent of all persons exposed to
`clo-mpine-
`'
`However, the crude rate ofagrauu-
`locytosis during the. studyperiod (38
`percent) wasless thanhalf that antic-
`ipalcd from.premarital: resmrch (l to
`2 percent). Figure l sboWs the annihil-
`uumber‘fof expected and actual cases
`of agranulocytosisvzover the study pe—
`riod. the expected number of cases
`
`was calculated conservativelx using
`the low/er percentage- estimate of l
`percent'basedon the .premarket clin—
`ical research. Because the rate. of
`leuko'pen'ia- was must-stem in‘ the pre-
`and postmarke‘t-data, the more favor-
`able postmarked findings on aganulti-
`cytosts appear to be theresult Of sys-
`tematic- monitoring, early detection of
`abnormalities in :whiite blood cell
`counts, prompt-1 reporting of - those
`counts to the national regisha'r. and
`prompt-discontinuation of el'ozapine.
`among; patients who were Vat risk ii):
`agranu-locytmis.
`
`Heath-rate
`
`lfk-spite intense monitoring 12 per-
`sons di'cdas a result of ag'mnulocyto-
`
`
`
`ruse:
`
`Prospecti'w: amdfsi‘s-of cfl'c‘cts of mics of compliance in reporting of white blood
`cell counts on incidence ofagmnulocytosis and related deathsamong 20,111) new
`patient: receiving clampine over a one-year. period
`
`
`Optinfistic scenario‘
`
`Realistic scenario’.‘
`
`i
`
`'
`
`
`N pre-
`N pre—
`Rate of
`Agimiulocytmis
`ventablc
`N
`[late of
`veritable
`N
`compli—
`.
`'
`deaths3 '
`deaths
`death (‘11)
`deaths-1
`darths
`anon ((1:1-
`Rate§(.%)
`N
`o
`2
`3.1
`o
`2
`901.. 1.00
`.33
`76
`4
`6
`. 5.0
`‘3
`4
`'75 tom.
`.GO
`1:91)
`14
`16
`10.0
`3
`5
`60.“...25
`7 3g
`‘ 1m
`
`23 p
`3—0
`(5.0
`4
`6
`'
`Gwen _
`. 1.00
`200
`‘ AW23.].percent tau-oldeifli among ram ofagmnulmytusis wgmHIm chin:nu‘mlx:r Infra-«s- a;
`mi-imns lchsofeomp'liance
`“ Assum page Mdeaflianmug mes ol- agmnutocytosisincreases as nIImb'r:rnfmsi:'3: increases with do
`«card levels: ofcompliamc »
`1 (0mmwithtwodeathsatfx) to’ 100 percent compliance in ramming
`
`I
`
`WWW o
`IPR ofU. S.
`
`Inryl996 V0147 No.1
`atentWNQ 7765 106
`
`sis-related complications between
`bebnrary 1990 and December 1994.
`Figure 2 shows the cumulative ex-
`pected and actual numbers of deaths
`related to agranulocytosis each calen—
`dar year during the study period. The
`expected death rate assumes a 1 per-
`cent mtc ofagranulOcytosis and an as-
`sociated mortality rate of 15 percent.
`This rate is consistent with museum—
`
`tive estimates lmsed on experience-
`abroad with .clmapine and on pub-
`lished researcher: Inianscrin, an anti-
`
`depisant that has leulmpenia as a
`potential adverse edect (4.5).
`The difl'crcncc between the pre-
`dicted and actual cumulative death
`
`'
`
`rates-— 149 predicted deaths com-
`pared with 12 actual deaths—sug-
`gests the benefits ofvrigorous patient
`monitoring. These data show that cur—
`rent medical practice and monitoring
`procedures have contributed sub—
`stantiaily toward saving the lives of
`many patients who require clumpinc
`therapy.
`Table 1 shows how patientsuwival
`might have been affected ovcr- the
`study period it' mrmitbring had been
`less rigorous. Actual clinical experi-
`ence in the US. from February 1990
`through December 1994 showed 90
`to 100 percent compliance with rc—
`portiug of white blood- cell counts. in
`that context, patients with agranulo—
`cytosis had an overall risk of tidal
`compliu'itions of 3.1 percent
`(12?.
`dentin among 382 cases. of agranulu-
`cyto'sis).
`At the other extreme are the initial
`findings on this topic from Fuihiud in
`1975—1976, wherein 50' percent rate
`of mortality emerged among patients
`whodcvdopcd agrauulocytosis (eight
`deaths among 16 cases 0F agrannlocy-..
`tests). Rates of White bleed cell moni—
`toring Were estimated tube 30 to 45
`percent. The outdated medical and
`monitoring conditions existing at» that
`time-clearly no longer apply; git/en
`the heigbtianed awareness of clump-
`inc and its therapeutic and adverse-
`eifects. However, hean the cur;
`rent US. experience. representing
`the highest level Of monitoring, and
`the early Finnish experience, once-an.
`interpolate intenncdialc-sccnarios of
`adequate, Eii'r, or poor levels of moni—.
`toring and the associated risk: ol’liztal
`Lemplicaiions of agianuiocytosis.
`
`55'
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`For example, a rate of compliance
`'with white blood cell monitoring of
`75 to 90 percent would be associated
`with a risk of fatal complications oFan
`Estimated 5 percent among patients-
`who developed agranuloéytosis,‘ a.
`monitoring rate of. 60 to 75.1pcrcent
`with an estimated 10 percent rate of
`fatal complications, and a monitoring
`rate of 45m 60 percent with an esti—
`mated '15 percent rate of Fatal compli—
`cations,
`the level recently' reported
`for deaths related to agnmulocyt’osis
`associated with mianserin (4). Thus if
`V monitoring standards in the US. had
`been less stringent between 1990 and
`1994-, between 30 and 149 deaths
`might have occurred. instead of the
`12 deaths that :mtnaily (xx-tuned.
`
`Prospa‘tive analyses
`Based on emiservative projections of-
`current-rates ol'accoss to clozapinc, at
`least zoom Americans per year are
`likely to be newly exposed to clbza-
`pine in the-coming years. If these pa—
`tientsare. treated .under-lcurrent mon—
`itoring conditions, about 76 patients
`(38 fiercent)» are likely to develop
`'agrunuliicytosis, and two patients are
`likely'tQ-dieof complications of arguin-
`ulooytosis(3 1: percent among agrann—
`locytosis cases) in each annual whorl.
`('iivenl'these rates, wlmt‘would hap-
`pen if-standard's For monitoring were
`loWered? Two principal scenarios,
`whoserate‘s areshown in 'iiible 2, can
`
`be considered. An optimistic scenario
`presumes that int-dim! pmtk-e has ad-
`vanced. enough that most cases of
`agranulocytosis.
`including sympto-
`nmtii: was, can be arrested without
`Eital' complicatidns'. Thus if one as—
`sumes that mieqnaey ofmonitoring has
`no bearing on fatal outcomes,
`two
`dentin» could he anticipated muong the
`next 20,000 new cit-minim patients if
`monitoring compliance remains at
`Curr-(mt levels.
`IF the rate of compli-
`ance drops, one will likely see an in-
`crease in the rate of agxmiulocytusis
`and an additional. two to four deaths.
`
`The second, more realistic scenario
`assumes that early detectirmrand con-
`tinued vigilance exert a favorable im-
`pact on the rate of agranulocytosis
`andthe rate of Fatalities. In this sce-
`
`nario, a wider range of outcomes can
`be pmjecred. and substantially poorer
`outcomes are likely.- l‘br example, the
`estimated risk of agranulucytosis
`would range From .381‘0‘ l percent and
`the rate ol‘fatnlities fi'vm Stu 15 per—
`cent. The projections shown in 12151.:
`2 stifle-st that if monitoring deterio-
`rates from current icvcl‘s, between
`fOur and 28 additional deaths may oc-
`cur among melt annual cohort of new
`patients.
`
`candusions
`
`appears to have contributed to reduc~
`ing mortality relrited to. cOmplimtions
`Ofagnmulocytosis substantially below
`projected rates dorivtxlfrorn premar-
`lret data. The rigorous safeguards} in
`place to maximize the opportunities
`for enriy detection of white bloodeoll
`suppression have been ossociated
`with liworablc outcomes in rates of
`
`both agranulocytosis and final compli-
`cations. Dmn‘eased vigilance would
`likely be msuciatcd with an increase
`in otherwise preventable deaths. 0
`
`Acknowledgments
`
`The author thanks Felix Aliellzino, M.D._
`and Sheila Whiter; M.D., of the drug reg-
`ishnlion and regulatory affilini
`-
`ment and Anthony Biuuuliini u the
`Clomril national registrynt Sandal Phar-
`maceutimls Corporation.
`
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`4. Adams PC; Mianseiin-imlueedngmuiquu
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`'
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`In the first five years of commercial
`distribution of clonapine in the us.
`the national clowpine registry system
`
`{.51
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`Coultcr DM, Edwards IR: MinnSerinnnd
`ng'mnulocytosis in New Zealand. Lancet
`336:785—757,
`l5l$Kl
`
`Psychiatric Services seeks expert reviewers in the following areas:
`
`OOutcome research, particularly in the area of psychopharmaoological treatment
`of mental disorders
`
`OBating scales for symptoms, outcome, and other aspects of treatment
`ODual diaglosis (mental illness and (lung abuse and mental illness and mental re-
`tardation)
`
`Psmirncssmws o 1211112171996 VoL47 - No.1
`
`O’Rnréfl psychiatric services
`{Patient and consumer perspectives and attitudes.
`
`Reviewers should be familiar. with-the-liternture in..tlwi_r areas of expertise,
`should have published in peer—reviewed-journa'ls, and should he Eimilinr with the
`content andfocus of Psychiatric Services.
`
`Prospective reviewers should send. a curriculum- vitzte, specifying man of in“—
`teiect, to. John A. Talbott, M11, Editor, Rsyd‘ziabw Services, A'P'A, 14th K Street,
`N.W,.Washi-ngton, DC. m5.
`
`5'6
`
`, AMN1011
`IPR ofU.S. Patent No. 7,765,106
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`_. January 1996 vol. 4-7 No-1—
`
`
`
`7
`
`
`
`Formgfiy tbspitnl and Cummntiiiyr'Psychiarry
`
`
`
`.
`, Ajoumal ofrhc
`'
`v. American Psychiatric
`
`,Asumiation
`
`
`Taking Issue
`
`7 How’rc WeW JobnATalbau, aw;
`
`Articles
`
`35 Gonffionsbfa Concurtent Rcvicwcr Pan! cum. MD.
`41 long-Tennlmm ofCIompinc andPsydio‘sodal Treatment on Psychiatric
`Syruptoms andCOgnic‘lve Functioning fem Grace, MD, Stephen B.Bel[u3,
`Pita, Michael I. Raulin, PhD" Marvin [Jim W} Barbara LPriesr,
`RN, Wktorflrenner; MA, K0113: Donnell}; PhD. Patricia Smith, RN, 1115.,
`and Satan 6mm, RN
`
`46 Efl'eccivenasof (lozapinc and aSooalImmmnggtamfor Seventy Disabled
`PmmimicWIS Anthony AMe‘ndmo, pm, Niels C'Bccb, 1421)., Paul
`Slave, 1’b.l)..]udifi5»=A.ris‘bet§ 0.0, Mark 513399.410? Mary Beth logue, MA,
`and Lechaklwia, MS.
`
`32 Efl'eccs of flu: Gloupine. National-WSW on Incidmce-of Dams-Related
`to-Agmnulocytosis ’ Cilmwuongrea P111).-
`
`57 Chmctensiics.m5cm'ce Use. dScnoustyMentallyIJIPcwous Livingin Ruml
`Aims Giver Sulliwm,_ Ml), M51811, C'advgrint: Ajarksofi, Phil, andliawn
`1.5pr BA.
`
`62 Quality. of-Iifc oflongStayPaticuLsDISdmgngrom-mo PsyChianjc Instr
`unions ’ julian 1121759112,.mcfiyin, DatiiflDafimn, MR.C.P5yc‘b._. anis—
`topber Couch,» M562, Graham Thomicrafi.MSa, MR'CI’SVCIL and Walter
`Will: BA, 3.5-6.
`
`68- Outcomes «Residential Trauncnixot-‘Substm Abuseinfiospitar. and
`Comm-Based ngiams RuaongMrm,.ij.D., Men'smfKing, M211,
`and MichaelAi-Pattmon, HA.
`I
`
`75 Severe Aggtusitm andRclatedCondmthmblemsAmong Runaway and
`Homdgss Adolescents Robert Macmillan, manning: Zbdrzg, Ms;
`25 Wchmpy ImfinMKoywz,MD
`25 Managed CamAHmmigGwckhstforEsmbhstnngTunc-hmd Psydmthaapy
`Groups Greg Ctosm; MA. LEG, andfamits-ESdbin, MD.
`27 law &P5yd1iai:ry; MamgedCatc and tthextGenmfiou of Mentill Health Law
`Paul S Appelbtmm, M1).
`
`U)l0
`
`State Hmlth CAI'cRefoim: 'n'ie Eficct (riflmefingon theCost of Public Mental
`HmhhScrvioes in Califm'nia
`Teb-wgz'vl-lu; P1101 Brmnfcuflet, 117.11. and
`Mary airman, MSEH.
`’
`'
`
`Columns
`
`Speaal Report
`
`:5 Baum in-Managcdflan: Highlightsofthe 1995m‘sdmtc anpsychian-icssinvim
`
`
`
`
`.
`10192730): 1: panama monthly- by unAfidizfiPaychludgAssudamncd-tomlandcxccutzvc oflicc. Lion x Swank
`kirk: ,
`
`“mnnignmnttzmrmdguc 1996b: thcAmerian Psydxinirk—Asswiuim-nma in fJSAScchd-dzss image-pm nimiiignnnm‘ud ii addiiibnalmail—
`Igurrmmwmfim Changc: lu' Psychiatric. Servings. Hun K Sm1.N.\u.Wuh'n'i_gir.-.ncanfi.
`-
`"
`‘
`IPR ofU.S. Patent No. 7,765,106
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`

`

`
`
`IA
`
`
`
`C
`
`Ajournzfl of the
`American Psychiatric
`Association
`
`, Formerly Hospital and
`Community Psychiatry
`
`
`
`HEALTH SCHEMES LIBRARY
`University of Wisconsin
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`‘
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`‘
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`Madison. WI 53706
`
`JAN 1 fl 1996
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`1305 Linden Drive
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`SC, of Services by
`[Rally Ill Person-5
`Ving in Rural Areas
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`O A Concurrent Reviewcr’s
`Guide to Coping W111 the
`Demands of Managed Carr:
`
`O CombiningClo‘mpine and
`Psychosocial Approachcs
`in Heath-lg Schizophrenia
`
`
`IPR ofU.s. Patent No. 7,765,106
`
`
`
`AMN1011
`IPR of U.S. Patent No. 7,765,106
`
`