ects of the Clozapine
`estry ystem on cience of _
`
`to A
`
`
`
`0 Gilbert Honigfeld, l’h.D.
`
`This material may be protected by Copyright iaw (Title 17 U.S. Code)
`
`Objective: Clozapine is the only medication distributed in‘ the US‘. :thron.gh a
`national patient registry system that provides the medication only ifresults of
`patients’ weelrly blood tests show no evidence 0F significant white-blood cell
`suppression, an effect that can be fatal if it progresses to adv.anced::_igranulo-
`cytosis. This study assessed morbidity and mortality related to agrxuuloeyto-
`_si5::(_l'uring the first five years of the national registry-system.
`Data
`li—‘om-‘the national registry database uli.lilIl.2lil1ed’:l!-y the (LS. 'ma_-rmfacturer. of’
`clozapine was used to determine the level of treating .systcnis"ndhcrc_n_c'e:to
`Hie"-mandated program. of weekly white blood=.c,ell5coui1t’s, number:of7in-
`stanoes in "which elozapinc treatment was clc:ticd‘:hccaosc:of—;p_rio'r'v
`nation-of white blood cell suppression, and number oFmses»oF;a_granjnloeyto-
`esis:.a?nd:dcatl1—s related to agrurnulincytosis among treated?palti1érrts.=fi:oni;l?'éhru-
`ary _l990, when clmnpine was aymmercially inh‘oduc’erl.i‘n'-tlic
`December 1994. The actual numbers of cases of agranuloc_ytos'is and::_re'la_terl
`deaths, were compared with expected outcomes based’ u-n- clinical.'resea'tcih
`done hefore the drug became available commercially. Results: Appto:rin1atc—
`1;» -97-percent oftrcating systeius had a high -ovemll'»lev'el ofadherenc'e,:=to the
`registry protocol. [n 28 instances, the pretreatment authorization
`.men_t..resultod» in denial of clozapine; after. additional were conside’rjed,7
`15 of the patients were cleared for treatment. The aclua.-l inoide_nces_;of I
`cases of agranulocytosis and 12 related deaths were lower than
`.
`995 cases" and [49 deaths.
`The clozapinc
`-fostered‘ early detection of white blood cell suppression, prevented‘ ?ncj't'r¢;a_zts
`-m'e_nt'wid1~-clozapineof patients who had prev?iously develn[le¢‘l"whitier-liliiod
`ccljl sunprcssion, and brought about lower than expectedArates.oEagranulo¢'y-
`tosis and associated deaths. (Psychiatric Services 47:52$6, I996) ‘
`
`side in the United" States- They repre-
`sent pntential mnd.idate.s for treat-
`ment with clozapinc, an atypical an-
`tipsychotic medic-zition indicated for
`the treatment-resistan-t patient Asof
`December 31, 1994, u tutalof 99,592
`patients in the (LS. h_‘ad’l)ee'n exposed
`lotclozapine, and more
`half of
`Vl'l‘l'f3I11 remainedon the medication at
`that time.
`,
`.
`Increased public interest in clum-
`pine and A enhanced Familiiariity of
`physicians with the met-lication . niake
`it likely thattherapcutic use or c-l'o7.a-
`pinc will become more mm-mun_ in
`-the coming yc_a.rs. However,
`cl_oza—_
`pine use is associated’ with -risk of
`.agrf.tn.ul.ocytosis_, a potentially {ml
`"blood disorder that
`is usually‘ to-
`vczsihle if detected early 'enough..
`Limitations--in social and medical‘sup-
`pm-t networks For persons with severe
`mental
`illness. underscore the need,
`-for.prooeclu'i1:s‘to- help safeguard this
`vulnerable patient group From such
`adverse side effects.
`'
`V ln lceéping with general principles
`developed by the Food and Drug-Ad-.
`ministration, currcul _procc(_luros -ll)!”
`distribution of elozapine stipulate
`that tl‘1c-medication. is’ a,\.;ailable'in the
`US. only through treatment systcxns
`registered with the national
`developed’ and maintained by the A-
`US. nuinufiteturer of clozupine. The
`ofthe registry is tottenhance
`:-paLient'vsafé‘ty by. facilitating. Carly dc-*
`.te.ction. ofzpotentially dangerous white
`blood cell suppression, ,d.i'_spensing-.
`'the'medioa1'ion‘ only to patients with
`current‘ hlnml
`tests, delineating re-
`
`.
`
`Dr. Honigfeld-is asmciate professor in the
`liepamnent of psychiatry at the Robert
`Wood’-lj0hn.wn Meclical School of the Uni-
`versity of Medicine and Dentistry of New
`jersey, 675 Hoes Lane. Piscatatray, New
`jersey 08854: He served as consultant to
`Sanduz Phwuuzceuficuls Corporation at
`theytiam: ofthe study.
`
`Wockhardt 101 1
`
`52
`
`,
`
`n 1990,, :1ppro_x_in1ately 5 million
`persons in the Uni't_ec'l*States'.suf—
`lerecl from severe "meuta_l
`rlr-.rs. Of those, more than half, about
`2.5 million had sehizoplu7enia= (1)-.
`Among persons with scl1izopl_1r__enia,
`between [0 -and 30 .per<:g=.nr do -not re-
`spond adetiuutely to staiidarll anti-
`[Jsychotic agents, because the: agents
`have suboptimaljetlicacy or: intolera-
`ble adverse ’elTec'L<'.'
`"I='l:'us
`250,000 and treatn\ent‘—I‘ésis-
`lzml persons with scliizophronia» "re:
`
`ésruumucsmvzns 9 J:.nuzty1996~ Vol.-47 No.1
`
`Wockhardt 1011
`
`

`
`Sponsilui-lities for patient monitoring,
`and eliminating as candidates for
`therapy anyone with a history of
`chzapine-related white blood cell
`guppfcsslotl.
`All potential candidates Eir the
`medication must. be cleared t.ln-ough
`the 'nat:iona_l ffiglshi’ -*0 1-d€“fil}’ Pm‘
`sons who have had significant Cl(J1::t-
`pine-relattxl while blood cell sup-
`prcssion in the past and who should
`not receive the Inedicatiou again be-
`cause of nIarl<edly increased risk of
`gglanulocymsis. White blood cell"
`counts are normally
`per cubic
`millimeter or greater. A white blood
`uall count below 3,500 per cubic mil-
`limeter inizlicates leulcopenia, a condi-
`tion of mild white blood cell suppres-
`sion that is generally reversible upon
`interruption of clozapine therapy.
`Ag-nmulocytosis, a potentially Fatal
`coniplicatiun, isindicated lay a white
`blood cell count helow 2,000 and de-
`
`fined hy an absolute neutrupliil count
`hclow 500 per cubic millimeter. Dis-
`continuation ofclozapinc is mandato-
`ry for patients with agrannlocytosis
`bec~.iuse they are at high risk of death
`secondatjv to a wide range of 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 clozapiac and lot‘ fiiur weeks af-
`ter {reahnent ends. The medication. is
`dispensed weekly only to patients for
`whom data on current white hloorl
`
`cell counts are available. The registry
`system also outlines the rcsponsihili.-
`ties of physicians, pl1a.rrnaci(-:5, pa-
`tients, and the medication’: manufac-
`turcr and wholesale distributors in
`
`ensuring proper use of the medica-
`tion. Distribution ol the medication‘ is
`(L
`limited to registered pharmacies,
`which agree to follow the
`no
`l!l0od—uo drug" guidelines.
`Treatmentsystems 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
`risksof elozapine therapy and the re-
`quirements for weekly monitoring,-.
`Subsequently, national registry stall
`Follow up with the physicians and
`plrarmacists involved to verify that
`the-problems have been corrected.
`
`clinical pinc-
`This paper
`ticc related "to the clovapine national
`regjshy system, reports on the inci-
`dence of agranulocyttisis and ‘agrono-
`locytosis-related deaths from Febru-
`ary 1990, when elozapine was. first
`distributed cominemially in the U.S.,
`to Deceniber 1994*, tultleoniparcs this
`clinical experience with expectations
`based on pt1eIn:n7lcF.t clinical" research
`projections.
`A
`This study does not a(l‘(lress.dir'er:t-
`ly the issue of optimizing the fre-
`quency and pattern.of white. blood
`cell
`testing, although the study's
`prospective analyses of rates ol7agran-
`ulocytosis and related deaths may
`have some hearing on this issue. The
`issue of whether formal alterations in
`
`the current reqiiiremeiit of weekly
`hlood tests
`result _in,an 7-‘aeeepl-
`able” increase in-risk-is the focus’ of
`
`separate epirlemiologic studies and
`will not be considered here. This
`
`study vspecifica-lly a(l(ljressed- current.
`quality assurance functioins
`-and
`sought
`to answer» the question of
`whether the nsx.-..voFa single, national
`registry of ¢:lozaipiiie.users
`the
`Uilited States’. ‘lias'»e11'.l.l'an'(:e(l= pafieiit
`safety -and icontrihuted» to the savingof
`lives.
`I
`
`Methods
`
`1‘be,rralio'rn-at
`All data _coming‘.: to ' the clozapine. . na-
`tional"
`enterc'<_l:'in_toaan in-
`tcgluted,
`eo1ripfuteri2.etl';.Vdatal1a.se-
`maintaine.d"5 the manufaetllrcn. Pa-
`tients’ computer records l
`- are - estab-
`‘lished -during the ‘initial phmie calls
`-made by
`Who’ are.s_oel<-ing
`clearance -toi-st_atta.spceificl patient on
`clozagine; "l:'he- records include the
`patients ide_n_tifyiIng' code number
`'£1l}€l
`initials,
`identifier-
`tion,
`the phannacy’s identification,
`dosage of" Vclozupine in mil-
`li_gmm;s,_ and whites Blood» cell .te=.st
`dates"-and‘ resi'1I'ts. ’
`_
`These data are 1:et’;u’_ned penna-
`uently, and .'éidt:l.itional data are added
`each week.
`more tllaU':60,0Q0- pa-
`tients. _curren_tly. rieceive clo7;zpine,.
`more than
`separate fields-of
`sent to--‘die inauuTae_ti._u7er’s
`each-xirfifir‘-lC_ lln. addi-
`national:
`‘in-ain-
`tion,: -separate .
`_adi4e,rTse
`taiued‘ to traclé all
`reactions-
`analyzed in this‘.re-
`
`r.sYoin1‘lll2sl¥lthtilSL0}aLmry 1996 W1:l.47 No.1
`
`port were rlmwn. from those sourccs
`and were provided by the ina.nuFac-
`turei;
`I
`‘We used these data to examine two
`process variables related to functions
`of the national registry system over
`the first five years ol"c>on1merc_-ial dis-
`tribution ofthc medication: -level of
`
`acilherence to the. registry i)rotocnl
`-and denial of clinir:al_l._v inappnipriate
`retreatment. We also examined "two
`outcome varial'ilcs—i_a'tc of agranulo-
`cylosis and rate of deaths related to
`agr.muloc_ytosis—and compared those
`rates with the rates that were_pre¢liet-
`ed in analysns contlucted before the
`medication was commercially distrib-
`uted in the U5.
`
`ltcsu-Its and discussion
`Adherence to
`protocol
`The manuliicturer's educational and
`
`servicing-_ activities, plus ‘the potential
`threat of disciplinary action such as
`deregistmfioli as a clozapine treat-
`ment system_..app‘n:uf-' to have resulted’
`in generally high levels of adherence
`to weekly In-ionitorirng; f0ver' the first
`five years of commercial (listribution.
`ofcltzaipiiie, more than 97"perceut of
`treating physicians and phan-maoists
`man.-aged their patients on clozapinc
`at high overall:-levels-of aclherence to
`the requirements—of the product. 121-
`beling. The remaining 3~_poreent have
`been e‘haz-acterized by
`levels
`of protoeolleomplianoe. National rog-
`istry dataishow thatra small peicent-_
`age ol’lrea1_nIent.*systems periodically
`Eel§3X:3(lltGl_1“.l‘l(:t) to .monitorirr-g, guide-
`lines.
`
`- Of themore than 10,000 physicians
`and phannacists currently iuvolyéd» in
`tlispezisixigiclozapine, about 700 are
`contacted annually because of poor
`compliance in reporting data to the.
`nalioual
`registry. National registry
`stall‘ institute corrective actions. in-
`cluding cducatio_n_.3
`.manage-
`ment training, and i ntensified-review.
`As new treatment systems
`added,
`and older 011% ‘may l:'ecom_e large or
`complacent,
`this iterative’ process
`continucs.
`
`.
`
`Between 1990 and I95-J2, analyses
`were perfonned to detenniue il'cor-
`rcctive actions "by natinnal'l‘re_gistry
`stall" were associated with improved
`-reporting of white’ blood cell counts.
`Iu Martin 1992 registry staff identi-
`
`53
`
`Wockhardt 1011
`
`

`
`centiof the required records of white
`blood "cell cmmts._ One year later, in
`April. 1993, despite the addition of
`_more_ than 400 patients_ to the case-
`loads at" these 100 physicians, for a to-
`tal 0F2=,767 patients, the percentage. of
`acceptable reports. ofwhite blood cell
`counts by these physicians_ha(l- im-
`pmved-to 61 percent.
`
`Denial of rctnmtmcnz
`Patients who have discontinued use
`of clozupine due to agrantxltvcytosis
`at increased risk ofdeve.lt)ping_ the
`reaction again, generally earlier in
`the:-qpy and in a more aggressive
`fbrm-, if cl07.'«1pine1's reinstituted (3).
`'I"hcnaLiuual registry clears each po-
`ten-Hal candidate for ciozapine them-
`py to reduce the chances nf reexpo-
`‘sure tn the mcdiuiliuu by persons at
`increased risk of d‘eveloping»ag1:mu-
`l0cyl0sis_
`lielween February 1-990 ‘and De-
`ccmber 1994, them were 28 instances
`in which potential-catldidates. For the
`medication weredenied retrealment.
`Nine insl1uI(.‘es
`involved: .eig_ht pa-
`tients who hadeonfirmcd histories of
`white blood: cell counts helorw 2,000
`or absolute ncutrophil counts below
`1.000. The nine instances included‘
`two altcunpts to obtain rctreéltrnent
`crlearzlnce for one patient In "four. oth-
`er instances the regisby was tested’-by
`the nm.|xufaclurer using i(._l,(.‘:_[lEill(.‘1:_lti<2n
`numbers of nun—reh-eahtbl_e patients
`to _as$urc that the systenr'fimctione(l_
`appropriately. In the _ other 15 in-
`stances, retreatment wasdenied until
`closer-inspection revealed errors‘ in
`data’; these patients were subsequent-
`lyclcarcd lbr retreatmcnt.
`
`Rate of agranulocytosis
`Between February l9J0l and Decem-
`ber I99-71, a total of 99,502 patients
`were exposed to clompine in- the l.-i._-_S'-.
`and had‘
`(if more than,onc
`white blood cell count. Duringfilre
`fin-L ¢:.ilcndur year in the-"study period
`(1"el>ru:uy througll Deceluher I990),
`9,807 patients were expnsed’te.c1'uza-
`pine. The‘ cumulative tutal . had in-
`(Ere-.:{st-.(l to 24,112 patients "by the ‘end
`ofcalendézr year 1991., to 47,246 nt’tl'1t: ,
`e'nd_o[ 1992, to 74,345 at‘ the cnil of
`I993, and to
`‘t[16'€l‘(d_'0f
`1994.
`»
`
`‘
`
`'
`
`Among the total of-99,502‘
`
`
`
`Figure -I
`
`Cumulative number of actual and predicted cases of aganulocytesis umung"pa-
`tieuts receiving clozapiue, 19904994" ‘
`
`1,000
`
`800
`
`400
`
`5 z
`
`200 -
`
`
`
`9
`
`___
`1990
`1991
`
`
`1993
`I 992
`
`1994 ..
`
`' Cuunudnliw. numbers nfimflnnl:-receiving L-Ivnupinc were 9.307 in 1990, 2=1,l_.-1:2 in 1991; -4'53-1_(i.in‘ 1992.
`7-1_.:I11.§ in IlM'i_ and 99.502 in 1994. Pu:d.I'.ct1>d number ofcasetwas calculated using: mnscrvafiye esti-
`mate nfn I
`|"N31'L\’tlll' mm nfagmnnlocylosis-, lxtsalon premarlcct clinical-nasearch.
`
`fled physidans who had more than six
`patients for whom more »than.:10-pen
`cent of the required reporlsvof
`blood cell counts in the latest “three
`months were missing; ’From.‘this
`the 1:00 physicians with highest
`percentage of patients for whom
`
`more than 1.0 percent of the
`wcretnissing were i:den:tifi‘ed'.” that
`time, 3:th_(;sc L00? pl'1_ysician’s;. were’ re-
`sponsihletfor 2;343;.patients'.
`=B"ef<">re-«‘tIxe ‘intenkention national
`registry stat}; percent. offltliose pa-
`tifcntsiwere missingmore th=an,1‘0,per—.
`
`
`‘Figure 2.
`Cumulative number of actual and predicted’-deaths relatedftoi complicutigns of
`agmnulocytnsis among patients m_cci'viug
`dozapinc, 1990-1994‘ {
`.
`
`.
`
`160
`
`140
`
`3
`
`Npatients
`
`1990
`
`1'9‘9i'
`
`L .V-
`
`-19J4-- -
`
`l12?iii..,I’99l.47;)
`t Cumulative munhcrs ofpatients, |‘cL_1:iiring
`7-L’!-1265.i.n 1993. and 99,502 in ’1a9nnaI_i¢'exI h'iimlré.r.'
`using cdxiécervntive esti-
`niatesv oia l—.pe-went rule: ufngr4'nulm-gtlzsiiand 8‘-3I5.‘[)'(‘1t:(:I|3.' rateoF on pre-
`1narluct.clim'c-al re.-scan,-h.
`_
`'
`
`gI i i , f
`
`i 9 s
`
`‘
`
`
`
`54
`
`Wockhardt 101 1
`
`PSYCHMIITRICSERVICBS 0 January 1996 Val.-£7 No.1
`
`Wockhardt 1011
`
`

`
`rabie I
`9
`Elfects ofactual and -hypothclic-‘al rates oi'con;p_liance. in'1'ep_o1ti,n_g ofwhite blood
`C611 c[')u|1‘l,S'O[l; incidence ol'agr;1nulot:ytnsis and related‘
`a1nt),ng_re-
`ceiving Cl"?-“Dine
`
`Rule of compliuum (96)
`
`Agranulocytosis
`———e———
`Rate (%)1
`N cases
`
`.D‘caih
`
`,
`(-‘2‘r'_.:)3
`
`.
`
`,-wxud
`mm 100'
`301:0‘ 455 -
`H)1vallIt:l'lC31
`75 to 90' :v
`m.m75
`45 to 50
`
`nu
`
`.50
`.80
`LCD
`
`332
`Hi
`
`597
`7.95
`995
`
`3.1
`50:0
`
`SI!
`10.9
`l5_0
`
`12.
`8
`
`'30
`30
`l-l9
`
`N pre-
`vcntablc
`deaths-"
`
`_
`--
`
`I3
`68
`l37
`
`I
`
`(‘uses among 99% patient: the cumulative numl)r.1' 01'-patiritits-irn:l11tlix'l'in the uufiunul l'L'g‘iSlI)" frmu
`I-‘(In-nary 1990 lhnmgll December 1994
`‘- Nd¢;ulis_ aunong N-cascaj of aogmnuloc,-tosis
`3 (,'4mqnn:'cl"\vi.tl'1'K dauhs at 91 in 100 percent x.un1pl-iance i:n‘reparflng
`4 Rah: :unung99.509. c.-ucs
`in the national tcgistn-_v fmm'Fd§nm.3' 1990 through -Hocnmher l9H-1
`5‘ mm; pa:-icnts u-cased when duzapim: was 5:31 distributed oomnicrdally in Finlnndvili l.9'i'$
`
`;‘\'r<_
`
`ilua‘ng.thr:. study: period, there were
`:2,931
`of--leul<openiz1(4:rude inci-
`(l.cuce- rate -of 2.95 vp(‘frcent),. 382 cases
`of
`pemexnt), and
`£12 dcatlis a$S0'(;:lIi.ted»Wi£l1 agr{muloc.y-
`losis {j.ll5lf-f2
`The rate of‘
`leukopetiiéx (,'t-uLlbrm.s.quilc closely to
`’ predictions lrasecli on pxtemarket clini-
`cal -rese'ardi..uf'approximately 2.5 to 3
`percent val’ all persons exposed to
`clo-'/.apiin'e.‘
`I
`H'owe.v.e!',- the- crude I-‘¢_1l.C ol-agra.uu-
`locytosiis during the s'tudyiperiud (.38
`percent)
`than -lliilfltliali antic-
`ipated v l‘:-‘olu .prcmarlcct resmrch (1 to
`21)ereent);__ lligure 1: shows-the
`uumli)er~.of-
`and‘ actual cases
`of agrunulocytosisv-.ove:' the study pe-
`riod;
`expected number of cases
`
`conservatively, using
`was
`the lower percentu’ge- estimate of I
`percent"based'1_m the premarltet clin-
`ical research. Because the rate ‘of
`let1l(open'in- was consistent in’ the pre-
`and postrnarlcet -data, the: more favor-—
`able pnshnurket: findings on _ag‘rannlu-
`c:ytoSié
`to beitllje result of Sys-
`l'cma[it.-:- tnoxiitoriilg, carlyzdctectiou of
`alanornialifim. in iwhiite -blood cell
`counts, prompt-I reporting of -
`counts to the national _r'egish.y,. and
`pmnnpt-discontinuation of clozzagiine.
`among. p::¢l.-i_cu_[s' who were Vat risk for
`agranu-locyfosis.
`
`Heath-rate
`I516-spite intense monitoring 12 per-
`sons
`a result of ag’I‘.anulocyt'o'-
`
`
`rantcé.
`
`Prospective anahnsis-_ofcli'cc1:s of rates of wxupliauce in reporting-of white blood
`cell counts on‘
`ofagmnulocytosis and related deathsvamnng 20,000 new
`
`pufient: -receiving cloyapine over a one'—y_car. period
`
`Rate nf
`com;yli—
`2-I'K=r= (‘kl
`901--—1.uo
`'75 1'09}
`60Atn~25
`~firo6o _
`
`’
`
`-
`
`Agnmulocytmis
`_
`'
`R1_nie§(.%)
`N
`.53
`M
`76
`.L7fl
`‘ mo
`200
`
`. so
`-1.60‘
`
`A
`
`-Optimistic slccvnaz-io‘
`
`=Ileelist_ic scenario’?
`
`N
`(‘l(§l.l’l'§h'
`2
`4
`5
`5
`
`N pre-
`ventahle
`(la-.-alhs?’
`o
`3
`1
`4
`
`l
`llatc of
`death (‘Z’)
`3.1
`l
`. 5.0
`10.0
`5.0
`
`N
`deaths
`2
`6
`16
`.
`.
`
`N pre-
`ventablc
`deaths“ '
`o
`4
`14
`23 b
`
`l
`
`‘£321
`
`V‘-\i'i¢_1_us
`
`rat: ol'._d'e;ith among tags of agranulzx-.ytnsis, wganllin: rif'Ihl:‘nu'mlx:r uf ad.
`'
`l
`I
`cat-Ies cl" agmnulocgatasis —iI'u'.rc‘,nsl‘s‘ 1:" n:umli:r nf m:«:.~: ;incn:uscs with (in-
`—
`_
`rzrcased léielsrqf .
`‘1 C0n|p:\:_ed3.will1.t$\1i.deatl:s at% to’ ll” pemcnt complianucc in rqmrfing
`1lmy:996 voL47 No.1‘
`
`sis-related complic-ations between
`1‘i*.ln1~ru'y 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 asrumes a 1 per-
`cent mtc ofagrainulocytosis and an as-
`sociated mortality rate of 15 percent.
`This rate is consistent with L‘01lSCl'Va.—
`
`tive eslimales based on expen‘enc¢=.—
`abroad with clorapine and on pub-
`lished research on mi-auscrin, an anti-
`
`depressant that has leulcnpenia as 21
`potr-.ntial' adverse eficcct (4,5).
`The dilIcrcIK:c between the pre-
`dicted and actual cumulative death
`
`rates—— 149 pwdicted deaths com-
`pared with 12 actual de.1ths—4<ug-
`gests the benefits ofvrigorous patient
`monitoring. These data show that our-
`vent medical pracficxe and monitoring
`procedures have coxatributcd sub-
`stantially toward saving the lives of
`many patients who require clozapinc
`therapy.
`Table. 1 shows how patient.surv'ival’
`might have been alifectcd over the’
`study period‘ if monitoring had
`less rigorous. Actual cliniwl 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 ag1‘an-ulc-
`cytosis had an overall risk of fatal
`complications of 3.1 ‘percent
`(‘I2
`dc-.-nits among 382 cases: of agranul/J-
`cytosis).
`At the other extreme are the initial
`findings on this ‘topic from Finland -in
`1975-1976, wherea 50' percent rate
`of mortality emerged among paticnts
`whodcvclopcd agumulocytosis (eight
`d'eal.hs among 16 cases 0F agrannlocy-..
`tqcis). Rates» of Wllitc l)lO0cl dull maili-
`turing ‘were eslinlated tcrhe 30 to‘ 45
`percent. The olttrlated -medical a|1_d
`monitoring conditions existing at that
`~liu1e.'c'le—:;rly no longer apply,’ given
`the heightened awarcxless of clozap—
`inc
`its llterupeutic and adverse.-
`elfects. However, between the cur;
`rent (18. ¢:tpcrien<—:e,. representing
`the highest level of monitoring, -and
`-the early Finnish experience, onet-.-an.
`intcrpblatc intenncdialc-scenarios of
`adequate, Elli‘, or poor levels’ of moni-.
`toring and the associated risk: olllizial
`‘complications of agianulocyiosis.
`
`55'
`
`Wockhardt 1011
`
`

`
`For example, a rate of compliance
`with white blood cell Inonituring of
`75 to 90 percent would be associated
`with a risk of Fatal comp'li<:ations ofian
`"estimated 5 percent among pali(:lllS_'
`who developed agrzmuloizytosis; as
`monitoring lftlto (if 60 to 75.lpcrccnt
`w1‘tl1 an estimated 10 percent rate of
`fatal complications, and a monitoring
`Late of 45m 60 percent with an esti-
`mated '1-5 percent rate of fatal compli-
`cations,
`the level recently" reported
`for deaths related to agnmulocytosis
`associated with m1':tns(*.rin
`Thus if
`V monitoring standards in the US. had
`been less stringent between 1990 and
`I-994, "between 30 and 149 deaths
`-might have occurred. instead of l.1l1C
`12 deaths that actiially occurred.
`
`Prospcdive analyses
`Based’ on cmzsenrative projections of
`current-rates olaccoss to clozapinc, at
`‘least’ —2(=l,0(l0 Americzms per your are
`lil_<<¥:ly- to be’ newly exposed to cloza-
`’pi'11ein_the-"comings years. If these pa-
`ti'ents"are. Ireatcd under current mon-
`itonng conditions, about 76 patients
`percent)» are lilrely to develop
`'agr4uufo<:ytosis, and two
`are
`lilcelyto-dietof complic-afions of a'gm‘n~-
`1: percent among agra.nn—
`locytosis cases) in each annual coliorl.
`these r.1tes,. wlmtwoultl ‘hap-
`pen if-standards For monitoring were
`lowered? Two" principal scenarios,
`whoserates areshown in liable 2, can
`
`be considered. An optimistic scenario
`presumes that In£i('liK"4l.l pmcti(-elu1sad-
`vanced. enough that most cases of
`agmnulocytosisl
`including sympto-
`mutii:
`can be arrested witlmut
`filial’ complications’. vTl_lUS if one as-
`sumes that il('l(’.qlh'I.(‘.‘y ofmonitoring has
`no bearing on fatal outcomes,
`two
`deaths. could be anticipated among the
`next 20,000 new clmzapine pafients if
`.monitoring conipliaiux: remains at
`(:urrc=.nt levels. It 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 rcalistic scenario
`assmnrfs that early detection.-:md‘ con-
`tinue'_(l viglanoe exert a favorable. im-
`pact on the mtfe of agranulocytosis
`andthe rate‘ of Ettalities. In this sce-
`
`nario, a widcr range of outcomes can
`be pmjocred. and substantizi-lly poorer
`outcomes are lil<ely.— Pbr example, the
`estimated risk of agranulucytusis
`would range from .38 to I percent and
`the rate ol-fatalities from 5h) 15 per-
`cent. The projections shown in 11151.:
`2 sugest that if monitoring deterio-
`rates froili current levels,
`l-yctween
`four and 28 additional deaths may oc-
`cur among each gum-ual cohort of new
`patients.
`
`Conclusions
`
`appcans to have contributed to reduc-
`ing mortality related to complications
`ofa.gr.u1ulocytosis substantially below
`projected «ates dcrivod"t'rox_n premar-
`ket data. The rigorous safeguards’ in
`place to maximize the opportunities
`for early detection of white bloodccll
`suppression have ljeen associated
`with tiworablc outcomes in rates of
`
`both agranulocytosis and finial couipli-
`cations.
`r)(‘.'(‘.1‘(-‘.aS(".(l
`\-.1‘gil'anc-.e would
`likely‘ be 2wsucia_t(:(l with an increase
`in otherwise preventahle deaths. 0
`
`Aclcnowledgmenls
`
`The ziuihor thanks Felix tklrallzino, M.D._
`and Sheila Waiter, M.D., of the drug reg-
`istration and regulatory aflilim
`-
`mt-.nt and Anthony Biuuclgiui u .Ll_1e
`Clozaril national mg‘isb‘y.at Sandoz Phar-
`maceuticals Corporation.
`
`Rdkrences
`
`l. Health cant" tclbnn for-Amedcans with sc-
`ram‘: nmut.-il llllllv‘_\'.\'lv:.‘i.‘ mport uf flu: Nsgtional
`Advisory Mental I'll‘:-aliii
`jourmtl cf'Psychia1.ry 15-0:14-47—I465_.
`
`_l~.')
`
`Kane 1.“. Ilonigfeld G-, Singer 1,, mi.-V C19.
`mpiue for thc trcatrncnt-resifint.scl_Ii2o-
`plireuic. AmlI_iv«:s'
`llf:('-:£ffl(1l‘ul.l’ lv‘:»y(:l'|'iiitrg
`45:789-796. l938
`'
`
`3. Fist-iultu AV: _-’tg1nml'oc_v_Itosis iucluccdJby_
`curtain plleuolllizmku-;
`il2::iva1ivi-.<s.- IRMA
`20S:l562—l.8GS, I959
`
`4. Adams PC: l~‘lviJn$€1ill-lI|€lfl.C6dvag‘I'§.lIll.ltIl_:}'-
`tosis‘. Bri1iSl1,tVIedlcal']olrPl\al 935':208—209.
`[932
`'
`'
`
`In the first five years of conimerciznl
`distribution of clozapine in the
`the national clozapine rcgistly syslcui
`
`{J1
`
`Coultcr DM, Edwards IR: Mi:mser_in;m_d
`ixgnnulocytosis in New Zealand. Lined
`33(i:7l‘l5—7l'i7,
`l5l$Kl
`
`Poet t by Journal
`
`‘Psychiatric Services seeks expert reviewers in the following areas:’
`
`{Outcome research, particularly in the area of psychopharniaoological treatment
`of mental disorders
`
`Qflating scales for symptoms, outcome, and other aspects of ufeatment
`ODual diawosis (mental illness and (lung abuse and mental illness and mental re-
`tardation)
`
`Oiflimtl psychiatric services
`{Patient and consumer perspectives and attitudes.
`
`witlirtlie-tliterflztture in_..tl1ci_r areas of expertise,
`Reviewers should be
`should have published in peer—reviewedjourna'ls, and should be Eimiliar with the
`content andfocus of Psychiatric Services.
`
`Prospective" reviewers should send. :1 curriculum. vitae, spécilying arau; of‘ in“-
`tenest, toijohn A. Talbott, M.D., Editor,
`Services, APA, I400 K Street,
`N.W§,.VVashi-ngton, D.'C. 20005.
`
`’ p Wockhardt 1011
`
`PSYCH1Kl'RlCSERYlt1§' . January 2995 Vol.47 - No.1
`
`Wockhardt 1011
`
`

`
`H
`
`‘vol; 4-; No.1
`
`
`
`’
`
`
`
`.
`
`A Ajoumal ofrhc
`V. zmncrican Psychiatric
`Association
`
`
`
`
`
`_
`
`50,-m.—_fiy
`
`and (-‘j(rnxnI»::Iii1,yV'Psychi_arry
`
`7 I-[ow’rc we Doing?
`
`_IobruI.Talb<-all, MD."
`
`Articles
`
`35 oonrcssaonsbfa Concurrent Rcvicwcr Paul C.MobJT. MD.
`
`41 long-Tcnnllnpacl; of(1ompincTrwt1n£-nt on Psydzialric
`Symptoms
`Functioning _‘Ie'fi%r'jI Grace, MD, Stephen B.BeI[u3,
`I’b.l)., Michael I. Raulin, »Pb.D., Mamin L1’-[em
`Barbara f.Priesr,
`RN, fiktorflrenner; MA, k'eny Dormelly, Pb.D.. Palricia Smith, KN, M.S.,
`and .S‘zL¢an Glam, RJ\{
`
`46
`
`Severely Disabled
`Clozapinc and
`‘ts Anthony A.Me‘nd1‘tto, ‘E_’b.vl).’, Niels Cflcch, Pb_D., Paul
`Slave, 1Ib.1)..5ju.di:1a.=A.r¢x-hex; 0.0, Mark Stacji, 41.9., Mwjy Beth logue, MA,
`and Ixee_[Baklwiz'.-, 31.5:
`
`32 Efiecls of flu: Glozzpine.Systcm on I_ncidc:m:e-ot‘ D“car,hs-'-Rdat_ed
`zov-Agmnulocyrosis ’ Cilbefi I-l(m!gfe1'2i, Pan"
`
`5-7 Charactetislicsandvsctvice Use.
`Gnr.-er ;S'z¢I[izwn,_ MJ)., MS;I?Ii-,
`L.S’p‘r-‘ttzez; 13..-1..
`
`mm
`Ajackson, 22:19., az3u1.lx_’anm*
`
`62 Quality. af-life ofIongstay.Padcn:s.Disdn:g9d:Fr'om.‘rwo Psychianic
`’
`11,-17: ‘A£D,.1:'KCI’:ycb., Dcw'i'2I"Day.w)'n, M.I?.CPsycb._. agn-5.
`topber Couch, ;1_LS'c., Graham Tbomicrofi: M.1?;'(Zl’Syc'lJ., and Walter
`W/flit RA, 3.56.
`
`Ahuse:in.Hospital-. and
`68- Outcomes ofRe¢3idx-nflal Treatment.-of
`Rudo_lf_F{.Mno5,.Pb.D., MetissafKz'ng, M.'1?H.,
`'
`
`and Micbaem;-P‘qzremon, BA.
`
`75 Sevctc Aggtcssibn
`Homdcss
`
`lhmaway and
`RobertE.Bool1J,.l‘ab‘LI2,aiz¢1Yz‘ni_t:1g 7baflg, M..$
`Ulazpy I171-fit’: ‘MKo7wz,
`
`Cate:
`Groups Greg
`27 law
`Paul 5. Appelbaum, M-J1
`
`MA. LEG, andfamjr§_—IiSalai1z, MD.
`of Mental Health Law
`
`Psychotherapy
`
`25
`25
`
`U)I0
`
`Stan: Halth
`
`of Public Mental
`l_.'ficct-§')f_(J_o1i_n':1(V:Al:i|g,on
`Teb-wAez'vl-lu; Pl_:.D., Brian=_[c‘igJet, 1.’b.I1, and
`’
`'
`
`onpsychiau-icfscmcm
`
`in
`Mary C.Ma5lan_(i, M.S.EH.
`I5 "Issues in-Managcd:’C:m:: Highlightsofthc
`
`Report
`
`
`
`Wockhardt 1011
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`
`
`
`
`IA
`
`C
`
`Ajournal of the
`American Psychiatric
`.Association
`
`V Formerly Hospital and
`Community Psychizrtry
`
`HEALTH SCIEMIES LIBRARY
`University of Wisconsin
`
`Madison. WI 53708
`
`JAN 1 0 1996
`
`1305 Linden Drive
`
`‘
`
`‘
`
`‘
`
`
`
`SC of Services by
`H Jntally Ill Persons
`Ying in Rural Areas
`
`6 A Concurrent Rcvit':wcr’s
`Guide to Coping \XF1t:11 the
`Demands of Managed Cart:
`
`O Combining_Clo7apine and
`Psy.chosocia_l Approachcs
`in Titatiilg Schizopllrcnia
`
`
`
`
`
`Wockhardt 1011