`Effects of the Cfozapme NflIIOIlfll
`Re’stry System onInCIdence of
`Deaths Related to Agr;
`
`:ocytOSIs
`I ThismaterialmaybeprotectedbyCopyrightlaw(Title17US.Code)
`
`0 Gilbert Honigfeld, Ph.D.
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`Qbiegfioe: Clozapine is the only medication distributed in the US. 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 effect that can be fatal if it prowesses to advanced 'a'granulo-
`c‘ytosis. This study assessed morbidity and mortality related to agrxnulbeyto-
`sis: during the first five years oF- the national registry- system. Meflm___ds_:' Data
`[mmthe national registry database maintained by the UHS manufachirer of
`clornpine was used to determine the level of treating systems adherenceto
`the mandated program of weekly white blood cell counts, number «FIII-
`stances in which clozapinc treatment was denied because ofprior delenni-
`nation of white blood cell suppression, and number oFmses oFagran-nloeyto‘
`sis.anddeaths related to ugrunulueylusis amongheated patientsfromFéhru-
`ary “190, when clovnpine was commercially intIoduc'ed.III the U.S.-, thmugh
`December 1994. The actual numbers of cases of manulocytosis and: related
`deaths were compnmd with expected outcomes based on clinical. research
`done before lime drug became available commercially. Re__'.s_IIlts: Approsinlam—
`ly 97. percent of treating systems had a high overall level of adherenceto the
`registry protocol. In 28 instances, the pretrenhnent authorization require
`ment resultedIn denial of clozapine; after additional data were ennsidered
`15 of the patients were cleared for treatment. The actual incidences. of- 332 I
`cases of agranulocytosis and 12 related deaths were lower than the expected
`995 cases and 149 deaths.Mm; The clozapinc national.registrysystem
`fostered early detection of white blood cell suppression, prevented retreat-
`ment with clozapine of- patients who had previously developed white blood
`cell suppression, and brought about lower than expectedrates ofagranulow-
`tosis and associated deaths. (Psychiatric Services 4752—56, 1996)
`
`Dr. Honigfeld is associate professor in the
`department of psychiatry at the Robert
`Woonhnwn Medial School of the Uni?
`varsity of Medicine and Dentistry of New
`jersey, 675 Hoes Lane. Piscatatcoy, New
`)ersey 08854: He sewed us consultant to
`Sandor. thnaceuficals Corporation at
`the time ofthe study.
`
`n 1990.,upp1'qxinmtely 5 million
`persons in the United States 5“}:
`feted frcm severe ‘IIIerIlal'Ilisor-
`III-.rs. OF those, more than half, about
`2.5 million had schizophrenia (1).
`Among persons with schizophrenia,
`between 10and 30 percent do not re-
`spond adequatelv to standard anti-
`psychotic agents bemuse the: agents
`have suboptimal efficacy or. intolera-
`ble adverse effects (2). Thusbetween
`250000 and 750,000 twatnIeotfisiS-
`lz'ull. persmis with schizophreniare.-
`
`sideIn the Uoiled States. They repre-
`sent potential mmlidates For
`treat-
`ment with clogapirw, an atypical an-
`tipsychoh‘c medication indicated 'th
`the treahnent-resistan-t patient. AsoF
`December 31, L994, :I tutal'of 99,509.
`patients in the (LS. had’heen exposed
`Inchmapine, and more than half of
`them remained'vn the medication at
`that time.
`Increased public interest in clum—
`pine and enhanced Familiagiity of
`physicians with the medication make
`it likely that therapwtic use ole-102a—
`pine will become more com-onto in
`the cooling years. However, climb
`pine use is associated with risk of
`agranulocytusis, a potentially fatal
`Bland di’soId‘er
`that
`is usually rc-
`versih’le if detected early enough.
`Limitations in social and IIIedicalSup-
`port networks For peméns with severe,
`intental
`illness underscore the need
`for Inocedums'to help safegumd this
`vulnerable patient group From such
`adverse side effects.
`in keeping with general principles
`developed by the Food and Drug Ad-
`ministration, currcnl procedures liIr
`distribution of clumpine stipulate
`that die-meditation isavailable'in the
`US. only through trellmeut systems
`mgistered with the national registry
`developed and maintained by the -
`U.S. mnufa'eturer of clozupine. The
`. purposeof‘the registry is to'enhance
`patient safety by. liteilitating early dc-'
`.tection. of:potentially. dangerous white
`blood Cell suppression. diSpensing-
`the medication only to patients with
`cm-rent' hlood tests, delineating ra—
`
`52
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`PSYGHA'HIIC mm 0 1211111111996- VOL-i7 No.1
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`This paper discusses cliniml pmc—
`ticc rehited'to the. clovapine national
`registry system, reports on the inci—
`dence of agranuloqrtosis and amou-
`locytosis-related deaths from Febru-
`ary 1990, when clozapiue was first
`distributed commercially in the 0.5..
`to December 1994», and compares this
`clinical experience with expectations
`based on ptcmmdret clinical research
`projections.
`'
`This study does not address direct-
`ly the issue of optimizing the fre—
`quency and pattern of white blood
`cell
`testing, although the study's
`prospective analyses of rates oregan—
`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 inan ,“aeccpl-
`able” increase in risk-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 "septa single, national
`registry ofall clozapiuousurs in the
`United States has enhanced: patient
`safety and contributed to the saving-of
`lives.
`I
`
`Methods
`
`sponSibi-lities for patient monitoring,
`and eliminating as candidates for
`therapy anyOne with a histnry‘ of
`clowpine-relatcd white blood cell
`suppressimr.
`the
`All potential candidates Err
`medication must be cleared Ihrough
`the national registry to identify per-
`sons who have had significant elimi—
`pine-reluted white blood cell
`sup—
`pression in the past and who should
`not receive the medication again be—
`cause of markedly increased risk of
`awayulocymsis. White blood cell
`counts are normally 5.000 per cubic
`millimeter or greater. A white hlood
`cell. count below 3,500 per cubic mil-
`limeter irn‘licates leukopenin, a condi-
`tion of mild white blood cell suppres-
`sion that is generally reversible upon
`interruption of clozapine therapy.
`Agnmulocytosis, a potentially Fatal
`complication. isiodicated by a white
`blood cell count below 2,000 and de—
`fined by an absolute neutropliil count
`below 500 per cubic millimeter. Dis—
`continuation ofcloznpine is mandato-
`ry for patients will: agr'anulocytosis
`liecnuse they are at high risk of death
`sectmdary to a wide range of oppor-
`tunisiie infections.
`The. registry system requires all pa-
`tients to lrave a baseline white blood
`cell count and weekly white blood
`cell counts throughout
`treatment
`with clampinc and for four weeks af—
`‘ter trenhnmrt ends. The. medication. is
`dispensed weekly only to patients for
`whom data on current white blood
`cell ommts are available. The registry
`system also outliucs the responsibili—
`ties of physicians, phannacies, pa-
`tients, and the meditations tumlullttl‘
`tutor and wholesale distributors in
`
`The mliomd 1.2ng
`All data anningrtothe clumpine na-
`tional remstry are colored-tumor: in—
`tcgmted,
`computerized _ data‘lmse
`maintained'by the manufacturer. Pa—
`ticuls' computer records-arc estab-
`lished during the initial phone calls
`made by physicians who arcscclc-in'g
`clearance to stint aspecificv patient on
`clozagine; The records include the
`patients identifying eude‘ number
`and initials, the physiciaris identifica—
`tion,
`the phannaey’s identifiattion,
`daily dosage ofivclozupine in mil—
`ligrams,
`:ind white liloorl» cell
`test
`(hates and results.
`_
`These data. are retained perm:-
`uently, and Additional data are added
`each week As more than-{50,000 pa—
`tients currently. receive elorapiue,
`nmre than 500,900 separate fieldsvof
`data-um sent to the inariul‘aotuim's
`national registry each Musk In addi—
`tions. separate datahascs .arc. lure-in—
`taiued to truck nil reported adrerse
`reactions. All. dam analyzed in thisre-
`EWUIIATRICSERWWS 9 januzry 1996 Vol.4? No.1
`
`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" guidclincs.
`Treatment 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 staff. who explain the
`I'iSlG of clozapine therapy and the re-
`quirements for weekly monitoring.
`Subsequently, national registry stall
`follow up with the physicians and
`pharmacists involved to verify that
`the problems lure been corrected.
`
`port were drawn fi‘om those sources
`and were provided by the manufac—
`turer;
`
`We used these data to examine two
`process variables related to functions
`of the national registry system over
`the limit five years ol’courmeicial dis—
`tribution of the medication: level of
`adherence to the. iemsiry protocol
`and denial ol‘ clinically inappmpriate
`i'eh‘eatment. We also examined two
`outcome vaiiul'iles—ra'tc of agnmulcr
`cytosis and rate of (lmths related to
`agmnulocytosis—and compared those
`rates with the rates that were predict—
`ed in analyses conducted before the
`medication was conuncrcially distrib-
`uted in the US.
`
`Results and discussion
`Adherence to registry protocol
`The mannfiicturer’s educational and
`servicing activities, plus the potential
`threat of disciplinary action such as
`dercgistmfion as a clozapine breat-
`mcnt system, oppmr- n have resulted
`in generally high levels of adherence
`to weekly monitoring.- iOver the first
`live years of commercial distribution.
`of clozapine, more than 97‘ percent of
`treating physicians and pharmacists
`managed their patients on clozapiue
`zit high overall levels of, adherence to
`the requirements of the. product. la-
`beling. The remaining 3 percent have
`been characterized by varying levels
`of protoml compliance. National reg-
`istry data Show that a small percent:
`age of treatment systems periodically
`relax‘adhomuee to monitoring glide-
`lines.
`Ofthe more than 10,000 physicians
`and plumuacists currently involved in
`dispensing clamping about 700 are
`unleaded annually because of poor
`compliance in reporting datn to the
`national
`registry. National registry
`staff institute corrective actions. in-
`cluding education, cliuiml manage-
`ment training. and intensified review.
`As new treatment systems are added,
`and older ones may become large or
`culnplacent,
`this iterative process
`continues.
`Between 1990 and 195-12, analyses
`were perfumed to determine il'ccr—
`rccfivt: actions by national-7 registry
`still were associated with imprtwed
`reporting of white blood cell counts.
`[0 Mandi 1992 registry staff identi-
`53
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`central the required records of white
`blood cell counts. One year later, in
`April 1993, despite the addition of
`more than 400 patients to the case~
`loads ul‘diesc 100 physicians, lbra to—
`tal on-J’GT patients, the percentage of
`acceptable reports ofwln'te blood cell
`counts by these physicians had im-
`provedm Iii percent.
`
`Denial of mmmmcnt
`Patients who have dismntinued use
`of clampine due to amnulocytosis
`are at increased rislc oldeveloping. the
`rcactiwn again, generally earlier in
`therapy and in a more aggmssivc
`form, if clampine is reinstituted (3).
`The national rcgistry clears each po-
`tential candidate for clozapine them—
`py to reduce the chances of rccxpo—
`surc to the mcrlicdtiuu by persons at
`increased risk of developing agmnu-
`loclesis.
`l‘l‘etween February 1-990 'and Dc-
`cembor 1994. there were 28 instances
`in which Intelrlial'cmldidateéi. for the
`medication weredenied reh-ealment.
`Nine inshulces involved eight pa-
`dents who hadconfirmed his [arias 01
`white blood cell counts below 2,000
`or absolute neutrophil counts below
`1.000. The nine instances included’
`two alluupls to obtain retreatnient
`clearance for one patient. In four oth—
`er instances the regisb-y was tested-by
`the umxul'acturer using idontificalion
`numbers of nun—renewable patiens
`to assure that the Systcmhmcfioned
`appropriately. In the _ other 15 in-
`stances, relreahnent was denied until
`closer inspection revealed errors in
`data; these patients were Subsequent
`lyclcarcd lbr retreatmcnt.
`
`Rate ofagranulocytosir
`Between Fobrualy 1990'and Decem-
`ber 199-1, 2: total of 99,502 patients
`were exposed Mclompine in the 11-5.
`and had records of niorc thanonc
`white blood cell count During the
`first udcndarycar in the-study period
`(February through Decemlicr 1990)
`9.807 patients were exposed to claw-
`pine. The cumulative total had in-
`creased to 24,112 patients by the end
`alcalendar year 1991-, to 47,248atthe
`end 91 1992, to 74345 at the end of
`
`
`Figure-I
`
`Cumulative number of actual and predicted arses of agmnulocytosis wrong-pa:
`tieuts reaching clorapiue, 1.9904994l
`
`
`1.000
`
`Npatient-s
`
`f!"
`
`
`
`
`
`l992
`1990
`1991
`1993
`199-1 ,
`' Cmnulnh‘w-e numhers nfmflmts-rcceivlng champion were 9.807 in 1990. 24,112 in 1991; 47mm 1991
`“QM-5 5" ”'1“. "I'll 99.592 in 1994. Ptulictod Illu'llbcl' ofcam'was almilated using: mnsa'vau've (51i-
`lnatl: nl'n l pammit mm (Ifagmnnlocytosis, based'on market clinical "march.
`
`lied phyxicians who had more'tha‘n six
`patients ‘lbr whom more thanJO per-
`cent of the required reports of white.
`blood cell counts in the latest three
`months were missing; me.'this list.
`the lm physicians with the highest
`percentage of patients for whom
`
`more than 19 percent of the reports
`were missing ware identiti'ediAt that
`time, . that: 100’ physicians. were, re
`sponsihlevfor 2943;.mficms.
`Before the intol'ventihn by national
`registry stat}; 58 percent of those pa-
`tiJr-mtx were missing more than I‘ll-per—
`
`
`
`Figure 2
`
`Cumulative number of actual and predicted deaths related to complicatiims of
`agmnulocytosis amendbpaticuls {waiving clozapin'e 1990—19!“
`160
`
`Npatients
`
` 140
`
`
`moi
`
`1993
`
`' Cumulative munhc-s ofimtieuts rcuziviugdimqninn xylem 989T «[1990.- 94112-111 l99l 47.2-16-m {$2.
`143-97:In 1993. and 99,502m 199‘}Mid!!! numberofdmths was calmla‘ted Hung cdmchative' csfi-
`armies 91:: l patient tutu ufngmnulm-vhzsusand a 15p‘cmmt rate oFus'ociatcdmortality.'lia'sed on pre—
`marluct diniml research.
`
`54
`
`1993, and to 99,502: by. the end of
`1994.
`.
`Among the total 0199,5302 patients
`WMCSERVICBS 0 January 1996 van No.1
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`sis-related complications between
`1'34)"me 1990 and Dcocmbcr 1994.
`Figure 2.5l1¢)ws the cumulative ex-
`pected and actual numbers of deaths
`related to agranulocytosis much calen—
`dar year during the study period. The
`expected death rate assumes a 1 per—
`cent rate ofagmuulocy‘tosis and an as-
`sociated mortality rate of [5 percent.
`This rate is consistent with muscula—
`five estimates lrased on experience-
`abroad with clonapiue and on pub—
`lished research on InifllECl'll'l. an anti
`depreSsant that has leukopenia as a
`potential adverse cfiect (4.5).
`The difl‘croncc between the pre—
`dicted and actual cumulative death»
`rates——l49 predicted deaths com—
`pared with 12 actual deaths—sug—
`gests the benefib nfvrigorous patient
`monitoring. Those 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.
`Tabla 1 shows how [utientsurVival
`might have been affected over the
`study period if monitoring had been
`less rigorous. Actual clinical experi—
`ence in the US. from February 1990
`through December 1994 showed 90
`to 100 percent compliance with re—
`porting of white blood- cell counts; in
`that context, patients with agranulo—
`cytosis had an overall risk of filial
`complications of 3.1 perccnt (l2
`deaths among 382 cases, of agranulo—
`cytosis).
`At the other extreme are the initial
`
`findings on this‘topic from Finland in
`1975—1976, wheren 50 percent rate
`of mortality Enlarged among patients
`whodcvclopcd agrmulocytosis (eight
`(133.th among 16 cases of Agrannlocyw
`torts). Rates of white blood cell moni—
`toring Wore estimated to he :10 to 45
`percent. The outdated medical and
`monitoring conditions existing at that
`time. clearly no longer apply, giyen
`the heighumed awareness of floral»
`inc and its diorapeotic and adverse.
`ellects. However, hemeen the cur—
`rent U.S. experience, representing
`the highest level of monitoring. and
`the early Finnish experience, one can
`interpolate intenncdiatclsccnarins of
`adequate, Eii'r, or poor levels of moni—
`toring and the associated risks olTEILal
`unnplicatious ofagranulocytosis.
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`55'
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`Rate of compliuum (‘36:)
`
`Elfects nFaciwal and hypothetical ram ol'compliancc iu'remxting ofwhite blood
`all counts on incidence ofagrnnulonytnsis andre'lated deaths amrmg patients re»
`
`ceiviug clampine
`Agrmnhcytasis
`Duluth
`" -_—'—_
`Rare, (m1
`N was
`
`.
`Rate (’392
`
`N cases
`
`N pne—
`anblc
`deaths"
`
`,wiwl
`H010 10071.3?!
`:mm 455 -
`nu
`Hylmthctlcal
`75 m 90 ,
`60m 75
`45 to 60
`
`.60
`.80
`L0]
`
`382
`is
`
`597
`795
`995
`
`3.1
`50m
`
`5.0
`10.0
`IS.“
`
`1?.
`8
`
`'30
`so
`I49
`
`_
`—
`
`is
`on
`
` l 37
`
`r"z
`
`i _\- (w among 99502 patients. the cumulative number (If-[minim imiudul'in tin: untimurl registry I'mm
`Frlhumy 1990 though Dcccmhcr I991
`i N deaths among New of gunning-195i!
`3 (imam-with K clubs all” to 100 percent Lunlpliami: in‘reparflng
`4 [hula M99502 cut: includvll in the :mtiunal‘rcgisny fnoandJruuq' I}!!! through lkxmmhe: mm
`3 um: wrong patients treated when donplm: was first distributed cumulcfdnlly in Fmianfivin 1975
`
`during the study: period, there were
`2,931 cases ofleukopenia (crude inci-
`doute mté of2.95 po’rcentL 382 cases
`of agranulgcytosis (.38 patent), and
`i2 dealin- aSsocizited with agrannlocy-
`losis (.0172 percent). The rate of
`leukopeui‘éx umfiinusquilc closely to
`’ predictions linsed» on premarket clini-
`cal researchnfapp'ruximately 2.5 to 3
`pen-mil of all persons exposed to
`clo-mpine.
`However; tho crude rah: of agrauu—
`lqcytosis during the study period (.38
`percent) was- less than half that antic-
`ipatod froluprcmarkct rcseardi (1 to
`2 percent); [figure 1 shnws the'annual-
`number of cxpeotcd und'actual cases
`of ag‘rnnulocytosis-ovgr the study pe—
`riod; The expected number of cases
`
`was calculated conservatively, using
`the lower perccntn'ge estimate of l
`perCent'hased on the premarket clin-
`ical mscarch. Because the mte. of
`leukopen'in was consistent in' the pre-
`and poshnarlcet data, tllfl'lllflfc 5mm—
`able pastrnnrkd findings on agnmnlh—
`mitosis appear to bathe result of sys-
`tcmalic- monitoring, early detection of
`abnormalities in 'wh'ite blood cell
`
`counts, prompt reporting of - tliosr:
`counts to the national regisny. and
`prompt-discontinuation of clumpine
`among. anCutsr wlm'wcrc at risk fa:
`agrannlocytusis.
`
`Uer‘ztb rate
`
`tilt-spite intense monitoring, 12 per-
`sons died as‘ a refill ofag’mnulocyto-
`
`
`ram-'2.
`
`PmpccfiVC amihrsis of diets of rates of mnquiauce in reporting of white blood
`Dbl! counts on incidencc ofagmnulocytosis and related dmths among 20,000 new
`patients receiving alumina over a. one-year. period
`
`Onfimnfic scumrio‘
`Realistic scenario?!
`
`{late of
`death (‘11)
`3.1
`5.0
`um
`ran
`
`N
`deaths
`2
`6
`16
`30
`
`N pre-
`veritable
`deaths“
`0
`4
`14
`23 p
`
`N pre-
`ventahle
`deaths"
`0
`‘2
`a
`"I
`
`N
`rlezrfhs
`
`‘3.
`4
`
`55
`
` Rate of Agmnulocymsis
`
`Cmnuli—
`.
`2.11m ('13
`Ba!e,(.%)
`
`N
`
`9U 11 r 100
`75 low
`601015
`451060
`
`.33
`.60
`.80
`
`1.00
`
`76
`[-20
`‘ lfnfl
`2m
`
`.
`
`‘ AW'133PIQKEBI rater smart]: among casts of agl‘artulrx‘yl‘nsis, mam-«lino: rifllurnumlmr ui‘mm: in
`mining budgot'eompliancc
`EAssn-inc: I-‘al'e: 05M amxg came: of agmnuloqnosis inmnsrs as number at nuns viflm with clo-
`tfl’flsc'd levels: ofcanvli'aim ,
`‘1 ‘bnipqedwixh two ileutlnatw to 100 percent compliance in reporting
`
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`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 nF-an
`estimated 5 perceul among patients-
`who developed agramilocytasis; a,
`moniwring rate of. 60 to 75'pcrccnt
`with an- estimated 10 percent rate of
`fatal complications, and a monitoring
`rate of 4510 60 percent with an osti-
`mated '15 percent rate of fatal oomph;
`cations, the level recently reimrted
`for deaths related to agnmulocymsis
`associated with mianserin (4). Thus if
`monitoring standards in the US. had
`been less stringent berm-ten 1990 and
`1994-, between 30 and 149 deaths
`might have OCcun‘cd, instead of the
`1‘2 deaths that actually occurred.
`
`Prospm‘live amlyscs
`Based on «unemtive projections of
`current rates ol'accoss to clozapiuu, at!
`least 20,000 Americans per your are.
`likély to be newly exposed to cloza—
`pine in the coming years. If these pa—
`tients are. [mated under Current mon-
`itoring conditions, about 76 palicnls
`(38- verdant) are likely to develop
`agmuulocytosis, and two patients are
`likely-m-dieof.Complications ofa’gm‘n—
`uloaytosis(3. 1.: percent among agranu—
`loeytosis cases) in each annual cohort.
`('iiven those mtes,. whalL would hap-
`pen if-standards For monitoring were
`lowered? Two principal scenarios,
`whose rates are shown in 'lahle 2, can
`
`be considered. An optimistic scenario
`presumer: that maliml practice has ad-
`vanced. enough that most cases of
`agranulocytosis.
`including sympto—
`nurtic cases, can lie arrested without
`
`Ertal complicationsl Thus if one as~
`sums-s that adequacy ofmonitoring has
`no hem-mg on fatal outcomes,
`two
`deaths could be anticipated among the
`next 20,000 new Clo/affine patients if
`monitoring compliance remains at
`our-rent levels.
`IF the rate. of compli-
`ance drops. out: will likely see an in—
`crease in the rate 01' aginuulouylosis
`and an additional. two to four deaths.
`The second, more malistic scenario
`assume-5 that early Jetwtiim'antl con-
`firmed vig'lanoe exert a favorable im-
`pact on the rate of agnmulocytosis
`andthe rate of Fatalities. In this see»
`
`uario, a wider nmgc'of outcomes can
`lie pmjected. and substantially poorer
`outcomes are likely; For example, the
`estimated risk of agranulucytusis
`would range From .38 to 1 percent and
`the rate of fatalities from 510 15 per-
`(gent. The projections shown in Table
`2 somest that if monitoring deterio—
`rates from curccnl
`levels, between
`four and 28 additional deaths may oc—
`cur among each annual cohort of new
`patients.
`
`candusions
`In the first five years of commercial
`distribmiou of clozapinc in the us.
`the national clampine mg‘uny syslcm
`
`appears lo have contributed to reduc»
`ing mortality related to. complications
`ofagi‘diiulm'tnsis substantially below
`projectul mics- dcrivod from premar-
`ket data. The rigorous safeguards in
`place to maximize the opportunities
`for early detection of white blood cell
`suppression have been associated
`with firvorablc outcomes in rates of
`both agranulocytosis and fatal compli-
`cations. Dtmreased figihnce would
`likely be associated with an incrmise
`in otherwise preventable deaths. 0
`
`Acknowledgments
`The author thanks Felix Ail-.llzino, M.D._
`and Sheila Waiter, MD. of the drug reg—
`isluuliun and regulatory affidn
`-
`ment and Anthony Biuuuliiui a
`[lie
`Clozaril nzlinnal mgish-y at Sandoz Phar-
`maocutimls Corporation.
`
`References
`l. Health can; réibnn [mime-scans with sc—
`um: mania] illmmix mpnrt uf flu: National
`Advisory Mental Halli: Cmncil. America.
`Journal ofPsychiatry mum—1465,1998
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`ta
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`Kane 1.“. lltmigfelrl G. Singer J, etval: Clo-
`mpiue for flu: mmmcnbresisfint schizo-
`phra'u'c. Archives up ('iiaimfl» fiyflhimry
`45:789—796, 1988
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`.‘l. Pisciulm AV: Agunulocytosis inducpd ’by
`certain pliermlllinziur; (lcl'ivflliflii- [AMA
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`4. Adams PC: Miansa‘in-imlumdaglanuquu
`tosis. Brifisthedlml journal '943-52205—269.
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`Conlter DM, Edwards IR: Miauseriu and
`ngmnulocyloxis in New Zealand. [aired
`336:785k7li7, I990
`
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`termt, to-Jolm A. Talbott, Ml), Editor, Psydziahic Services, A'PA, I400 K Street,
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