CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TI0N NUMBER:
`
`20-592/S—019
`
`Trade Name:
`
`Zyprexa 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
`
`Generic Name:
`
`olanzapine tablets
`
`Sponsor:
`
`Eli Lilly and Company
`
`Approval Date:
`
`January 14, 2004
`
`Indications:
`
`For the benefit of maintaining bipolar patients on
`monotherapy with Zyprexa after achieving a
`responder status for an average duration of two weeks
`was demonstrated in a controlled trial. The physician
`who elects to use Zyprexa for extended periods should
`periodically re—evaluate the long-term usefulness of
`the drug for the individual patient.
`'
`
`

`

`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-592/S—019
`
`CONTENTS
`
`
`
`Reviews / Information Included in this NDA Review.
`
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`X X X
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`—_
`__I—_
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`—"-I—-
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`_—
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`Risk Assessment and Risk Miti_ation Review s
`
`Pro rieta Name Review s
`
`Administrative/Cones n ondence Document s
`
`

`

`. CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-592/S-019
`
`APPROVAL LETTER
`
`

`

`5!;ch
`5"'{to
`
`:9
`+5“
`
`. PublicHealthService
`(8 DEPARTMENTOFHEALTH&HUMANSERVICES
`5
`h
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 20—592 / S-019
`
`Eli Lilly and Co., Inc.
`Attention: Gregory T. Brophy, Ph.D.
`Lilly Corporate Center.
`Indianapolis, Indiana 46285
`USA
`V
`
`Dear Dr. Brophy:
`
`Please refer to your supplemental new drug application (NDA) dated November 20, 2002,
`received November 21, 2002, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act for Zyprexa (olanzapine) Tablets, 2.5, 5, 7.5, 10, 15, and 20 mg. This supplemental
`NDA provides for the use of olanzapine in the long-term treatment of bipolar I disorder.
`
`We also acknowledge receipt of your amendments dated November 4, 2003 and November 13,
`2003. Your submission ofNovember 13,2003 constituted a complete response to our September
`22,2003 action letter.
`
`Application approved. We have completed the review of this application as amended. It is
`approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling
`text, per our discussions of January 13, 2004.
`
`Final Printed Labeling. The final printed labeling (FPL) must be identical to the enclosed
`labeling (text for the package insert). Please submit the FPL electronically, according to the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format — NDA.
`Alternatively, you may submit 20 paper copies of the FPL as soon as it is available, in no case
`more than 30 days after it is printed. Please individually mount 15 of the copies on heavy—weight
`paper or similar material. For administrative purposes, this submission should be designated
`‘
`“FPL for approved supplement NDA 20—592/S-019” Approval of this submission by FDAIs not
`required before the labelingIS used.
`.
`
`Waiver of Requirement for Pediatric Studies. All applications for new active ingredients, new
`dosage forms, new indications, new routes of administration, and'new dosing regimens are
`required to contain an assessment of the safety and effectiveness of the product in pediatric
`patients unless this requirement is waived or deferred. We are waiving the pediatric study
`requirement for the use of olanzapine in the long-term treatment .of bipolar I disorder.
`
`'
`
`No Postmarketing Commitments Required. We note that there are no postmarketing
`commitments for this supplemental application.
`
`

`

`NDA 20-592 / S-019
`
`~
`
`Approval Letter
`
`.
`
`2
`
`Promotional Materials. In addition, submit three copies of the introductory promotional
`materials that you propose to use for this product. Submit all proposed» materials in drafi or
`mock-up form, not final print. Send one copy to this Division and two copies of both the
`promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising and Communications (DDMAC), HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`
`’
`
`Rockville, MD 20857
`
`Dear Healthcare Professional Letters. If you issue a letter communicating important
`information about this drug product (i.e., a “Dear Healthcare Professional” letter), we request
`that you submit a copy of the letter to this NDA and a copy to the following-address:
`MEDWATCH, HFD-410
`'
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`-
`‘
`
`If you have any questions, please contact Doris J. Bates, Ph.D., Regulatory Project Manager, at
`301-594-2850, or via e-mail at batesd@cder.fda.gov.
`
`Sincerely,
`
`.
`
`(See appended electronic signature page)
`
`Russell Katz, M.D.
`.
`,
`.
`' Director
`Division of Neuropharmacological Drug Products
`.OffiCe of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`'
`
`Enclosure (Agreed-Upon Labeling) [The electronic signature page will follow the labeling]
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`_ Russell Katz
`1/14/04 12:48:23 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-592/S-019
`
`APPROVABLE LETTER
`
`

`

`g DEPARTMENTOFHEALTH&HUMANSERVICES
`
`"dza
`
`
`
`I
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 20-592 / S-019
`
`Eli Lilly and Co., Inc.
`Attention: Gregory T. Brophy, Ph.D.
`Lilly Corporate Center
`Indianapolis, Indiana 46285
`USA
`
`Dear Dr. Brophy:
`
`Please refer to your supplemental new drug application (NDA) dated November-20, 2002,
`received November 21, 2002, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act for Zyprexa (olanzapine) Tablets, 2.5, 5, 7.5, 10, 15, and 20 mg. This supplemental
`NDA provides for the use of olanzapine in the long-term treatment of bipolar I disorder.
`
`We also acknowledge receipt of your amendments dated December 12, 2002, January 21, 2003,
`March 19, 2003, July 10, 2003, and August 7, 2003.
`
`We have completed the review of this application as amended, and it is approvable. Before this
`application may be approved, however, it will be necessary for you to address the following
`comments and requests.
`
`CMC: Categorical Exclusion
`We have completed our review of the information provided by your firm, and we agree with
`your request for a Categorical Exclusion from the requirement to perform a full Environmental
`' Assessment for this application.
`
`Clinical
`
`1. We have completed our review of the clinical, statistical, clinical safety, and clinical
`pharmacology / biopharmaceutics information submitted in this supplement. We have
`incorporated a number of comments into the revised labeling appended to this letter, as
`bracketed comments, text insertions [underlined], or deletions [strikethrough]. Please address
`these changes specifically in your complete response.
`
`'
`
`In particular, because patients in the open-label phase of the trial (the phase in which we
`believe the duration of the treatment effect is best determined) had met “responder” criteria
`for only about two weeks on average, and about half of the patients in the controlled portion
`A of the trial had left the study in less than two months, we believe it would be very difficult to
`determine, from this trial, the duration of the effect of the treatment as maintenance.
`
`1:
`
`rm
`
`‘
`
`J
`
`2. As you know, we have observed cases of hyperglycemia / diabetes mellitus in patients
`treated with atypical antipsychotics. We are addressing this as a class labeling issue. We have
`
`

`

`NDA 20-592 / S-019
`
`Approvable Letter
`
`2
`
`therefore incorporated the desired labeling language for the diabetes mellitus / hyperglycemia
`warning into the labeling at this time.
`
`As part of your complete response to this approvableletter, please also provide the following
`information for Study HGHL:
`”(4)
`:1
`A formal analysis of time- to--event, excluding sites 34 C
`An exploration and analysis of treatment—emergent suicidality and an analysis of the HAM-D
`scores for items 1 and 3 as a separate analysis to examine possible precipitation of depression
`in this population. Included as part of this analysis we would like to see a comparison of the
`incidence of patients who start with a HAM—D item 1 or item 3 score of 0 to 2 and then
`progress to a score of 3 or 4.
`Re-coded patient disposition table HGHL.10.3 (which is also table ISS.6.1). We have noted
`apparent discrepancies between the data in this table, the data found in some of the other
`[1(4)
`tables in the submission (see page 3207 of study report HGHL), and the data inC 3 files
`such as SUMMARY.xpt and/or COMMENTS.xpt (specifically, the coding categories of lack
`'of efficacy, patient decision, and physician decision). Please explain these discrepancies.
`With respect to Point (c) above, we also note that Patient 212 is listed as a discontinuation
`secondary to an adverse event at Visit 110. However, this patient met relapse criteria at Visit
`101. Please explain this .discrepancy in coding
`A definition for the term “Reporting Interval Completed” as used1n the disposition tablesin
`Study HGHL.
`A definition of the term “Days1n Remission” as seen in Table HGHL.14.11. Please also
`clarify when patients were randomized, as the protocol-specified randomization criteria do
`not appear to have been met in all cases (see patient 455).
`Table HGHL. 14.12 presents symptomatic relapse as estimated percentages stratified by time
`intervals (see Table HGHL 14.11). Please provide the percentage of patients relapsing, as per
`Table HGHL.14.11, for the interval 21 -28 days and the interval= 35 days. Please also
`provide ananalysis of time in ‘remission’ compared to time to ‘relapse’ and an analysis of
`time in ‘remission’ compared to time -to-event.
`A re—analysis of cholesterol laboratory values using a high of 250 mg/dL after a normal
`baseline measurement, or a change of 50 mg/dL from baseline, with the analysis performed
`as outlined1n point (i) below.
`A presentation ofthe laboratory values for eosinophils, uric acid, urine ketones, and
`cholesterol, stratified from the beginning of the open-label period to the last visit in the
`double-blind period for study HGHL and, separately, for all other studies with double-blind
`extensions.
`
`A detailed description, including results of any tests performed or consultation received, of
`the convulsive event seen in the open-label period of study HGHL.
`Within the active and placebo-controlled databases, for any potentially clinically significant
`EKG or syncopal events, SAEs related to EKG findings or syncope, or discontinuations
`secondary to either EKG findings or syncope, please provide vital signs for each patient,
`including orthostatics and EKG data taken at the time of the event. If none are available, this
`should be stated.
`
`g)
`
`h)
`
`j)
`
`k)
`
`1)
`
`Although this point is not essential for approval of your submission, we would also like an
`explanation for those patients whose time in study was greater than 365 days, given that the
`
`

`

`NDA 20-592 / 3-019
`
`-
`
`Approvable Letter
`
`‘
`
`3
`
`protocol required both Study Periods HI and IV to have a combined maximum duration of 12
`months.
`
`Labeling (Package Insert)
`In addition to responding to the points listed above, it will be necessary for youto submit draft
`labeling revised as shown in the attachment to this letter (see also point 1 under Clinical, above).
`We believe the attached draft labeling presents a fair summary of the information available on
`the benefits and risks of ZYPREXA (olanzapine) as long-term therapy in the treatment of bipolar
`I disorder.
`~
`
`Please use the proposed text verbatim. You will see that we have proposed a number of changes
`to the draft labeling submitted in your November 20, 2002 submission, and explanations for
`these changes are provided in the bracketed comments embedded within the proposed text.
`Division staff are willing to. discuss these proposed changes in detail and to meet with you to
`discuss any disagreements you might have with any part of the proposed labeling format or
`content.
`
`g
`_
`Promotional Materials
`In your complete response to this letter, please also submit three copies of the introductory
`promotional materials that you propose to use for this product. Please submit all material in draft
`or mock-up form rather than final printed format. Please send one copy to this Division and two
`copies of both the promotional material and the package insert directly to:
`
`- Division of Drug Marketing, Advertising, and Communications, HFD—42
`Food and Drug Administration
`5600 Fishers Lane
`.
`
`Rockville,‘ MD 20857
`
`Options Under 21 CFR 314.110
`Within 10 (ten) days after the date of this letter, you are required to amend the application, notify
`us of your intent to file an amendment, or follow one of your other options under 21 CFR
`314.110. In the absence of any such action, FDA may proceed to withdraw this application as
`provided for under 21 CFR 314.65. Any amendment should respond to all of the comments and
`requests in this letter, including those incorporated by reference. We will not process a partial
`reply as a major amendment, nor will the review clock be reactivated, until all deficiencies have
`been addressed.
`
`.
`Opportunity for Informal Meeting Under 21 CFR 314.102(d)
`Under 21 CFR 314.102(d), you may request an informal meeting or telephone conference with
`the Division of Neuropharmacological Drug Products, to discuss what further steps need to be
`taken before the application may be approved.
`
`This drug product may not be legally marketed until you have been notified1n writing that this
`application has been approved.
`
`

`

`NDA 20-592 / 3-019
`
`Approvable Letter '
`
`4
`
`If you have any questions, please call Doris J. Bates, Ph.D., Regulatory Project Manager, at 301-
`594-2850.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division of Neuropharmacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure (Revised Draft Labeling) [The electronic signature page will follow the labeling]
`
`

`

`_2__5Page(s) Withheld
`AFPWWtHO Latta
`
`___Trade Secret /Confidential (b4)
`
`X Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`‘ Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Russell Katz
`
`9/22/03 12:30:06 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`. APPLICA TION NUMBER:
`
`20-592/S-019
`
`LABELING
`
`

`

`APPROVED AGREED-UPON LABELING
`
`1
`
`ZYPREXA®
`(Olanzapine) Tablets
`
`ZYPREXA® zvms®
`(Olanzapine) Orally Disintegrating Tablets
`DESCRIPTION
`ZYPREXA (Olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class.
`The chemical designation is 2-methyl-4-(4-methyl-il -piperazinyl)-lOH-thieno[2,3-b]
`‘
`[l,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular
`weight of 3 12.44. The chemical strt’wture is:
`
`3
`
`,CHN
`N.)
`
`/ N
`I
`
`/ \
`S
`
`CH3
`
`Olanzapine is a yellow crystalline solid, which is practically insoluble in water.
`ZYPREXA tablets are intended for oral administration only.
`Each tablet contains Olanzapine equivalent to 2.5 mg (8 1111101), 5 mg (16 mol), 7.5 mg
`(24 mol), 10 mg (32 umol), 15 mg (48 pmol), or 20 mg (64 mol). Inactive ingredients are
`carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate,
`microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium
`Dioxide (all strengths), FD&C Blue No.2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide
`(20 mg). The 2. 5, 5.0, 7.5, and 10 mg tablets are imprinted with edible ink which contains
`FD&C Blue No.2 Aluminum Lake.
`
`ZYPREXA ZYDIS (Olanzapine orally disintegrating tablets)1s intended for oral administration '
`only.
`Each orally disintegrating. tablet contains Olanzapine equivalent to 5 mg (16 mol), 10 mg
`(32 pmol), 15 mg (48 mol) or 20 mg (64 mol). It begins disintegrating in the mouth within
`seconds, allowing its contents to be subsequently swalloWed with or without liquid.
`ZYPREXA ZYDIS (Olanzapine 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 5HT2A/2c (Ki=4 and 11 nM, respectively), dopamine D14 (K.=11-31 nM),
`muscarinic M1_5 (Ki=1.9-25 nM), histamine H1 (Ki=7 nM), and adrenergic (1.1 receptors
`(Ki=l9 nM). Olanzapine binds weakly to GABAA, BZD, and B adrenergic receptors (Ki>10 11M).
`The mechanism of action of Olanzapine, as with other drugs having efficacy in schizophrenia, is
`unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated
`through a combination of dopamine and serotonin type 2 (SHTZ) antagonism. The mechanism of
`action of Olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is
`unknown.
`
`,_,.
`
`O\OOO\IO\UI-hLAN.—
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`APPROVED AGREED-UPON LABELING
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`Antagonism at receptors other than dopamine and SHTZ with similar receptor affinities may
`explain some of the other therapeutic and side effects of Olanzapine. Olanzapine’s antagonism of
`muscarinic M..5 receptors may explain its anticholinergic effects. Olanzapine s antagonism of
`histamine H; receptors may explain the somnolence observed with this drug. Olanzapine’s
`antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this
`drug.
`
`Pharmacokinetics
`
`Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours
`following an oral dose, It is eliminated extensively by first pass metabolism, with approximately
`40% of the dose metabolized before reaching the systemic circulation. Food-does not affect the
`rate or extent of Olanzapine absorption. Pharmacokinetic studies showed that ZYPREXA tablets
`and ZYPREXA ZYDIS (Olanzapine orally disintegrating tablets) dosage forms of Olanzapine are
`bioequivalent.
`Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to
`54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to
`47 L/hr (5th to 95th percentile; mean of 25 L/hr).
`' Administration of Olanzapine once daily leads to steady-state concentrations in about one week
`that are approximately twice the concentrations afler single doses. Plasma concentrations, half-life,
`and clearance of Olanzapine may vary between individuals on the basis of smoking status, gender,
`and age (see Special Populations).
`Olanzapine is extensively distributed throughout the body, with a volume of distribution of
`approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to
`1100 ng/mL, binding primarily to albumin and al-acid glycoprotein.
`Metabolism and Elimination— Following a single oral dose of 14C labeled Olanzapine, 7% of
`the dose of Olanzapine was recovered in the urine as unchanged drug, indicating that Olanzapine is
`highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and
`feces, respectively. In the plasma, Olanzapine accounted for only 12% of the AUC for total
`radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major
`circulating metabolites were the 10-N-g1ucuronide, present at steady state at 44% of the
`concentration of Olanzapine, and 4’-N-desmethyl Olanzapine, present at steady state at 31% of the
`concentration of Olanzapine. Both metabolites lack pharmacological activity at the concentrations
`observed
`
`Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary
`metabolic pathways for Olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the
`flavin-containing monooxygenase system are involved'm Olanzapine oxidation. CYP2D6 mediated
`oxidation appears to be a minor metabolic pathway1n vivo, because the clearance of Olanzapine1s
`not reduced in subjects who are deficient in this enzyme.
`
`Special Populations
`Renal Impairmen -— Because olanzapine is highly metabolized before excretion and only 7% of
`the drug is excreted unchanged, renal dysfimction alone is unlikely to have a major impact on the
`pharmacokinetics of Olanzapine. The pharmacokinetic characteristics of Olanzapine were similar
`. in patients with severe renal impairment and normal subjects, indicating that dosage adjustment
`based upon the degree of renal impairment is not required. In addition, Olanzapine is not removed
`by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
`Hepatic Impairmen :— Although the presence of hepatic impairment may be eXpected to reduce
`the clearance of Olanzapine, a study of the effect of impaired liver function in subjects (n=6) with
`clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the
`pharmacokinetics of Olanzapine.
`
`

`

`APPROVED AGREED-UPON LABELING
`
`'
`
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`Age — In a study involving 24 healthy subjects, the mean elimination half-life of olanzapinewas
`about 1.5 times greater in elderly (>65 years) than in non-elderly subjects (S65 years). Caution
`should be used1n dosing the elderly, especially if there are other factors that might additively
`influence drug metabolism and/or pharmacodynamic sensitivity (see DOSAGE AND
`ADMINISTRATION)
`Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There
`were, however, no apparent differences between men and women in effectiveness or adverse
`effects. Dosage modifications based on gender should not be needed.
`Smoking Status -—— Olanzapine clearance is about 40% higher in smokers than in nonsmokers,
`although dosage modifications are not routinely recommended.
`Ra_ce — No specific pharmacokinetic study was conducted to investigate the effects of race A
`cress-study comparison between data obtainedin Japan and data obtainedin the US suggests that
`exposure to olanzapine may be about 2-fold greater in the Japanese when equivalent doses are
`administered. Clinical trial safety and efficacy data, however, did not suggest clinically significant
`differences among Caucasian patients, patients of African descent, and a third pooled category
`including Asian and Hispanic patients. Dosage modifications for race are, therefore, not
`recommended.
`
`Combined Effects — The combined effects of age, smoking, and gender could lead to substantial
`pharmacokinetic differences in populations. The clearance in young smoking males, for example,
`may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be
`necessary in patients who exhibit a combination of factors that may result in slower metabolism of
`olanzapine (see DOSAGE AND ADMINISTRATION).
`For specific information about the pharmacology of lithium or valproate, refer to the CLINICAL
`PHARMACOLOGY section of the package inserts for these other products.
`
`Clinical Efficacy Data
`
`Schizophrenia
`The efficacy of olanzapine in the treatment of schizophrenia was established in 2 short-term
`(6-week) controlled trials of inpatients who met DSM III-R criteria for schizophrenia. A
`single haloperidol arm was included as a comparative treatment in One of the two trials, but this
`trial did not compare these two drugs on the full range of clinically relevant doses for both.
`Several instruments were used for assessing psychiatric signs and symptoms in these studies,
`among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
`psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The
`. BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and
`unusual thought content) is considered a particularly useful subset for assessing actively psychotic
`schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI),
`reflects the impression of a skilled observer, fully familiar with the manifestations of
`schizophrenia, about the overall clinical state of the patient. In addition, two more recently
`developed but less well evaluated scales were employed; these included the 30-item Positive and
`Negative Symptoms Scale (PANSS), in which is embedded the 18 items of the BPRS, and the
`Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the
`following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative
`subscale or SANS; and CGI Severity. The results of the trials follow:
`(1) In a 6-week, placebo-controlled trial (n=l49) involving two fixed olanzapine doses of l and
`10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to
`placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis
`cluster, on the PANSS Negative subscale, and on CGI Severity.
`(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine
`(5.0 i 2.5 mg/day, 10.0 i 2.5 mg/day, and 15.0 i 2.5 mg/day) on a once daily schedule, the
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`two highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were
`superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the
`highest olanzapine dose group was superior to placebo on the SANS. There was no clear
`advantage for the high dose group over the-medium dose group.
`Examination of population subsets (race and gender) did not reveal any differential
`responsiveness on the basis of these subgroupings.
`In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for
`'
`schizophrenia and who remained stable on olanzapine during open label treatment for at least
`8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to
`20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms
`of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however,
`criteria were met for stopping the trial early due to an excess of placebo relapses compared to
`olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary
`outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in
`patients stabilized for approximately 8 weeks and followed for an observation period of up to
`8 months.
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`Bipolar Disorder
`Monotherapy —- The efficacy of olanzapine in the treatment of acute manic or mixed episodes
`was established in 2 short-term (one 3-week and one 4—week) placebo-controlled trials in patients
`who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials
`included patients with or without psychotic features and with or without a rapid-cycling course.
`The primary rating instrument used for assessing manic symptoms in these trials was the Young
`Mania Rating Scale (Y-MRS), an ll-item clinician-rated scale traditionally used to assess the
`degree of manic symptomatology (irritability, diSruptive/aggressive behavior, sleep, elevated
`mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
`appearance, and insight) in a range from 0(no manic features) to 60 (maximum score). The
`primary outcome in these trials was change from baseline in the Y—MRS total score. The results of
`the trials follow:
`(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine
`(5--20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placeboin the
`reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the
`first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size
`' and site variability, was not shown to be superior to placebo on this outcome.
`(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine
`(5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placeboin the
`reduction of Y-MRS total score.
`
`(3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of
`- bipolar disorder who had responded during an initial open-label treatment phase for about two
`weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of
`olanzapine at their same dose (n= 225) or to placebo (n= 136), for observation ofrelapse
`Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50%
`of the placebo group had discontinued by day 23 of double-blind treatment. Response during the
`open label phase was defined by having a decrease of the YMRS total score to— 12 and I-LAM-D
`21 to = 8. Relapse during the double-blind phase was defined as an increase of the YMRS or
`HAM-D 21 total score to = 15, or being hospitalized for either mania or depression.‘ In the
`randomized phase, patients receiving continued olanzapine experienced a significantly longer time
`to relapse.
`Combination Therapy — The efficacy of olanzapine with concomitant lithium or valproate in the
`treatment of acute manic episodes was established in two controlled trials in patients who met the
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`DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included
`patients with or without psychotic features and with or without a rapid-cycling course. The results
`of the trials follow:
`
`(1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate
`therapy with inadequately controlled manic or mixed symptoms (Y-MRS 216) were randomized to
`receive either olanzapirre or placebo, in combination with their original therapy. Olanzapine (in a
`dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate
`(in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL, respectively) was
`superior to lithium or valproate alone in the reduction of Y-MRS total Score.
`(2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or
`valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS 216) were
`randomized to receive either Olanzapine or placebo, in combination with their original therapy.
`Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with
`lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 ug/mL to 125 ug/mL,
`respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total secre.
`
`INDICATIONS AND USAGE
`
`Schizophrenia
`ZYPREXA is indicated for the treatment of schizophrenia.
`The efficacy of ZYPREXA was established in short-term (6-week) controlled trials of
`schizophrenic inpatients (see CLINICAL PHARMACOLOGY).
`The efi‘ectivene‘ss of oral ZYPREXA at maintaining a treatment response in schizophrenic
`patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed
`for a period of up to 8 months has been demonstrated in a placebo-controlled trial (see CLINICAL
`PHARMACOLOGY). Nevertheless, the physician who elects to use ZYPREXA for extended
`periods should periodically re-evaluate the long-term usefulness of the drug for the individual
`patient (see DOSAGE AND ADMINISTRATION).
`.
`
`'
`Bipolar Disorder
`Acute Monotherapy —— ZYPREXA is indicated for the treatment of acute mixed or manic
`episodes associated with Bipolar I Disorder.
`The efficacy of ZYPREXA was established in two placebo-controlled trials (one 3-week and
`one 4-week) with patients meeting DSM-IV criteria for Bipolar I Disorder who currently
`displayed an acute manic or mixed episode with or without psychotic features (see CLINICAL
`PHARMACOLOGY).
`~ Maintenance Monotherapy — The benefit of maintaining bipolar patients on mono