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`This material may be protected by Copyright law (Title 17 US. Code)
`
`Reducing Clozapine—Related Morbidity andertality:
`5 Years of Experience With the Clozaril National Registry
`
`Gilbert Honigfeld, Ph. 0., Felix Arellano, M.D_., Jitender Sethi, Ph.0.,
`Anthony Bianchini, and Jeffrey Schein, Dr.PH'_., M.P.-H.
`
`MR311393
`
`Madison,WI53706
`1305LindenDrive
`
`The Clozaril National Registry (CNR) wascreated to help protect patients from developing poten—
`tially fatal agranulocytosis secondary - to treatment with the antipsychofic . Irredic'ine clo7'4’1pit1e. The
`CNR. designed and maintained by the manufacturer of the branded Clozaril (clozapine),'has'thc prin-
`cipal goals of ( l) prophylaxis—preventing» inappropriate retreatment, and (-2-) quality assurance—-
`oversec'm adherence to a “no blood. no drug" policy. This article reviews the estimated impact'of the
`CNR on clorapine-related morbidity and mortality over the first 5 years of commercial experience in
`the. United States- Method: Completed‘ata on leukopenia and agrannlocytosis, gatheredfronr the CNR
`database for the period of 1990 ~l994. were reviewed and compared with data from the .pre-CNR peri-
`' 0d. Results: Use of clozapine in 99.502'patients according to package labeling'requircments' (distribu-
`tion of the medicine linked to mandated white blood cell count retiring} was associated with a total of
`382 cases of agranulocytosis (0.38%) versus anexpectcd cumulative total of995 cases-(based on-the
`prc-CNR rate of l% to 2%). Based onthe expected agranulocytosis rate, up to ['49 deaths migh't-have
`been anticipated. Instead there were only -12 death's attributed to complications-of agranulocytosis.
`Conclusion: The CNR provides.foruniversal-r‘echallcnge. protection as wellas- controlled dispensing
`ofclozapine. It also servesas an early. Warning system to promote the safe and cll'cctive use of clnza-
`pine The CNR includes quality assurance mechanisms designed to enhance compliance. Despite the
`added logistic requirements this system places upon physician. pharmacist, and manufacturer, the
`CNR has helped toreducesubstantiallypotentialfatal outcomes. TheCNR.reinforcesbothpatient and
`socialed fatalities the Neurnpsychopharmacology Advisory Committee to the U5' Foodand Drug
`Administration has unanimously recommended a-reduction-111 frequencyofthe white bloodcell count
`testing requirement after 6 months to every l4_d'ays._ instead of weekly. Finally, the CNR.database
`containing white blood cell count anddemographic data on every patient in the. UnitedStateswho has
`received the medicinehas served as a unique epidem‘iologic database.
`(JClin Psychiatry 1998;59lsupp13].3—7)
`
`About 1 adultin 100in the United States (approxi—
`
`mately 1.5 million) suffers from schizophrenia.‘2At
`least 10% to 20% of these patients are unresponsiveto
`typical antipsychotic pharmacothe'rapy.“ Another group
`of patients may respond to antipsychotics but experience
`dose-[uniting extrapyramidal symptoms (EPSJQr‘tardiye
`dyskinesia (TD). A large-scale survey of psychiatric pa-
`tients treated with conventional antipsychotics found an
`
`From the University ofMedic'me andDentistryofNew »
`Jersey. Robert WoodJohnsonMedical SCIIOOL Peshataway (Dr.
`Honigfeld)and Nouartir Pharmaceuticals Comoraliw1.b‘trst
`Hanover; NJ.. (Dr's. Arellar'w Sell-11', and92-1221}: 1211er
`Biamhini). Dr. Arelllmo15 currently at Zéneta
`Pharmaceuticals, l/Vr‘lmz'nylon,-fkl.
`Supported by an unrestricted edumh'onal'qmnt from
`NovarlisPharmaceuticals Comomtion
`Reprint requests to: Gilbert Honigfeld Pica, (haiverszty of
`Meditinc and Dentistry ofNew Jersey, Robert WoodJohns-mt
`Medical School 675 Hoes Lane Piscataway. N108844—5635.
`
`J Clin Psychiatry 1998;59 (suppl 3)
`
`overall proportion of TD. of 23%.5’ The prevalence of TD
`was calculatedto be about 5% per year of cumulative ex-
`posure to themedication for younger- patients for at least
`the first 4 to 5 years; this frequency is probably much
`higher.u1 older patients5 Tardiive' dys‘kin'esia is a major
`cause.of subcessful'malpructitw litigation against psychia-
`trists.6Thus in thosepatientswho do not respond to con-
`' ventional antipsyeho'ric therapy or for WhomEPS become
`unacceptable. such-treatment is often reduced or voluntar-
`ily discontinued by thepatient.5’
`'Clozapine(Cloza1il) an atypical dibenzodi-azepinean-
`..tipsychotic. has been found to offertherapeutic benefits
`superior tochlorpmmazine for a-group ofhard—to-treatpa-
`tients: (1-) neuroleptiononreSponsive patients , and (2)
`these potentially sensitive to the adverse effects of neuro-
`_lep_ties,3"".l2 Apivota'l. comparative study in 268 treatment—
`rbsistant patients demonstrated the therapeutic superiority
`of clozapine- to chlorpromazine in' relieving both positive
`and ‘ negative. symptoms- Among patients treated with
`
`'3
`AMN1034
`
`IPR of US. Patent No. 7,765,107
`
`AMN1034
`IPR of U.S. Patent No. 7,765,107
`
`

`

`Honigfeld et at.
`
`clorapine alone, within 6wa 30% Were judged to be
`responders. compared with only. 4% of patients treated
`with chlorpromazinc plus ben'ztrbpine (p < .001)? Cloza—
`pine has also been associated witha near absence of EPS
`and no documented cases of TD attributed to clozapine
`alone.'3'l7
`
`Despite these benefits, cloza'pine use has been limited
`only to those patients who. arertéSis-tant to or intolerant of
`other antipsychotic medications. This policy is "based
`largely on premarketing clinical research and foreign
`postrnarkcting experience during the 19705 and early
`19805, which showed that approximately 1% ‘to.2.%“of
`treated patients developed agranulocytosis, a potentially
`fatal complication.” 35 Bringing these data of the [9705
`into closer focus, however, revealed that the condition was
`
`reversible and that the risk of._death was related to the time
`and clinical conditions under which the diagnosis of
`agranulocytosis was made. When. clozapine-rela‘ted agra—
`nulocytosis was diagnosed after the onset of infection, as
`many as 50% of the initially affected patients died. But
`when their condition was detected by blood test. before
`they developed complications, and the medication Was
`promptly discontinued. no patients with .agraituloCyt'osis
`died.zz These results suggested that a patient surveillance
`system providing anearly warning of significant decreases
`in whiteblood cell counttWBC} could helplitnitrthe num—
`her and severity of episodes of agrantilocytosisFi‘” Clona-
`Pine was approved int-1989f0r use in the United-ewes.
`contingent on the manufacwrer’s implementation ofsuch a
`surveillance system, the Clown! NationalRegistry (CNR).
`Clozapine and the risk ofagramtldcymsi's. Agranulo-
`cytosis is defined as .an absolute neutrophil CounttA-NC)
`below SOC/[11111331. The onset of clozapine—iinduced agranu—
`locytosis is usually marked by a gradual. fall in WBC
`counts. often over several weeks;,rapid_ WBCdropsswithin
`1 week may also occur. but are much less .comrnonu7
`Most instances of clozapine-rclatcd; agranul-ocytosisoc-
`our early in. the Course of treatment. the retrospective
`analysis of 366 agranuloCyt'osis cases between l973 and
`[990, 75% occurred within the-first 118 weeks oft-reat—
`mentFE? The peak period ofrisk for-agranulocytosis was 2
`found to be during the third montho't‘treatnient?8
`When clozapine therapy is ' stopped upon identification
`of marked leukopeni'a, patients usually [ccovcr medieally
`and hematologically within 14 to 24 daysand without se-
`quelae. However rechallenging patients who have experi-
`enced clozapincdndueed amnulocytosnleads-to the node-
`velopment of: the dyscrasia. Theonset-ofthe new episode
`is usually more rapid and moreaggressive than the original
`episode. ln 9 patients known to have beenrechallenged
`the average time to the onset or leukopenia (WBC < 3000/
`mm”) or'agranulocytosis was 24:4. weeks-for; the first-epi—
`sode and 146 weeks for the second."9 Suchpanents should
`not be exposed to clozapincagain, since the risk of.a fatal
`outcome is apparently increased.71°373°
`
`It is .notpossible to predict who will develop agranulo—
`cytosis, and the reaction is not dose-related. 3" Although
`some data have suggested the possibility of genetic predis—
`position to clozapine--induced agranuljocytosis.31 others
`have not.” It has been suggested thatthc presence of the
`alleles HLA-B38 DR4, and DQw3 might be associated
`with an increased susceptibility to agranulocytosis3‘ How-
`ever, no reliable genetic markers have yet been identified
`
`METHOD
`
`‘
`
`The Clozaril National Registry: Principles and
`Requirements
`Clozapine is dispensed only through participating treat-
`ment systems registered with the CNR. Each treatment
`system consists of a physician. a pharmacist. and a quality
`assurance chairperson who commit to work together to
`implement the 5 major principles of the CNR: rechallenge.
`protection, centralized patient registration, weekly.IWBC
`monitoring, limited 7—day distribution of the medi‘cationff
`- and quality assurance. Except for rechallenge protection 9
`priOr to' treatinan all active clinical 'decision-rtmldng and
`patientmre responsibility occur at the: level of the physi-
`cians and pharmacists and their staffs, who together'com—
`prise each local Clozaril Treatment System. The specifics
`ofeach of the 5 basic functions are spelled” out belowi
`I. Reebatlenge protection Screening of. all patients
`through the CNR database prior to initiating cl'ozapine
`treatment prevents patients from receiving the medicine
`again if they have a record of ever experiencing clozapine—
`related agranulocytosis or severe leukbpenia‘lgranulocym.
`penis.
`2. Centralized beatment system and patient registra-
`tion. The heart of the CNR is anintcgrated, computerized,
`confidential database that is maintained by the manufac-
`turer. All physicians and phannacists who plan to use
`elozapine. for the benefit of Specific patients mustagree to
`abide by the package labeling requirements and register
`Zwith the CNR. Earth patient must be registered with the
`CNR before clozap'ine trcannent begins, Patients are iden-
`tified only by their initials, Socialhecurity number (SSN),
`gender. anddate of birth-
`'3. Weekly WBC monitoring. All patients taking c1073-
`Vpine must. have a baseline complete blood cell count
`(CBC) before starting therapy, In order for patients to he—
`ginxdozapinetherapy, their baseline WBC must be above
`3500/mm“; The WBC is then monitored weekly thereafter
`as long as they stay on the medicine, and for 4 additional
`weeks followmg treatment termination. Continuation of
`therapy requires that the WBC remain above 3000/mm3. if
`a patient‘5 total WBCIs found to be below 2000/mrn and/
`or the granulocyte count is below lOOO/mtn’, clozapine
`therapy must be discontinued and never reinstitutcd The
`CBC’and'WBC may be conducted by any laboratory of the
`physician‘s choice.
`
`J Clin Psychiatry 19985“mid2
`IPR of US. Patent No. 7,765,107
`
`AMN1034
`IPR of U.S. Patent No. 7,765,107
`
`

`

`appear, the CNR staff institutes cor-
`rective actions.
`including educa-
`tion, clinical management training,
`and intensified review. These ser—
`
`vices, combined with the prospect
`of de-tegistration for a noncompli-
`ant treatment system. have resulted
`in overall
`levels of adherence to
`
`weekly monitoring of 97%.14
`
`Assessment of Observed Versus
`
`Expected Rates
`Both leukopenia and agranulo-
`cytosis
`incidence rates obtained
`over the 5-year course of this study
`were compared with rates projected
`from the pre-CN'R period. Speci—
`fically,
`the pre—connnercialization
`leukopenia rate was 2.8%, and the
`agranulocytosis rate was estimated
`at 1% to 2%.
`
`RESULTS
`
`
`
`DOCTOR.‘ His form islor recording required WHO mire. Duis- information mustbe supplied to
`me phanmm‘m weekly. :1 advance of dispensing. Prescriptions milM21"be filled Withouta current.
`acceptable WBC count.
`
`Patients
`
`Paliant‘slnilials: LJ D
`CLOZARIL Status
`
`
`
`‘n'flhtfiudm
`I HI! DID
`I
`immanent; I
`
`“65%?th EIZI CE! [I]
`
`TotaiWBCmmttpettrm’HIO‘.
`I_ II III—I2103
`Interrupted
`Dismmhmed
`lsWBC eoumAeqeptauero-aspmsmg? I:I LI
`
`pnescr'uaue REMINDEHS:
`O Ina-11 NBC count falls
`0 Warrant should not be o Itwt was
`0 if total W8C: counlulls
`below 20m (2.0:10’]
`counts are between new
`mamotauxw)
`‘nitiuled ilWBC count is
`permm". therapy should
`loss than 3500 (3.51104)
`(31mm) and :sm (35x10') net "are.[lumpy shout!
`be discerninued and patter:
`per m'rr'.
`per mm" lwim mldywac
`beinterrupted and
`should neverbe lechellengm
`courts and dillciuiial
`patient osdymmi‘lored.
`widtt‘t OZARIL.
`mlsshouldbcperlonmd.
`,
`""—' "' '
`
`
`Pratt-amt
`
`i 3mm:
`
`Physician's Name (typed‘tx prinlcd):
`
`Ll Check here i this manna-eras a new address
`Address:
`
`City. State:
`Phone Nun‘lbar:
`
`'
`
`" -.
`
`_
`
`Physician'5DEA/ID Number:ELIm
`Today: Date: I
`I I33 I33
`Today's etoatmr Dosage: CD3 quilhllg'day
`
`mmfiIflE‘
`
`_ _
`F'trarmacisrs Name (typed or pt'nted);_______
`ammwawmwwrtnilirtm
`
`‘am ammmlwienu new) fllllhl'ln"in110mm. mam”. «91mm mos may ”mum watt
`sin-erratum
`MOTEIlE—fizlfrusnrz WMWMqMMIMWfiWWNJMflNWW‘MYUML REGISl'Rl/bytha
`Mmmusmm-«ms
`9W mmmmm-tmmw. Nae/mm}fiaysfiifltma:
`WWW A!!!” amm’mm WT” 9.0. '61- ”00, "Ohm, “077170! F‘l'la [MIN-555‘. To you":
`ammo-autumn“ rain-M44421]!
`a up: a..- nm‘gmn
`MHHIISA
`!l!w§
`flEleF I
`3!!!
`
`
`
`ReducingClozapine-Relaled Morbidity and Mortality
`
`
`Figure I. Clozaril National Registry WBC Reporting Form*'
`
`National Registry WBC Count
`IDIdCLOZARIL'
`
`Reporting Form
`
`(dozapInel—
`
`Agranulocytasis—related mor-
`bidity and mortality: US. postmar-
`kctt‘ng experience. For the 5-year
`period between February I990 (that
`day of commercialization) and De—
`cember 1994, a total of 99.502 pa,-
`tients were registered with the CNR
`and treated with clozapine. Of
`these, 2931 (2.95%) developed leu-
`kopenia (WBC<3500/tnm3). An
`additional 382 patients (0.38%) de-
`veloped
`agtanulocytosis
`(ANC
`< SOO/mm’); 12 (0.012%) of these
`agranulocytosis patients died from
`secondary infections, despite adher—
`ence toblood'monitoring requirements.24
`These findings contrast with the 1% to 2% cumulative
`incidence of risk of agranulocytosis expected!" on the ba-
`sis-of premarketing clinical research data in 1743 US. pa—
`tients.30 as well as studies carriedout in Europe during the
`19705 and 198053933345 Conservatively assuming a-l%
`cumulative incidence of risk of agranuloeytosis,
`the
`99,502: elozapine-treated patients would have resulted in
`approximately 995 cases of agranulocytosis by the end of
`1994.
`
`“After assessing the patient'3 WBC count.- the presenhiog physician transmits this fonn In the
`pharmacist who may then dispense a 1-week supply of elozapine;
`
`4. Limited distribution Eachprescriptionforclozapine
`must be accompanied by a record ofthe current WBC and
`identified by the patient'3 initials, SSN, and date ofthe
`blood sample. The 3-pan Clozmil National RegistryWBC
`Count Reporting Form-(Figure 11) is typically used for this
`purpose. Prescriptions may befilled'orily at participating
`pharmacy service providers registered With the manufac-
`turcr of Cluwil. A 1-week supply Of. medication is dis-
`pensed to patients, linkedto acurrent WBC '__
`5. Quality assurance.As a means of identifying treat-
`ment systems, physicians, andpharmacists whose adher-
`once to the CNR proloeols my be subStandard. a large,
`full-time CNR staffis charged with reviewing data on a
`retrospective basis. Their primary function is to identify
`discrepancies, suchas missing data or low WBCs associ—
`ated with continued prescriptions If such anomalies
`
`J Clin Psychiatry 1998;59 (suppl 3)
`
`Concerning anticipated fatalities. the proportion of pa-
`tients who died after developing agtanulocytosis when
`treated with the antidepressant medication mianserin was
`approximately 20%.”37 Although this patient cohort is
`unique and different from a schizophrenic population.
`based on this figure, up to I49 deaths would have been
`
`5
`AMN1034
`
`IPR of US. Patent No. 7,765,107
`
`AMN1034
`IPR of U.S. Patent No. 7,765,107
`
`

`

`Honigfeld et at.
`
`expected'in._patients treated with elozapine over the 5-year
`period [9901.0 1994. Instead. the actual number of persons
`who died due to complications from clozapinearelated
`agrartulocytdsis was 12."
`leukopenia- occurred in 2931 of these patients (cumu—
`lative-incidence..2.95%). This figure is very similar to that
`obtained during premadreting clinical research, which was
`2.8% of- all persons exposed to clozapine. This suggests
`thatthe reducedrisk of agranulocytos-is in patients treated
`with clo7apine was not secondary to a reductionin leuko-
`penia. Rather.
`it reinforces one of the major rationales
`of the CNR that early detection of leukopenia throngh
`regular WBC monitoring, combined with prompt discon-
`tinnation of treatment in patientswhoseWBCS fall below
`3000Imm‘, will minimire the further progression to
`agranulocytosis and the associated risk of death.”
`The primary goal of the CNR has been to reduce mor-
`bidity and mortality associated with agrauulocytosis, but
`.additiOn‘aI benefits. have also accrued from close patient
`monitoring.“4 For example, the large, and complete. data-
`base of all treated patients facilitates epidemiologic 1111a]y-
`sis. it has allowed researchers to track WBCs in ‘all pa-
`tients over. time and to accurately calculate death rates and
`causesof death inthis population.
`Aflacause'mofiality. Schizophrenia is a disorder with
`an age—related risk of death that isapproximately 2 to 2.5
`times higher than the risk in the general population,3‘ ‘
`largely due to. a high suicide. rate.4"“ This translatesinto a
`decreaseinlife expectancy of 21.9% for males and 16.4%
`for females..._for a net loss of 16.years for males and 13
`years for females;15' In a recent epidemiologic analysis of
`all causes of death in 67,072 registered patients '(< 54
`years of age)~bei11g.treated with clozapine at the time of
`death, Walker et al.’25 found an overal-l'reduction in mortal-
`ity rates compared with non—clozapine—treated controls.
`The risk of death from all causes was decreased except
`respiratory diseases, pulmonary embolism, and cardiac
`conduCtion disorder, which were rare. These modestin—
`creasesvvere more than-compensated for, however. by a
`major decrease in the rate of suicide that was large enough
`to reducetheoverall death rate to a point approaching the
`death rate of- the general population.2’
`
`DISCUSSION
`
`Despite theserious adverse potential represented by
`agranulocy'tosis, clozapine13 the treatment for patients
`with chronic schizophrenia who failto respond optimally
`to ‘othcr anti-psychotic agents.3“"2Clozapine was approved
`by the U8. Food and Drug Administration111 I989 for
`treatment Of these patients, provided the manufacturer
`implemented anearly warning system tominimize the rislt
`of: agtanulocytosis. The CNR has served that function.
`'AnalySes of 5 years of patient data comprising all patients
`who have received elozapine in the United States since
`
`
`
`commercialization confirm that although the rate of leu-
`kopenia remained unchanged at near 3%. the Clozaril Na-
`tional Registry—supported use was associated with far
`lower than expected agranulOcytosis-related morbidity
`and mortality.‘ Twelve of 99.502 patients treated with
`clozapine through December 31. 1994. died from infec-
`tions secondary to agranulocytosisf‘ Previous experience,
`based on a 1% cumulative incidence of Vagranulocyto'sis.
`would have predicted as many as 149 deaths.:4 0n the ba—'
`sis of this favorable experience concerning agranulncyto-
`sis and associated fatalities. the NeuropsycltophartnaCol-
`ogy Advisory Committee to the 'U;S. Food and Drug
`Administration has unanimously recommended a reduc-
`tion in frequency of the white blood cell count testing re-
`quirement after 6 months to every 14 days, instead of
`weekly.
`.
`Suicide, which accounts for up to half of all deaths in
`patients with schizophrenia,“ decreases'dramatically-in
`patients receiving clozapine.25“ This finding contrasts
`with earlier studies in patients reCeiving other untipsy-
`chotics that showedincreases in depression and potential
`suicidality.4““ The specific mechanism of- clozapine-
`related suicide reduction is uncertain. but significant. 11:4
`ductions in both positive and negative symptomaro'logy '
`are almost certainly involved. as is the associated benefit
`of clozapinc-induced eumymia.‘9’1
`The CNR also provides an important mechanism [or "
`monitoring and optimizing compliance of both patients.
`and treatment systems. Because patients must present. for
`weekly WBCs before they can receive their medicirtibttit:
`has been suggested that. this regular contact may be one
`factor that contributes to good outcomes. Weekly contact
`with healthcarc professionals might play a preventiverole
`as well. because it permits early intervention in patients
`who evidence suicidal plans or ideation.‘5
`Treatment systems compliance with the CNR protocol
`requirements is crucial to the success of. clozapine treat-
`ment. Treatment systems that do not adhere to CNR moni—
`toring standards can be identified through retrospective
`analyses; subsequentinterventions have proven to be ef— _
`fectivein restoring system compliance, thus enhancing:
`patient safety and clinical efficacy. The compliance.of.
`physician-phannacist treatment systems duringthe first 5
`years of the CNR was 97%This contrasts with the situa-
`tion during the I970s before the benefits of close WBC; ‘
`count monitoring were appreciated, .when the frequencyof
`WBC monitoring was estimated to be 30% to 45%:and I
`was associated initially with agranulocytosis mortality- of 7
`up to 50%. '9‘4
`-
`»
`The CNR provides a system for universal rechallenge.
`protection as well as controlled dispensing of- elozapmc _
`'lhe CNR serves as an early warning system topromote.
`the safe and cllcctivc use of clozapine. It also includes
`quality assurance mechanisms designed to enhance corn— ,
`pliance. Despite the logistic requirements that this system
`
`_
`
`.
`
`J Clin Psychiatry 1998;m183‘2
`IPR of US. Patent No. 7,765,107
`
`AMN1034
`IPR of U.S. Patent No. 7,765,107
`
`

`

`Reducing Clozapine—Related Morbidity and Mortality
`
`'-..d
`
`'—''m’r—I
`
`new....
`
`2..
`n.
`
`'
`
`. Shopsin B. Feincr N. The current status of clozapine [letter]. ,Psychophar-
`macol Bull l983:l9(4):563—564
`. Krupp P. Burr-1:.- P. Lcinmx-associated granuloeytopenin: a review of the
`situation. Psydiophannacology (Berl) 1989199291 18-8121
`Krupp P. Barnes P. C10mpineassrxjated agraiurlocytosls: risk and atrial-
`ogy. Br] Psycbiulty 1992_16'0(5uppl I7):38—40
`HmigfcldG. Efi'ects of the cloupinc nutiomd registry system on incidence
`ofdeaths related to agtanulocytosis. Psychiatr Serv 199641(1 )152—56
`WalkcrAM,12m 1 .l. Arellano F ct al. Mortality in cutrmt'aml fumter
`users of clnrapine. Epidemiology l997:8:67l—6Tl
`Dale DC. Abnomlalitics of leukocytes.
`III: Isselhacher K, Adams R.
`Braunwald E. ct ul eds. Hmison'5 Principles of InternalMedicine. Tokyo
`Japan: Kuuitkt Priming: 1980:283—290
`Lieberman IA. Saffcnnan AZ. Clinical mafile IIf clonpine: adverse reac-
`tions and agrmulwytosis Psychiatr Q 1992:6303:5 L70
`Alvir .IMI Ijehcnnau .IA Saffcmlan AZ. ct al. Cloutpine-induced agranu-
`locytosis: incidence and risk factors in the United Suites. N Eng! 1- Med
`1993;329:162-167
`'
`Sall'emquA. Lieberman .I. Alvir .I. C! a]. Rcchallcnge in CIozapinc-ilnhiced
`agtanulocytosis. J cm: nydtophurmawl 1992;339':I’29rI—t297
`Clozaril. Physicians‘ Desk Reference. Montvalc. NI: MedicalEconomics
`Company: 1998:1834—1838
`Lieberman .IA Yunis J. Egon E. ct n]. HLA-B38 [1124,0st13 and cloza—
`pine-induced agranulocymisu: Jewish patientswithschizoplucnta Arch
`(Ian Psychuury 1990;47945—948
`Clans FHJ Abbon PA, Witvtiet MD. cl 8]. No diluctclinicalrelevance of
`the human lcucocyn: antigen (Hl.A) system in cloupinc-indncedagranu-
`locywsis; Drug Sat'199’l;7(suppi 023-6
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`
`2‘).
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`39.
`
`4o.
`
`41.
`
`45.
`
`47.
`
`48.
`
`49.
`
`50.
`
`5|.
`
`places upon physician, pharmaCist, and manufacturer. the
`CNR has helped substantially in reducing fatal outcomes
`related to clozapine-induced agranulocytosis. The CNR
`reinforces both patient and treatment system compliance.
`Finally. the CNR database. containing WBC data on
`every patient in the United States who has. received this
`medicine, serves as a unique epi'demiologic database. al~
`lowing this kind of precise safety assessment.
`
`Drug mamas: hen/.trop'me (Cogentin and others). chlorpromazine (Thor-
`mine and others). clozapine (Clozaril).
`
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`J Clin Psychiatry 1998;59 (suppl 3)
`
`7
`
`AMN1034
`
`1:11; orgs. Patent No. 7,765,107
`
`AMN1034
`IPR of U.S. Patent No. 7,765,107
`
`

`

`THE JOURNAL OF
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`CLINICAL PSYCHIATRY
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`VOLUNIE 59
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`1998
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`SUPPLEMENT 3
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