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`Page 1 of 9
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`,
`
`The same
`drug InformatIo a 2
`you trust
`‘35
`
`
`
`
`. PDR online
`
`. CME and CE
`
`- Multi-drug interaction tool Clinical trials registry
`
`- PDR for Herbal Medicines MEDLINE searching
`' Dru
`ouricin
`
`Page 2 of 9
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`
`PHVSlClANS’
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`
`PHYSICIANS’ DESK REFERENCE®
`1788IELI ,L-ILLY
`
`Velban—'Cont.
`
`’
`
`Extravasation during intravenous injection may lead to
`cellulitis and phlebitis. If the amount of extravasation is
`great, sloughing may occur.
`~
`OVERDOSAGE
`Signs and Symptomsf—Side effects following the use of Vel-
`ban are dose related. Therefore, following administration of
`more than the recommended dose, patients can be expected
`to experience these effects in an exaggerated fashion. (See
`Clinical Pharmacology, Contraindications, Warnings, Pre-
`cautions, and Adverse Reactions.) There is no specific anti-
`dote. In addition, neurotoxicity similar to that with Oncovin
`may be observed. Since the major route of excretion may be
`through the biliary system, toxicity from this drug may be
`increased when there is hepatic insufficiency.
`Treatment—To obtain up-to-date information about the
`treatment of overdose, a good resource is your certified Re-
`gional Poison Control Center. Telephone numbers of certi-
`fied poison control centers are listed in the Physicians’Desk
`Reference (PDR). In managing overdosage, consider the pos-
`sibility of multiple drug overdoses, interaction among
`drugs, and unusual drug kinetics in your patient. Overdoses
`of Velban have been reported rarely. The following is pro-
`vided to serve- as a guide should such an overdose be
`encountered.
`Supportive care should include the following: (1) prevention
`of side effects that result from the syndrome of inappropri-
`ate secretion of antidiuretic hormone (this would include re—
`striction of the volume of daily fluid intake to that of the
`urine output plus insensible loss and perhaps the adminis-
`tration of a diuretic affecting 'the function of the loop of
`Henle and the distal tubule); (2) administration of an anti-
`convulsant; (3) prevention of ileus; (4) monitoring the cardi—
`ovascular system; and (5) determining daily blood counts for
`guidance in transfusion requirements and assessing the
`risk of infection. The major effect of excessive doses of
`Velban will be myelosuppression, which may be life threat,
`ening. There, is noiinformation regarding the effectiveness
`of dialysis nor of cholestyramine for the treatment of
`overdosage.
`Velban in the dry state is irregularly and unpredictably ab-
`sorbed from the gastrointestinal tract following oral admin-
`istration. Absorption of the solution has not been studied. If
`Velban is swallowed, activated charcoal in a water slurry
`may be given by mouth along with a cathartic. The use of
`cholestyramine
`in
`this
`situation
`has
`not
`‘been
`reported.
`Symptoms of overdose will appear when greater-than-
`recommended doses are given. Any dose of Velban that re-
`sults in elimination ofplatelets and neutrophils from blood
`and marrow and‘their precursors from marrow should be
`considered life threatening. The exact dose that will do this
`in ’all patients is unknown. Overdoses occurring during pro-
`longed, consecutjve-day infusions may be more toxic than
`the same total dose given by rapid intravenous injection.
`The intravenous median lethal dose‘in mice is 10 mg/kg
`body weight; in rats, it15 2.9 mg/kg. The or'al median lethal
`dosein rats'1s 7 mg/kg.
`Protect the patient’s airway and support ventilation‘dnd
`perfusion. Meticulously monitor and maintain, within ac~
`ceptable limits, the patient’s vital signs, blood gases, serum
`electrolytes, etc. Absorption of drugs from the gastrointesti-
`nal tract may be decreased by giving activated charcoal,
`which, in many cases, is more efl‘ective than emesis or la-
`vage; consider charcoal instead of or. in addition to gastric
`emptying if the drug has been swallowed: Repeated doses of
`charcoal over time may hasten elimination of some drugs
`that have been absorbed. Safeguard the patient’s airway
`when employing gastric emptying or charcoal.
`DOSAGE AND ADMINISTRATION
`This preparation is for intravenous use only (see Warnings).
`Special Dispensing Information—WHEN DISPENSING
`VELBAN IN OTHER THAN THE ORIGINAL CON-
`TAINER, IT IS'IMPERATIVE THAT IT BE PACKAGED IN
`THE PROVIDED OVERWRAP WHICH BEARS THE FOL-
`LOWING STATEMENT. “DO NOT REMOVE COVERING
`UNTIL MOMENT 0F INJECTION. FATAL IF GIVEN IN-
`TRATHECALLY. FOR INTRAVENOUS USE ONLY”“(see
`Warnings). A syringe containing a specific dose must be la-
`beled, using the auxiliary sticker provided, to state. “FATAL
`IF- GIVEN INTRATHECALLY. FOR INTRAVENOUS USE
`ONLY".
`Caution—Itis extremely’important that the intravenous nec-
`dle or‘catheter be properly positioned before any Velban is
`injected. Leakage into surrounding tissue during intrave-
`nous administration of~ Velban may cause considerable'ir’ri-
`lotion. If extruvasotion occurs, the injection should be dis-
`continued immediately and any remaining portion of the
`dose should then be introduced into another vein. Local in-
`jection of hyuluronidase and the application of moderate
`heat to the area of leakage will help disperse the drug and
`may minimize discomfort and the possibility of cellulitis.
`There are variationsinthe depth of the leukopenic response
`that followstherapyvntli'VélbanForthis reason, it is rec-
`ommen‘ded that the drug be given no more frequently than
`
`once every 7 days
`A ult Patients —Itis wise to initiate therapy foi: adults by
`a ministering a single intravenous dose ,of ,3.7 rug/In2 bf
`body surface area (bsa). Thereafter, white-blood-cell counts
`
`
`
`
`
`should be made to determine the patient’s sensitivity to
`Velban.
`A simplified and conservative incremental approach to dos-
`age at weekly intervals for adults may be outlined as follows:
`First dose ......
`.. 3.7 nag/m2 bsa
`Second dose
`5.5 rug/m2 bsa
`Third dose ..
`7.4 nag/m2 bsa
`Fourth dose
`9.25mg/m2 bsa
`Fifth dose
`......................... 11.1 mg/m2 bsa
`The above mentioned increases may be used until a maxi-
`mum dose not exceeding 18.5 mgilm2 bsa for adults is
`reached. The dose should not be increased afier that dose
`which reduces the white-cell count to approximately 3,000
`cells/mma. In some adults, 3.7 ring/m2 bsa may produce this
`leukopenia; 'other-adults may require more than 11.1 nag/1n2
`bsa; and, very rarely, as much as 18.5 rug/m2 bsa may be
`necessary. For most adult patients, however, the weekly
`dosage will prove to be 5.5 to 7.4 mg/m2 bsa.
`When the dose of Velban which will produce the above de-
`gree of leukopenia has been established, a dose of 1 incre-
`ment smaller than this should be administered at weekly
`intervals for maintenance.'Thus, the patient is receiving the
`maximum dose that does not cause leukopenia.’ It should be
`emphasized that, even though 7 days have elapsed, the next
`dose of Velban should not be given until the while-cell count
`has returned to'at least 4,000 /mm3. In some cases, oncolytic
`activity may be encountered before leukopenic effect. When
`this occurs, there 'is no need to increase the size of subse-
`quent doses (see Precautions).
`.
`Pediatric Patients—A review of. published literature from
`1993 to 1995 showed that initial doses or'Velban in pediatric
`patients varied depending on the schedule used and
`whether Velban was administered as a single agent or in-
`corporated within a particular chemotherapeutic regimen.
`As a single agent for Letterer-Siwe disease (histiocytosis X),
`the initial dose of Velban was reported as 6.5 mg/mz. When
`Velban was used in combination with other chemotherapeu-
`tic agents for the treatment of Hodgkin’s disease, the initial
`dose was reported as 6 mg/m2. For testicular germ cell car—
`cinomas, the initial dose of Velban was reported as 3 mg/m2
`in a combination regimen. Dose modifications should be
`guided by hematologic tolerance.
`Patients with Renal or Hepatic Impairment—A reduction of
`50%111‘ the dose of Velban'15 recommended for patients hav-
`ing a direct serum bilirubin value above 3 rug/100 mL. Since
`metabolism and excretion are primarily hepatic, no modifi-
`cation is recommended for patients: with impaired renal
`function.
`The duration of maintenance therapy varies according to
`the disease being treated and the combination of antineo-
`plastic-agents being used. There are differences of opinion
`regarding the duration of maintenance therapy with the
`same protocol for a particular disease; for example, various
`durations have been used with the MOPP program in treat-
`ing Hodgkin’s disease. Prolonged chemotherapy for main-
`taining remissions involves several risks, among which are
`life-threatening infectious diseases, sterility, and possibly
`the appearance of other cancers through suppression of1m-
`mune surveillance.
`In some disorders, survival following complete remission
`may not be as prolonged as that achieved with shorter pe-
`riods of maintenance therapy. On the other hand, failure to
`provide maintenance therapy in some patients may lead to
`unnecessary relapse; complete remissions in patients with
`testicular cancer, unless maintained for at least 2 years, of-
`ten result1n early relapse.
`To prepare a solution containing 1 mg of Velban/mL, add 10
`mL of Bacteriostatic Sodium Chloride Injection (preserved
`with benzyl alcohol) or 10 mL of Sodium Chloride Injection
`(unpreserved) ’w the 10 mg of Velban in the sterile vial. Do
`not use other solutions. The drug dissolves instantly to give
`a clear solution.
`Parenteral .drug products should be inspected visually for
`particulate matter and discoloration prior to administra—
`tion, whenever solution and container permit.
`Unused portions of the remaining solutions made with nor-
`mal saline that do not contain preservatives should be dis-
`carded immediately. Unused preservative-containing solu-
`tions made with normal saline may be stored in a refriger—
`ator for future use for a maximum of 28 days.
`The dose of Velban (calculated to provide the desired
`amount) may be injectedeither into the tubing of a running
`intravenous infusion or_~directly into a vein. The latter pro-
`cedure is readily adaptable to outpatient therapy. In either
`case, the injection may be completed in about 1 minute. If
`care is taken to insure that the needle is securely within the
`vein and that no solution containing Velban is spilled ex-
`travascularly, cellulitis and/or phlebitis will not occur. To
`minimize further the possibility of extravascular spillage, it
`is suggested that the syringe and needle be rinsed with ve-
`nous blood before withdrawal of the needle. The dose should
`not be diluted in large volumes ofdiluent (ie, 100 to 250 mL)
`or given intravenously for prolonged periods (ranging from
`30 to 60 minutes or more), since this frequently results
`in imitation of the vein and increases the chance of
`extravasation.
`Because of the enhanced possibility of thrombosis, it is con-
`sidered inadvisable to inject a solution of Velban into an ex-
`tremity in which the circulation is impaired or potentially
`impaired by such conditions as compressing or invading ne-
`oplasm, phlebitis, or varicosity.
`Procedures for proper handling and disposal of anticancer
`drugs should be considered.'Several guidelines on this sub
`
`
`
`
`
`Information will be superseded by supplements and subsequent editions
`
`ject have been published.“10 There is no general agreement
`that all of the procedures recommended in the guidelines .
`are necessary or appropriate.
`HOW SUPPLIED
`Vials, 10 mg, 10-mL size (No. 6B7)—(1s) NDC 0002-1452-01
`The vials should be stored in a refrigerator (2° to 8°C, or 36"
`to 46°F) to assure extended stability.
`REFERENCES
`1. Dyke. Treatment of inadvertent intrathecal injection of
`vincristine. N Engl J Med, 1989, 321: 1270—7 1.
`2. Michelegnoli MP, Bailey CC, Wilson L, Livingston J,
`Kinsey SB. Potential salvage therapy for inadvertent in-
`trathecal administration of vincristine. Br. J. Haemotol-
`ogy, 1997, 99: 354—367. (Mfr. Control No. GB97113451A)
`3. Zaragoza MR, Ritchey ML, Walter‘A. Neurourologic con-
`sequences of accidental intrathecal vincristine: A case
`report. Med. Pediatr. Oncol., 1995, 24(1): 61—62.
`4. Recommendations for the Safe Handling of Parenteral
`Antineoplastic Drugs, NTH Publication No. 83-2621. For
`sale by the Superintendent of Documents, U.S. Govern-
`ment Printing Office, Washington, DC 20402.
`5. AMA Council Report, Guidelines for Handling Paren-
`teral Antineoplastics. JAMA, 1985',2:53(11)1590—1592.
`6. National Study Commission on Cytotoxic Exposure~
`Recommendations for Handling Cytotoxic Agents. Avail-
`able from Louis P. Jeffrey, ScD., Chairman, National
`Study Commission on Cytotoxic Exposure, Massachu-
`setts College of Pharmacy and Allied Health Sciences,
`179 Longwood Avenue, Boston, Massachusetts 02115.
`7. Clinical Oncological Society ofAustralia Guidelines and
`Recommendations for Safe Handling of Antineoplastic
`Agents. Med J Australia, 1983; 1:426—428.
`Jones RB, et al: Safe Handling of Chemotherapeutic
`Agents: A Report from the Mount Sinai Medical Center.
`CA—A Cancer Journal for Clinicians, 1983; (Sept/
`Oct)258—263.
`9. American Society of Hospital Pharmacists Technical As-
`sistance Bulletin on Handling Cytotoxic and Hazardous
`Drugs. Am J Hosp Pharm, 1990;47:1033—1049.
`10. OSHA Work-Practice Guidelines for Personnel Dealing
`with Cytotoxic (Antineoplastic) Drugs. Am J Hosp
`Pharm, 1986;421:1193—1204.
`Text revised May 19, 1999
`PA 2565 AMP
`
`[051999]
`
`8.
`
`ZINC-INSULIN CRYSTALS
`See under Iletin® (insulin).
`
`OTC
`
`Ba
`
`'
`ZYPREXA®
`[zi-prex-ah]
`(Olanzapine) Tablets
`ZYPREXA® ZYDIS®
`(Olanzapine) Orally Disintegrating Tablets
`DESCRIPTION
`ZYPREXA (olenzapine) is a psychotropic agent that belongs
`to the thienobenzodiazepine class. The chemical designation
`is 2-methyl-4-(4-methyl-1-piperazinyl)-10H—thieno[2,3-bl
`[1,5lbenzodiezepine The molecular formula is C17H2°N4S,
`which corresponds to a molecular weight of 312.44. The
`chemical structure is:
`
`B
`
`[CH3
`N
`
`N
`
`N...
`Q.I
`H
`Olanzapine is a yellow crystalline solid, which is practically
`insoluble in water.
`ZYPREXA tablets are intended fororal administration only.
`Each tablet contains olanzapine equivalent to 2.5 mg (8
`1111101), 5 mg (16 pmol), 7.5 mg (24 umol), 10 mg (32 meal), or
`15 mg (48 1.111101). Inactive ingredients are carnauba wax,
`crospovidpne, hydroxypropyl cellulose, hydroxypropyl meth-
`ylcellulose, lactose, magnesium stearate, microcrystalline
`cellulose, and other inactive ingredients. The color coating
`contains Titanium Dioxide (all strengths) and F D & C Blue
`No. 2Aluminum Lake (15 mg). The 2.5, 5.0, 7.5, and 10 mg
`tablets are imprinted with edible ink which contains F D &
`C Blue No. 2 Aluminum Lake.
`ZYPREXA ZYDIS (olanzapine orally disintegrating tablets)
`is intended for oral administration only.
`‘
`Eachvorally disintegrating tablet contains olanzapine equiv-
`alent to 5 mg (16 mal) or 10 mg (32 meIl). It begins disin-
`tegrating in the mouth within seconds, allowing its contents
`to be subsequently swallowed with or without liquid.
`ZYPREXA ZYDIS (olanmpine orally disintegrating tablets)
`also contains the following inactive ingredients: gelatin,
`mannitol, aspartame, sodium methyl paraben and sodium
`propyl paraben.
`CLINICAL PHARMACOLOGY
`Pharmacodynamics:
`Olanzapine is a selective monoaminergic antagonist with
`high affinity binding to the following receptors: serotonin
`
`,
`
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`

`PRODUET-TINFORMATION‘ FIQY. i‘l
`
`
`
`ELlililLW/J789
`
`
`suggests-that exposure toolanzapinexmay’be abbut2-fold
`greater inrtheJapanese when equixfalentdoses are admth
`istered .Clinical trial safety andeflicacy'data;howevé_r,did
`not suggest clinicallysignifipant diflerences- among Cauca‘
`sian patients, patients ofAfricaxsdesoent, and atth pooled
`category including AsiafixandaHispanicpatientsi Dosage .
`modifications: for race’ are, therefore, not'recommendedn
`Combined) Efl‘e'cts—The .combinediefl'ects- of- age;\smok'ing‘,
`and gender could leadto substantial pharm'acoldnetic dif-
`ferenceé‘z’ini populations. The'clearahce‘in“ young. smoking
`males, for example,- may be 3:times lfigherthandhat‘in el—
`daily nonsndoking females;Dosing modification may be net:-
`essaryin‘pzitientsmhoexhibifiascomb'inationtofifa'ctors that
`maytresultc'm-slowerjnetabolism of olanzapine; (see DOS-
`AGE AND ADMINISTRATION).
`: '
`,, 7
`w?
`Clinicalefi'icocyDafa:
`v“;
`Sélfi‘io hte‘nia’h 1‘? '5'
`.134“...,1 z
`
`1'»
`i ",l
`
`'
`
`.r
`am:
`
`.
`
`umni'aiies ‘
`langapme(E—Ztriiigiday” once ,
`
`5HTmb (K,=4-an,dlli; 11M; r‘espéctiilely),.,dopamine .D1_4
`(K,=11-31.nM),inusca11nic Mi-‘s (Kano—25mm, histamine
`H1 (K,=7 nM), and adrenergic :11 receptors _(K,-=19 nM):
`Olanzapinebind'shveakly toQABAA,BZD; andifl adrenergic
`receptors (K1 > 10 11M).
`1» v
`The mechanism of action of olanzapine aswith'nthd‘tdrugs
`having eflicacy'an schizophreniagislunknown',‘However,.it
`hasbeen proposed that-this drug's eflicacy'1hschizophrenia
`is mediated through‘ahofiibliiation ofi'ddpamine and seroto-
`nin-type 21(5HT5) antagonism; The mechanism oflactionof
`olanzapinejn the treatment 'ofacute manic episode's‘associ-
`ated with Bipolar I Disordenis‘unknownk
`J - m '1
`Antagonism at receptors other than dopamineaud5H1};
`with similarereceptor aflinities mayzexplain some of‘the
`other therapeutic andside effects Bf olanzapine. Olanzap-
`ine’s antagonism of' muscarinicMLgreceptorsmay explain
`its anticholinergic efl‘ects; Olanzapine’s antagonismlof his-
`tamine H1 receptors may explain"the ~somnolence observed
`The efficacy of‘olail aipiiieinthé‘l1hanaféflient‘of themani-
`with this drug”. Olanzapine’s antagonismof adrenergic oi
`festatiohsof psychoc disdrdei‘s' Was established in'Z’indit-
`thi‘in (6-Week) controlledtrials of,mpgtient's who met DSM
`re<>eptors may explain theorthostaln'c hypotension obseryed
`with this drug.
`.1
`'1 .. >
`a
`
`Pharmcokinetics: 1
`3
`_~.
`31-R criteria for stEii'zdphrenia.”A single'halppérifl‘ol afi‘xl
`was includedas atcomparativeflu‘eatmhnt'
`neof:the two
`Olanzapineis 'well absorbed andteachbs peak concentra-
`ZYPREXA‘ fs°cdxitraindiéated in patients with" a ltnown’liyL
`tions mapproximately 6 hoursfollowing aniotabdoseeItIS
`trials,"liut‘ihist’iial did not cpiiiphr thesetwdrugsonthe
`H:
`c.1-
`13 .
`at:
`v
`.5;
`eventd'ésgs ‘for both:
`'
`°''
`pePshns1t1v1tytothe product.
`'6‘ '
`eliminated extensively by:first-pass metabolism, :with'ap-
`fiflhfangeofclinicallyiieg
`‘
`WARNINGS.“ ’-
`~
`.
`~
`. mu
`Sevefdl in triiments were used for ass'eslfjig ps hiatric
`od doesnot afiectthe rate one».
`the systemic circulation.
`Neuroleptic Malignant Syndrome (NMS)—A potentially ta-
`proximately 40% of the.gist; metabolized before‘rehching
`,and s p ms in these studies, amogg them“
`‘6Bfiiel"
`tent of. olanzapineIabsorptiom Pharmacokifietic'studies
`Psychiatric
`Satin Scale,(BPRSFa'mpltmteminventoryof ;
`ta}symptom complex:somethneslreferred to as Neurgleptlc
`showed that ZYPREXA tablets andZYI’REXAZYDIS (clan,
`Malignant Syndrome(NMS)=has.been reponted'1n aesocia-
`geiieralpsychopathology traditiopally usedtoevaluate the é
`
`tibn‘with administrationuof antipaychoticfifugsyincluding
`zapine orally disintegrating tablets) dosageforms of olanza-
`ofdriig‘treafluent in psychosis. The3.lf’RSpsychosis .
`Elustefl‘émceptualdisprgamzatggnall cinatory behatdor,
`. olanzapine. .Glinical manifestations oflNMS me hyperpy-
`pineare bioequivalent.
`=
`v
`1 Vol
`rexia; mndcleliigiditx‘alter‘ed mentalsstatus and evidence bf
`Olanzapine displays linear kinetics over the clinicaldosing
`auspciousness‘vandiinusualthoughconte ’ )'isioonsidk‘fed a
`autonomic instability (irregular pulse . or .blood :pressure,
`iciilarlypsefiulsubset forassessmgactivelypsychotic
`range.Its Halflife ranges from 21. to 54hours (6th to95th
`tachycardiasdiapho'fiesismnd cardiac‘dys’rhythmlaiiiAddir
`‘sclii’z’ophrenicp'atieiits. A secdnd traditionalassessment, the
`percentile;.mean of 30 hr); andxapparent plasma clearance
`tiénalsigns mayincludeelevated creatinifie phosphokinase,
`Eliii‘fcal GlobalIifipr'éssidn(C'GI), reflects theimpressmn of
`rangesfrom 12to 47 LA]: (5th to 95thpercentile;mean:o£25
`myoglobinuria (rhabdomyolysis), and acute renal failure.
`L/hr)
`n
`. ,
`a,,...
`acigilledpbserver,fully familéTarwith the manifestations of
`1zophrenia,about the over
`clinical“ tate9f.the patient.
`The diagnostic‘e‘valuation of p‘atients with this syndrome is
`Admmlstratxonv of olanaapiiie once daily leads tpisteady-
`complicated In arriving at a diagnosis,~itIS important-.to
`In a tion,.Etwo more recently deyeloped b'ut’l’ess“well eval~
`state concentrationsein’ about one week that are approxie
`
`excludecaseswvhe're therclinicai presentation includes.both
`Mens-
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`matelytwice the concentrations ai'tenl'single dosesufilasm'a
`i
`e3:331"
`hich1s
`
`concentrations, half-lifep-and .c'leai-anoe ofolafizapine. may
`firionsmedicalillnéss (e.g.3pneumonia, systemic infection,
`
`etc)and’untreated er inadequately treated extrapy-Iamidal
`vary between individuals on the basis of'smokingystatus;
`émbédkie‘ii'thei
`forAei
`sessmgLNegativeSymptoms (SANS). The:tngl5
`signsand- symptomlePSfiOther importantvconsiderations
`gender andagelseQSpecialxPopulations), "-1
`-.
`ni
`belowfocusonthefollowingoutcomes:BANSS.totalpild/or
`irrthedifl'erential diagnosis-includeyentralaahficholinergic
`Olanzapine is extensively distributed throughout the .b'ddy,
`
`toxicitwcheat strokefldrugffever, andyprimarcheritral nere
`with a vbluine'ofdistribution offlpprbidriiafiely 1000 L It is
`BPRSt “pal BEES psychosis cluster;'PANSjiegative sub-
`mussystemjiatlmbey ..~:.
`.céws.
`us: cum 5.0M)
`raw 4
`scale of; SANS;andCGI Severity, Th? resjitsof the ti‘ia'ls
`».\.
`93% bound to plasma proteins over the concentrationrange
`
`follow;
`,
`'
`'
`' L ’L ‘
`The mamagemént'pf'NMSshoqld include: 1) immediate 'dia~
`of.7 bol1100 ng/mL, bindingprimarily-«(taalbmin :and(1%}
`continuation ofiantipsychotic' drugs fand'othemdmgsrnqtzem
`
`acid glycoprotein.
`4
`I
`.,1,
`.1
`.112.-
`,
`(1)In avfiwp’ek,p help)0
`trolls trial1 n—l149)invov1ng
`two fiicedmlanzapinedosesyif1, £33:10pig/day)(o ‘
`dell
`sential to: cohourrre‘nmthemrpy; 1‘2). intensive. symptomatic
`
`Metabolism and' Elimination‘vFollbwing. a single oral dose
`treatmentandi medical monitoring; and 3) theatmentpf any
`of IKClabeled olanz'apine; 7% of theBase of olanzapinewas
`sgheddle),oEanzapine, at ’lQmeg/Pd ut,not at
`day),
`recover‘ed'in theunnecas unchanged drug indicating that
`concomitant serious medicaltpi-oblems for'whichispecific
`W‘s summer to lacehoon,
`Stotal,scor§ so911
`the,extracj:airedBl? total),,on Pe.BPRS, psychdsmkluster,
`treatmentuare iavailablec: There is 1 no;general agreement
`clanzapine is highly metabolized. Approximately .5’7%.and
`30% of the dose was récoVeréd'1nthe urineland— feces,rev
`on the PANSS Negativasii
`e,_andpd£CGI fiverity,
`A m(.
`NMS,
`,,
`Yu-I“,
`.
`' -.
`about specific phhrmaoological treatment regimens for
`spectively. In the»plas'ma, olanzapine accounted for‘only
`(2) In afigveek,~pla9ebo-controlledtrial (n=‘253 involvingcfi
`fixed dose rangesaif,olanzapinqgfi.0+2.5 mg/day, 140.0125
`12% oftheAUC fortotal radioactivityindicatingisignificant
`Ifa‘patieht requires" antipsychotic drug-treatment alter rreA
`hig/day,_and,1§.,0:2.5mg/day) ana oncedaily schedule, the
`exposureto metabolitesAfier multiple dosiiig,‘the‘major
`bovery fromNMS}the potential réintroductiontofdrug then
`two highest olanzapine dose groups (aotual‘mean,doses of
`circulatiiig metébolitehwerethe 10‘-N-glucuron1de.presbnt
`apy should be carefully considered. The‘patientishmfldwbé
`at stea'dyistate. at44% ottherbri‘cent’ration ofwlanzapine,
`12findA6 mg/dayprespecjively) were aupezior(to plaéeljo on
`fiPRS ,tpta] score, BPRS,psychosisclusfer, apd'CGI seyerity
`carefullyismonitoredflsincmreturrences <1_f,NMS havebeen
`reported. :
`ea:
`: at
`;:L in ..
`(.3! y" n
`and 4’-Nxdesmethyl oianzapineppresent at steady Statepat
`scoreflhalfighbst glanzapinefiqsesrorp was memento
`Tardive‘Dyskinesia-rA syndrome 'of potentially irreversible,
`31% of the concentration 6f olanzapinéfngoflb metabolites
`placelgg onthe SANS.There was no clearadvantage forthe
`lack pharmacological: activity at?) the J concentrations
`involuntary;dyskinetic mov'eméntsmay:deveIOpixl'patiénts
`high dose. group oventhe medium @se grgup.“
`observed -'
`1
`c‘ «I
`\ 1.
`11/
`r «
`treated wifliinnfipswhofic’dmgs»Mltho‘uhithepi-evale'nde
`of‘vthe syndromel appearsto be' liighest’dmorfg the hiderly,
`Direct glucuronidatign and cytochromePJIBO_(CY1’) medi-
`Examination} of population subsets Iracennndrgender) did
`not reveal any differential responsivenessxan the basis .of
`atdd‘oxidatioxtare theprimary metabolic pathways fordlap- ‘
`especially=elderly Womengiit is impossibleto belyrupémprevz
`zapipe."In vitro studies suggest that CYBsElAZ‘and EDS,
`these subgroupings.,
`,1
`,
`:1“ .m. 1
`‘
`alence'estimatest’o predictiabtheinception of antipsychotic
`an'dtthe flavimcontmnihgrmonooxygenase system:are in-
`a",
`Bipolar Mania.m1" 1
`, fee
`a» 3, n
`treatment-,3which patients are likelymadevelop--the”synx
`volvedin olanzapine oxidation. CYP2D6 mediatédbiddation
`drums.Whether antipsywlhotic drug products difi‘emin their
`The eflicacy of olanzapine1n the treatment of acfite' ‘m'a’nic
`appearsto be a minormetabolicpathWay'“in vivo’,[because
`potential to causet'ardivéflyskinesia: fanmkn'owri
`3.1371
`episaa’ee w’as estéhhshedim‘Tahort:‘terIii-(are3week‘and
`theclearance of elanzapine is not reducedin subjects who
`The 115k of developing.mrdwe‘dysféinesia'ax‘d-the likelihiiod
`one 44-week) place'boi-cénti'olledtrialsd'n patie'rith‘wild met
`are'deficientmthis enzyme.
`..
`' rs
`o
`‘.
`.-
`thatit willz‘becorneirreversible are’believedrto im‘reaselas
`the DSM-{IVcriteria'for Bip'oiioa Disorder “With iaeiuror
`.
`Sp‘e‘cial Populations— n
`.1
`.'
`the duratiombf treatment an‘d'tlie total cuhmlative dosebf
`mixed epibodes‘.‘Theset-1‘ials included‘patidnts witli'firwith“-
`Renal.Impainiient‘s-Because‘olanzapiiieishighly mambo
`antipsychoticldmgs administered to the.patientiincreas'e
`course.
`1""
`'outpsychotichfeatui’es ‘and‘With or‘Witho’iit a~rapidcycling
`However; the syndromecan develop; althoughem’uchless
`lized beforeexcretionrandionlii7% of thedrug'is excreted ,
`uncharged; renal dysfunction alone is:unlikely:tothave a
`commonlxlafter‘relatiVely brief:treatmentperiods atlow
`, This pnmary‘ratihg'1nstrument usedfor‘a‘ssessi‘xi’gmanic
`major impactonthe.pharmacokinetics ofvola'nzapine, The
`doses.
`.
`1 Y! C‘
`i
`.. ~3 ’< *
`'13.xer’
`sym to’ms iiithdsé trial’s’w‘astheYdufigMa’iiia RiitingSéale
`There is no known treatment for established cases‘oi‘tar— ‘
`
`
`pharnmcokzmetic chara‘cterisfics ofolanzapine were. similar
`(Y-’M S), and “1'itenf‘clinibian=i'ate”d sédlfi traditionally
`in patientswithrsevere renal impairment and normal sub-
`divefdyskinesia,~although the syndrome may remit; phiL
`jectsgin'dicatingthat dosage adjustment based upon: the doL
`use to assess the 3d g‘i‘ee of m ‘i'c‘symptcmatologyi’n‘f5
`tialionr' completely-if: antipsychotio treatmént'i‘s'lwitm
`rangefmm 0(no maliic features)to 60 (maximum séoi‘é}.
`drawn. Antipsychotic treatment, itself, however, marsup—
`gree ofrenal impairmentfi not required. In‘ addifio'ryplani
`eprimary outcomeinthe trialsliv'fls‘chanée‘h‘oih b‘ase-
`11“
`zapineis not removed by dialysis. The effect ofrenal 1111173111}
`press (or pafliallytsuppress) the signsand Symptomsnffihe
`ment on metaboliterelimination has‘not been‘studied.
`:1 —
`line”in the Y-MES‘totalscore: he resuft'séofthe trials follow‘:
`syndrome andethereby may possibly mask the underlying
`Hepatic Impairment—Although the presencepf hepatic im—
`(1)lb ohe‘S-weelilplacebo—oontrolled tflal (n=é7) w‘hi‘cll ih-
`process/The effect thatzsymptoniatiosuppression has‘ upon
`pairment-‘mayrbe expected to reduce theclearagice of olan-
`volved adosprange oi‘blanz' inc (5720 mg]g/da once
`thelongetermwourse ofthe syndmme jsrunknown.
`.
`daily, starting at'10ihg/day);6a"011} hie:rwas superiorto
`zapine, a study of thaeflect of-irfipairéd‘diver function in
`Given these considerationsfolanzapine should be prescribed
`placebo1n the reducti‘oii'oi‘I-MRSloalsggorie In aniden-
`subjects (n=6) with clinically significant»(Childs PnghSGlas:
`tically'défdignédtribl ciiductedsmultaneo slyfévi'mthe
`in a manner thatis n'mst- likely ‘to’minimize the occurrence
`siflcation-A and Bhirrhosis revealed little ‘efi‘ect omthe
`of tardive dyskinesia. Shronic antipsychotic treatment
`'firs'tjtrial, olariiapinedemonstratedasimilartreatment
`phan'nacokinetics of olanzapine.
`.1.- ‘no-
`. ‘
`r» ‘3
`shouldgenerally bea‘eserved for patients (1)11thsufl'er from
`Age—fin a study involving. .24 healthyzsuhjects, the .meeh
`difi'erence, But possibly duetosample”)size aii'dbs1te vari-
`4-111
`elimination halfih‘fe ,of'olanzapine'was about;1:5 etimes
`aphronic illness that'is. known to respondfimentipsychotic
`ability, was not shown to'besuperior to' placebo on, this
`outcome
`drug's, and (2) for whom.a1temative,2vequallyeffective;but
`greater. in elderly, (>652years) than .in'nonJeldeflysubjects
`potentiallyless harmful tréatmants areznof available or ap-
`(£65 years). Cant-10m should be used ifi‘dosingthe' elderly,
`prépriate.11n patientsmho dorequire chronic treatment, the
`especially if thefe'are other factors that‘mightradditively in-
`smallest dbse3and the shortest duration of treatment pro-
`fluenceidrug metabolism andiorpharmacodynamic=sensitiv-
`ducing a satisfactory clinical response shouldibe‘spum.
`ity‘lseeDOSAGE'AND AD