`
`
`
`
`
`Efects of the Clozapme National
`Re’stty System on I e1dence of
`
`
`-Deaths Related to Agra *-
`
`0 Gilbert Honigfeld, PILD.
`
`This matedal may be protected by Copyright law (Title 17 US. Code)
`
`Obiective: Clozapine is the only medication distributed in‘th'e U.5‘. through a
`national patient registry system that provides the medication only ifresults of
`patients. weekly blood tests show no evidence of significant White--blood cell
`suppression, an effect that can be fatal if it progresses to advanced. 'agranulo-
`cytosis. This study assessed morbidity and mortality related to ngmuuloeyto-
`_ sis during the first five years of the national registry system M_‘____etliods:' Data
`Item the national registry database maintained by the U..S manufacturer of
`clompi'ne was used to determine the level of treatingsystcms' adherenceto
`the mandated program of weekly white blood cell counts, number ofIII-
`stances in which cloznpinc treatment was denied because of prior deterInI-
`nation of white blood cell suppression and number oft-Ase: of'wrmulocyto—
`sisanddeaths related to agrunu'locytosis among treated patientsdram." éliru-
`ary "$90, when clornpine was mmmercia‘lly inhadneed.m-the US.-flirt-fough-
`December 1994. The actual numbers of cases of agranulocytmfiis and:related
`deaths were compound with expected outcomes [named on clinical Itsearc'h
`done before the drug became available commercially Be__'.s__ulis: Approximate—
`ly 97 percent of treating systems had a high overalllevel ofadherenceto the
`registry protocol [11 28 instances, the pretreatment authorization require-
`ment resultedIn denial of clozapiue; after. additional data were considered,
`15 of the patients were cleared for treatment. The-actual incidences- of-332 I
`cases ofagranulocytosis and 12 related deaths were lower than theexpeoted -
`995 cases and 149 deaths Lament. The clozapine nationalregistrysystem
`fostered early detection of white blood cell suppression, prevented retreat-
`ment with clozapine of patients who had previously developedwhite lilim'd
`cell suppression, and brought about lower than expected rates ofagra'nulOCy—
`tosis and associated deaths. (Psychiatric Semiccs 47:-52—56,1996}
`
`Dr. Hoadgfeld-is amciate professor to the
`department of psychiatry at the Robert
`Womljahnson .64ch School ofthe Um“
`msity of Medicine and Dentistry of New
`jersey, 675 Hoes Lane. Piscataway, New
`)ers'ey 0W4;- He served as consultant to
`San-do; thuaceuticulv Corporation at
`thetinu: ofthe study.
`
`In 1990,, npproitinmtely 5 million
`
`persons in the United States suf-
`fered from severe "IIIeIItztl disor-
`ders. (”If those, more than half, about
`2.5 million had schizophrenia {1).
`Among persons with schizophrenia,
`between [0-and 30 percent do not re-
`spond adequately to standard anti-
`psychotic agents because the: agents
`have suboptiuwlfeflicacy or: intolera-
`ble adverse ’ell'eeLsfiZ). Thus hem-en
`250900 and 750,“)ll'ltreatnient4resis-
`taut persons with schizophrenia» to:
`
`sideIn the Un‘ited States. They repre-
`sent potential mndidates for treat-
`ment with cloupinc, an atypical an—
`Hpsychotic medication indicated for
`the treatment-resistant patient As of
`December 31, 1994. a total'of 99,502
`patients in the (LS. hadheen exposed
`to'clmapine. and more than half of
`them remained’on the medication at
`that time.
`Increased public interest in clout-
`pine and . enhanced Familiarity of
`physicians with the medication make
`itlikely that’therapwtic use 'or clou-
`pine will become more com-mun in
`the coming years However, eloea—
`pi'n'e use is associated with risk of
`.agmuulocytosis, a potentially fatal
`'blood dismder that is usually rc-
`vex-sible if detected earl-y enmigh,
`Linutations in social and IIIedicalsup-
`p-ort networks to: peisons with severe
`Intental
`illness. underscore the need
`for prom—aches to help safeguard this
`vulnerable patient group From such
`adverse side elfccts.
`in keeping with general principles
`developed by the Food and DnIg -Ad-,
`ministration. current proecdums liIr
`distributton of elozapine stipulate
`that themedication15 availableIn the
`U.‘5. only through hezlhneut s}stems
`registered with the national registry
`developed and maintained by the
`US. manufiteturer of clozupine. The I
`. purposeol’the registry :is to'enhanee
`patient sufii'ty liv liteilitating curly de-
`tection of:potentially. dangerouswhite
`blood Cell suppression, dispensing-.-
`die medication only to patients with
`mnfrent' blood tests, delineating ra-
`
`52
`
`Isvununcmvm 9 1mm [996 we No.1
`
`PAR1011
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`CBM of US. Patent No. 7,668,730
`Page 1 of 7
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`Page 1 of 7
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`
`Sponsibi-lities for patient monitoring,
`and eliminating as candidates for
`therapy anyone with a history of
`downtime-related white blood cell
`Mipression.
`All potential candidates for the
`medication mustbe cleared through
`the 'natiOnnl registry to identify per-
`sons who have had significant clona—
`pine-related while blood cell
`sup—
`pression in the past and who should
`not receive the medication again be-
`cause of markedly increased risk of
`mmnulocymsis. White blood cell
`counts are uornnrlly 5.000 per cubic
`millimeter or greater. A white blood
`cell count below 3,500 per cubic mil-
`limeter iruilicates leulmpenin, a condi-
`tion of mild white blood cell suppres-
`sion that is generally reversible upon
`interruption of clozapine therapy.
`Agrnnulocytosis, a potentially Fatal
`complication, isindicated 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 agranulocytosis
`because they are at high risk of death
`sectmdary to a wide range ofoppor—
`tum'siic 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 cloznpinc and for four weeks af—
`ter h'enhnmn ends. The medication. is
`
`dispensed weekly only to patients for
`whom data on current white blood
`
`cell counts are available. The registry
`system also outlines the I'CsponsihilL
`ties of physicians. pharmacies, pa.-
`ticnts, and the medication} manufac—
`turer and Wholesale distributors in
`
`ensuring proper use of the medica—
`tion. Distribution of the medication is
`
`limited to registered pharmacies,
`which agree to follmv the “no
`blood—no drug" guidelines.
`'li'eatment-systems that fail to Fulfill
`their obligations to report results of
`weekly monitoring of patients? white
`blood cell counts are contacted by. na-
`tional registry stat}; who explain the
`risksof clompine therapy and the re-
`quirements for weekly monitming.
`Subsequently, national registry stall
`Follow up with the physicians and
`pharmacists involved to verily that
`the-problems lmve been corrected.
`
`This paper discusses clinical prac—
`tice related 'to the clampine national
`registry system, reports on the inci—
`dence of agrariulocytosis and ‘1 “mon-
`locytosis-related deaths from Febru-
`ary 1990, when clonapine was. first
`distributed commercially in the (1.5..
`to. December 1994*, and compares this
`clinical experience with expectations
`based on prawn-that clinical research
`projections-
`'
`This study does not addressdirect-
`ly the issue of optimizing the fre—
`quency and pattern of white. blood
`cell
`testing, although the study's
`prospective analyses of rates ol'ragran-
`ulocytosis and related deaths may
`have some hearing on this-issue. The
`issue of whether formal alterations in
`
`the current requirement of weekly
`blood tests will result imam insomni-
`uhlc” increase in-ri‘slr-is the focus of
`separate epidemiologic studies and
`will not be considered here. This
`
`study specifically addressed current
`quality assurance functions and
`sought
`to answer» the question of
`whether the useof'a single, national
`registry of all _c'l07.a.piueuSurs in the
`United States" ‘haslgenhnnced patient
`safety and contributed» to the savingof
`lives.
`I
`
`Methods
`The. national registry
`All data echoingstothe clozapine..na.—
`tional'registry an: enema: lumen in—
`tegrated,
`computerized; database-
`maintz’u‘ned-i: by the manufaemrcn Pa—
`ticuts' cornputu‘ records-arc- estab-
`‘lished during the initial phone calls
`made by physicians. who arewclr-ing
`clearance tolstnrt‘aspecific patient on
`clozapine‘g The ream-(ls include the
`patient's identifying code number
`and initials, the physician's identifier-
`tion, the pharmacy’s identification,
`daily dosage of Velozupine in mil—
`ligrams. :‘md white Blood cell test
`dates-and results. *
`_
`These data are retained penna-
`ucntly, and .ndditional data are added
`each Week. As more than-60,000. pa-
`tients. Currently. receiire elornpinfi.
`more. than 509,9“) separate fieldsof
`datam-e. sent to-“the [maul-network
`national registiy eoehzwcek. :In. addi.
`tion; separate . databases are urn-ire
`mined in truck nil reported adherse
`reactions. All dan'r analyzed in thisire-
`
`PSYOIIATRICSERVIWS 0 prim-71996 Vol.4? No.1
`
`,por-t were drawn. from those sources
`and were provided by the manufac-
`turer;
`.
`We used these data to examine two
`process variables related to functions
`of the national regism' system over
`the first five yarns orcOnunei-cial dis—
`tribution ofl the mediation; level of
`adherence to the. registry protocol
`and denial ol‘ clinically inappropriate
`retreatment. We also examined 'two
`outcome varial‘iles—ra‘tc of agnmulo—
`cytosis and rate of deaths related to
`agmnulocytosis—and compared those
`rates with lllc rates that wereprerlict—
`ed in analyses con‘rhicted before the
`medication was commercially distrib-
`uted in the U.S.
`
`Results and discussion
`Adherence to registry protocol
`The manufiicturer's educational and
`
`scniciug; activities, plus the potential
`threat of disciplinary action such as
`deregi’stmfion as a cloznpine treat-
`ment system,.appnnr tohuve resulted
`in generally high levels of adherence
`to wccld'y Inimitoring; Over the first
`five years of commercial distribution.
`oiT'clompine, more than 97‘ percent of
`treating physicians and pharmacists
`managed their patients on clozapinc
`at high oveiall- levels'o'f. adherence to
`the requirements'of the product. la-
`beling. The remaining 3-percent have
`been clmrdeterized- by varying. levels
`ofprotoeol compliance. National reg-
`istry data Show that n small percent:
`age oftrwlrnentststems periodically
`relnx‘adhemuue to .monitorirqg, guide—
`lines.
`
`. Of the» more than 10,000 physicians
`and phannacists currently involved in
`(liSPcnsing‘clozapinc, about 730 are
`contacted annually because of poor
`compliance in reporting data to the.
`national
`registry National registry
`stat? institute corrective actions. in-
`cluding education, 3 clinical manage-
`ment training, and interiSilied-review.
`As new treatment systems an: added,
`and older ones only become large or
`complacent.
`this iterative process
`continues-
`
`.
`
`Between 1990 and “392, analyses
`were performed to detenniru: il'co'r-
`rective actions by national-registry
`stnll were associated with improved
`reporting of white blood cell count;
`In Maui! 199?. registry staff identi-
`
`53
`
`PAR1011
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`CBM of US. Patent No. 7,668,730
`Page 2 of 7
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`Page 2 of 7
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`
`
`E I i i i ?
`
`! 9 I
`
`
`
`
`Figure-I
`
`Cumulative number of actual and predicted cases of agmnulocylosis among-pa-
`tieuts receiving clamping, 19904994l
`
`Npatients
`
`
`
`
`
`
`
`1990
`
`1991
`
`
`19'?“ .
`’
`1993
`1992
`' Cumulative numhers nfpnflnntxreceiving (-lozupimwcrc 9.‘807In 1990, 24.1112III 1991.47.271Gin 1992.
`7-1£15In um and $9,‘snzIn 1994. anlicmd number ofcamwas aloulaled usinga conservative (sli-
`Inah: urn I nmutnt nut. (Ifagmnnlocytmls, lmsedmprenurlcct clinical Itsarch
`
`lied physidans who had morethan six
`patients for whom more than :10pgr-
`cent of the required reports of white.
`blood cell counts in the latest three
`months were missing. Fromxthis list,
`the 100 physicians with the highest
`percentage (If patients for Whom
`
`more than 10 percent of the reports
`were missing .w'ere identified.7 At that
`time,dicsc LOO physicians waive re-
`sponsihle for. 2343.patients.
`Beforetheintervention by Italian!
`registry stafi; 58: percent. ofthbse’ pa-
`tir-J'Imwere missingmore than 109a:
`
`
`‘FigureZ.
`
`Cumulative number of actual and- predicteddeaths related to complicatimn of
`agnmulocytosis among patients receiving clozapin‘g 1990—1994'
`160
`
`I40
`
`Npatients
`
`
`
`
`
`
`
` 1992' 19%
`
`' Cumulative munhcts ofinticuts Imuvwgchmmmr wart:‘i897 in:19902.4.112in.1991 472.451“ l$2..
`743-165In 1993. and 99.302In 1991Whiz-xi numberofdanths.was cachIla'!cd using admgrv'ah've' esti-
`Ir'Inksvia 1pauml run: ufngm'nulnnfnxis and aism rate oFxssodatedmortality.based on pre—
`market.clinical twin
`
`cent at the required records of white
`blood cell cnunts._ One year later, in
`April. 1993, despite the a difiun of
`more than 400 patients. to the case
`loads (Ifdicsc 100 physicians, fora to—
`tal or21,767 patients. the perceulnge- of
`acceptable reports nfwhite blood nell
`counts by these physicians had im-
`proved-ta 61 percent
`
`Denial of mmmmcnz
`Patients who have dismntinued use
`
`of clamping due to agrannluéytusis
`are at increased fish ofdeveloping. the
`reaction again, generally earlier in
`therapy and in a (nun: aggressive
`lbrrm if clampine is reinstituted (3).
`'I’hcnatiuual registly clears each po—
`tential candidate for clozapine diein-
`py to reduce the chances (If reexpo-
`Sure tn the meditation by persons at
`increased- risk of developingagmnu-
`lacy/unis.
`l‘l‘elween' February 1-990 and Dc-
`cember 1994, them were 28 instances
`in which [thIItial'umdidateS ibr the
`medication weredenied retreuunent.
`Niuc inshmces invnlvedi eight pa-
`tients who had confirmed histories of
`white blood: cell counts below 2,900
`or absolute neutroplu‘l counts below
`1.000. The nine instances included—
`two attempts to obtain rctrentrnent
`clearance for one patient In'lbur. ol-ll-
`er instances the regisby was tested-by
`the miul'aclurer uSing ideritifiijtion
`numbers of nun-retreal‘ahle patients
`to :55er that the system fimctioned
`appropriately. In the other 15 in-
`smnces, rchcahnent war denied until
`closer-inspwtion revealed errors in
`data; these patients were Subsequent—
`ly cleared for retreatment.
`
`Rate ofagramdocytosis
`Between Februaiy 1990'an‘d Decem-
`ber 1994, a total of 99,502 patients
`were exposed toclompine in. the U55;
`and .had‘ (ecunls of more thanOnc
`white blood cell count. Duringvlhe
`first calendar year in the-Shirl): period
`(February thmugll Decemligr 1990),
`,9,807 patients wet-re exposed to claw—
`pine. The cuIIIulal-Jvc (Dial had in-
`creamed to 24, 112 patients by the end
`ufwlendar year 1991-, to 47246at the
`end of. 1992, to 74,345 at the cud of
`1993, and to 99,502 bv the encl'of
`1994.
`'
`'
`
`Among the total of99502 patients
`
`54
`
`WMCSERVIGBS 0 January [.996 Vol-i7 mm
`
`PAR1011
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`CBM of US. Patent No. 7,668,730
`Page 3 of 7
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`Page 3 of 7
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`
`
`sis-related complications between
`blél‘mrary 1990 and December 1994.
`Figure 2 slmws' the cumulative ex-
`pected and actual numbers of deaths
`related to amuloeytosis each calen—
`dar year during the study period. The
`expected death rate assumes a 1 per-
`cent mic oEangmIOcytosis and an as-
`sociated mortality rate of 15 percent.
`This rate is consistent with mnscwa—
`tive cslhnales lmsed on experience-
`abroad with .clo7apine and on pub-
`lished research on Inianscrin, an anti-
`depismit that has leuknpenia as a
`potential adverse effect (45).
`The diflixencc bcbveeu the pre-
`dicted and actual cumulative death
`
`rates—149 predicted deaths com-
`pared with 12 actual deaths—sug-
`gests the benefits of rigorous patient
`monitoring, These data show that cur-
`rent. medical practice and monitoring
`procedures have contributed sub—
`stantially toward saving the. lives of
`many patients who require clozapinc
`therapy.
`Table. 1 shows how mutantsurI/ival
`might have been alluded over the
`study period it" nmnitoring had been
`less rigorous. Actual cliniml experi-
`ence in the US. from Fcbmmy 1990
`through Deeember 1994 showed 90
`to 100 percent compliance with rc—
`portiug of white blood- cell counts. in
`that context, patients with man-ulc—
`cytosis had an overall risk of fatal
`complications of 3.1 percent (12
`deaths among 382 cases of agranulu—
`eytOSis).
`At the other extreme. are. the initial
`
`finduigs on this topic from Finland in
`1975—1976, wherein 50' percent rate
`of mortality emerged among patients
`whodcvclopcd agmuultx-ytosis (eight
`deadls among 16 cases of agranulocy-..
`inns). Rates of White blind cell moni—
`toring 'Wcre estimated to he 30 to‘ 45
`percent. The outdated medical and
`monitoring conditions existing at that
`time-clearly no longer apply; given
`the heightianed awareness of elozap-
`ino and its therapeutic and nth/arse.-
`ellects. However. haMeen the cur;
`.rent U.S. experience, representing
`the highest level at monitoring, and
`the early Finnish experience, one'cau.
`interpolate intemchiale-sccnarios of
`adequate, Eur, or poor levels'of moni-.
`toring and the associated risks oliliztal
`wmplicatious alagiamdocytnsis.
`
`55'
`
`PAR1011
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`CBM of US. Patent No. 7,668,730
`Page 4 of 7
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`
`Table I
`Effects nfaaual and-hypothetical mics oi'conipliance. in"t'emlling ofwhite blood
`cell munts on incidence ofagmnulocytosis and relatad'death's among patients re-
` ceiving clnzapine
`
`Agmnulocytosis
`
`lialc Ol complim I!!! (96)
`
`Rate (%)I
`
`N cast-5
`
`.D‘eath
`
`.
`Ball: (if
`
`g
`. N cases
`
`' N pre-
`veritable
`deaths"
`
`min]
`9010. 100‘
`301p 455 -
`Humilleflcal
`75 m 90 ,
`(IO-tn 75
`45 to 60
`
`.38
`ml
`.60
`.8)
`L0]
`
`382
`lfi
`597
`79G
`995
`
`3.x
`50:0
`
`in
`Ill.“
`15.0
`
`19.
`8
`
`'30
`80
`I49
`
`_
`—_
`
`18
`68
`I37
`
`x :‘\'I
`
`‘ .\‘ (use: among 99509 pail-nix the cumulative number ol-patimitx- I'mulntllx'l' in the national taxis-113'” from
`Féluuary 199!) “magi December 1991
`1Ndeaths among N- cases: of agranuloq‘tosis
`3 Grin-[milwithN (lath: at 90 In 100 percent tempt-lame:IIIreporting
`3 [We aunt-599.509. cases includedIn the nationalrcgim from Fain-new use through Denomina- mm
`1 imuuflm patients treated when donpinr: was first distributed commercially in Ftnlumlvin {97$
`
`duringthe. study: period, there were
`2,931 cases uf-leullopenia (crude inci-
`dence. rate. of 2.95 percent}. .182 cases
`(If agmu‘lncvtosis(.38 percent), and
`[2 deaths aSsocLitedwith agrénulocy-
`tests {.0512 percent).71?he rate ,of'
`leukopeuia unifiirmsquilc closely to
`’ predictions hassclon pramarlc-et clini-
`cal researehli'approximately 2.5 to 3
`percent of all persons expowd to
`clo-xapine.
`However, the crude rate ofagrauu-
`loeytosis during the studyperiod (.38
`percent) waslass thanhalf that antic-
`ipatud {coin premarlcct research (1 to
`2 pereent)‘. [figure 1: shows the annual-
`uumlierbf expects-x} and actual cases
`of agranulocytosisvzover the study pe—
`riod; The expected number of cases
`
`was calculated conservatively using
`the louver percentage- estimate of t
`perpent'hasedon thepremarl’cet clin—
`ical research. Because the rate of
`leuko'penia- was «insistent in‘ the pre-
`and postmarke‘t data, the: more favor-
`able pnstnmrket findings onagramtln-
`cytosis appear to betheresult of sys-
`t'emalic- monitoring, early detection of
`abnominlifies in 'white blood cell
`
`counts, prompt-1 reporting of - tlisse
`count-s- to the manual .r‘egishy, and
`pmmptrdismnfinuation of cl'ozap‘ine.
`among: patients who wcrc'at risk to:
`agrani-Iloeytnsis.
`
`Heath-rate
`
`l5)(:spite intense monitoring, [2 per-
`sons disilas a result of agiunulocyto—
`
`
`ma:
`
`Prospective aimlys'is-of effects of rates of compliance in reporting-of white blood
`cell counts on incidence ufagmnulocytosis and related denthsvamnng 213,000 new
`patient: meshing clampine over a one-year. period
`
`
`Ontariistic scenario‘
`
`Realistic scenario?
`
` Rate oi Agmuulmrymsis
`
`comp];
`.
`'
`anon. (3:)
`Rate;(.%)
`N
`
`N
`deaths
`
`N pre-
`ventable
`dually-1
`
`[late of
`death (‘2’)
`
`N pre-
`veritable
`N
`deaths W '
`
`3.1
`.51)
`10.0
`l5.“
`
`2
`6
`16
`30
`
`0
`4
`I4
`93
`
`0
`:1
`3
`4
`
`2
`4
`
`55
`
`‘ 38
`90111100
`.60
`'75 tom
`, .80
`60m 75
`
`45mm _- Loo
`
`76
`mm
`I if!“
`200
`
`'
`
`‘ AW :31percent ratedd'egith among camolagmnuhxtytosu, wgmllqn: o'i'thn'uumlxzr «ram-s- at
`“titans labels oleomplim-Ice
`‘-issuing rate (Ideafllamoug we; ol' agtanulocytosisincreases as numh'r:-r nfmsl:'s him with do
`messed levels:qlco'nlplia‘nec »
`1(th withtwosaunas) to [Mpemcn't compliance in ramming
`
`mmmesmvm“. January I996 Vol47 No.1
`
`
`
`Page 4 of 7
`
`
`
`For example, a rate of compliance
`'with white blood cell monitoring of
`75 to 90 percent would be associated
`with a risk of Fatal cnmplimtions OFan
`Estimated 5 percent among [unionis-
`wha developed agranulocytosis,‘ a.
`monitoring rate of. 60 to 75'pcrccnt
`with an- estimated 10 percent rate of
`fatal complications, and a monitoring
`rate of45'to 60 percent with an ostri-
`maied '15 percent rate of fatal compli—
`cations,
`the level recently reimrted
`for deaths xelaterl to agnmuloeymsis
`associated with mianserin [4). Thus if
`V monitoring standards in the US. had
`been less stringent between 1.990 and
`1994, between 30 and 149 deaths
`might have occurred. inst-cad of the
`12 deaths that actually mzcurred,
`
`Hospafive analyses
`Based on memtive projections of
`current rates ol'acccss to clozapinc, at
`lea-st 20.000 Americans per year are
`likely to be newly exposed to cl'oza-
`‘pine in the-mining years. If these pa-
`tientsure. treated under current mon—
`itoring conditions, about 76 patients
`(383 Wheat)» :ur:
`likely to develop
`'agrwulbcytosis, and two patients are
`likely-to-dieofcomplications ofa'gm‘n-
`Minsk-(3.1: percent among agranu—
`loeylosis cases) in each annual cohort.
`(iivenrthese rates, what’would hap—
`pen if standards for monitoring were
`lo'wered? Two principal scenarios,
`whoserate‘s areshown in 'liihle 2, can
`
`be considered. An optimistic scenario
`presumes that maliml pmfice has ad—
`vauoed. enough that most cases of
`agranulocytosis;
`including sympto-
`nmtii: cases, can be arrested without
`Eital' oomplicatidns'. Thus if one as—
`sumes that mlequacy ofmonitoring has
`no bearing on filial outcomes,
`two
`deaths could be anticipated among the
`next 20,000 new clmriine patients iF
`.inonitoring compliance remains at
`Current levels.
`IF the. rate of compli-
`ance drops, one will likely see an in-
`crease in tho rate of agimiulooytosis
`and an additional. two to Four deaths.
`
`The secoml, more malistic scenario
`assumes that early detecticm and con-
`tinued vig‘lanoe exert a favorable im-
`pact on the rate of agranulocytosis
`andthe rate of Fatalities. In this sce-
`nario, a wider range of outcomes can
`he pmjectexl, and substantially poorer
`uutwmes are likely. l‘br example, the
`estimated risk of agrxnulucytosis
`would range 5'0"] .38 to l percent and
`the rate ol‘ fatalities fi'om 5h) 15 per-
`cent. The projections shown in Table
`2 summit that if monitoring deterio-
`rates from current levels, between
`{Our and 28 additional deaths may oc-
`cur among Loch annual cohort: of new
`patients.
`
`canclusions
`
`appears to have contributed to reduc—
`ing mrtulity reliitcd to. cOmplimtions
`ofagumulncytnsis substantially below
`projected rates dcrivtxl'fi'orn premar-
`L'et data. The rigorous safeguards, in
`place to maximize the opportunities
`for early detection of white bloodccll
`luppression have heen lassocin-ted
`with fiworablc outcomes in rates of
`
`both ngranulocytosis and fatal compli-
`cations. Dacremed vigilance would
`likely be wwciatcd with an increase
`in otherwise preventable deaths. 0
`
`Acknowledgmerus
`
`Th1: author thanks Felix Arellzino, NH),
`and Sheila Whiter M.D., of the drug reg-
`istration and wgulatory affiu'rs
`-
`ment and Anthony Biuucllini u the
`Clozaril national mgish‘yat Sandal Phar-
`maeeutimlc Corporation.
`
`Mums
`l. Heals: carc'rclimn Ric-Americans with se-
`um: menial illnimm: mpnrt Hf ihrstglional
`Advisory Mental I-Ioaltli macaw.
`Journal cf'Psychiatry 1mim—i465.~1993
`
`.10
`
`Kane 1M. Ilimigfdd G, Singer ,1. eat; Clo-
`mpiue for thc heamwnt-mislunt.sdfim
`glut-mic. Amllivm" of (Tamil fiyflhijitry
`45:789—196. 1988
`'
`
`3. Pisciultu AV: igunnlbcytosis hiduccd,’by
`curtain [Illeuolllizlziun‘ (lcfivaliflti- [AMA '
`208:1562—1868, l969
`
`4. Adams PC; Miansmin-imhleedagmuihqa
`tosis; British-Medialjtiumal firms-$09.
`[.932
`'
`'
`
`In the first five years of commercial
`distribution of clumpine in the us.
`the national clowpine rcgistly system
`
`9.
`
`Coulter DM, Edwards. IR: MimISeriuaud
`ugmnulocytosis in New Zealand. Lined
`Sillii'lifi—THT, lllllll
`
`Peer Reviewers Sought by Journal
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`Psychiatric- Services socks apart review-rs in the following areas:
`
`PSYGiIATRlCSERYIG‘B' o jznuary I996 VoL47 'NoJ
`
`OOutcome research, particularly in tho area of psychopharmaoologiml treatment
`of mental disorders
`
`fiBating scales for symptoms, outcome, and other aspects of treatment
`ODual diagnosis (mental illnrm and drug abuse and mental illness and mental re-
`tardation)
`
`Oillnrétl psychiatric services
`
`{Patient and consumer perspectives and attitudes.
`
`Reviewers should be familiar. withrthe-litemture in.,thoi_r areas of expertise,
`should have published in peer-reviewedjoumals, and should he. Familiar with the
`.oontent and-focus of Psychazh'ic Services.
`
`Prospective reviewers should send. a curriculum-vitae, spécilying arms of‘iu':
`temst, to John A. Talbott, Ml), Editor; Psychiua‘ic Senflces, A'PA, l4tl0 K Street,
`N.W,.Washi-ngtnn, D;C. 20005.
`
`PAR1011
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`Page 5 of 7
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`,, WW 1996 not. 47 No-1—
`
`
`
`Ajoumal of the
`
`'
`6. American Psychiatric
`
`V Association
`
`
`
`fimnrri'y Hospital and Qinxntntlity'l’sydfizrry
`
`Tal'dnglssue
`
`Articles
`
`7
`
`35
`
`41
`
`46
`
`How’rc We Doing?
`
`jobrlzLTalbl-iu. MD;
`
`Confusions'ot‘a Continent Refiewcr Paul CMolu; MD.
`
`long-Tenn Impact ofCIonpinc andPsydt‘o‘social Treatment onWe
`Wins andCognitive Functioning Jgg‘éty Grace, MD, Stephen RBelfus,
`Pita, Michael I. Raulirz, »Pb.D., Marvin [Hem MJ)‘. Barbara LPriesi;
`RM, WktorBrenner; MA, Keny Donnelly, PhD. vaia’z: Smith, 1m, 114.52,
`and SM 6mm, KN
`
`Efl’ecumofaonpinc and aSodal-Icarnfinggtramfoe Severely Disabled
`Psychiatric Inpatients Anthony Manditto, Phil, Niels C'Bcch, Pb_D., Pam
`Slime, I’leJudidJsAf-zls‘bei: 0.0, Mark ShaggMLl, Mary Beth logue, MA,
`and hichaldzuin, MS.
`
`Effects of the Clouphic. NationalkcgisuySysmm on Inddaice-ot‘ Dennis-Related
`lo-Agmnulocytost‘s Gilbert 110311,ng Pan
`
`Chmaaaisitsznds-ccvice Use. dSenonstyMeaullyHIPasons livingin natal
`Areas Giver Sulliwm,_ Mil, insert, (marina Afat‘ki‘brt, Pb;19., and Karen-
`Lspfizzer; 11A.-
`
`Quality. (If-life oflnng-Stayl’atimts midmgedIFrOm mo PSyChian-jc Instr
`unions ’ jutmn 11-17: l4£D,.1:‘1?-.'Cl’sydz, Davi'flvayson, MitePsych, Chris—
`mpber Couch,» M55, Graham ViromiecoftMSc, MR'CI’Sycfl, and mute:
`Milt, BA, 3.56.
`
`Outcomes ofReaidr-nflal Trmmcntsof Substance Abusein Hospital- and
`COmmunity-Based Progiams Rudolf HMnosszD, Mchkmjfilcing, MPH,
`and MidmelAi-Pattmon, BA.
`I
`
`Columns
`
`75
`
`23
`
`’5
`
`N\1
`
`Ln[0
`
`Homeless Adolescents Robert 15.800113, mu, andHntaig Zbaflg, MS
`
`Dammints: Elecnooonvulsive'mazpy Imfin'M'waz, MD.
`
`Managed Care: Ammmnmbicmng Tune-Hunted Psychotherapy
`Gmups Greg Chub}; MA. LDC, andja’tizitelisabz‘n, MID.
`[aw &£Syd1iany: Managede: and theNextGenelation of Mental Health Law
`Paul S. Appelbralm, MU.
`
`sun: Halth extension 'nic 2am- daemon the-(inst of Public Mental
`Health Services in'Caliromi'a Teb-w‘et'Hli; 1?th Brianfeign, PM). and
`Mary attractant; MSEH.
`’
`'
`
`SPCCIalRCPOfl
`
`'5
`
`Balm in-Manaecds'Can: Highlights .afthc 1995mm OilPsychianic-‘Setvic‘m
`
`
`
`ignrrmmmmmsmm changes [0' Psychiatric Serviclei. H'flD K 5mi.n.\v..w:s1iingimltcyms.
`
`PAR1011
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`IA
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`(3
`
`A journal of the
`American Psychiatric
`Association
`v Formerly Hospital and
`Community Psychiatry
`
`
`
`HERLTH SCIENEES Llfl‘flAfiY
`University of Wisconsin
`
`4‘
`
`’
`
`‘
`
`Madison. WI 53706
`
`JAN101996
`
`1305 Linden dee
`
`
`
`SC, of Services by
`many H1 Persons
`Ving "in Rural Areas
`
`9 A Concurrent Reviewcr’s
`Guide to Coping Widl the
`Demands of Managed Cart:
`
`O CombiningClo'mpine and
`Psychosocial Apptoachcs
`in Trcating Schizophrenia
`
`
`
`
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`PAR1011
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`CBM of US. Patent No. 7,668,730
`Page 7 of 7
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