Zyprexa

Description for Zyprexa

ZYPREXA (olanzapine) is an atypical antipsychotic that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C₁₇H₂₀N₄S, which corresponds to a molecular weight of 312.44. The chemical structure is:

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 μmol), 5 mg (16 μmol), 7.5 mg (24 μmol), 10 mg (32 μmol), 15 mg (48 μmol), or 20 mg (64 μmol). 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, 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) is intended for oral administration only.

Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 μmol), 10 mg (32 μmol), 15 mg (48 μmol) or 20 mg (64 μmol). 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 propylparaben.

ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only.

Each vial provides for the administration of 10 mg (32 μmol) olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH.

Uses for Zyprexa

Schizophrenia

Oral ZYPREXA is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial [see Clinical Studies] .

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as comparedwith adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many casesthis may lead them to consider prescribing other drugs first in adolescents [see WARNINGS AND PRECAUTIONS] .

Bipolar I Disorder (Manic Or Mixed Episodes)

Monotherapy

Oral ZYPREXA is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenancetreatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17),efficacy was established in one 3-week trial [see Clinical Studies] .

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as comparedwith adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many casesthis may lead them to consider prescribing other drugs first in adolescents [see WARNINGS AND PRECAUTIONS] .

Adjunctive Therapy To Lithium Or Valproate

Oral ZYPREXA is indicated for the treatment of manic or mixed episodes associated with bipolar I disorderas an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies] .

Special Considerations In Treating Pediatric Schizophrenia And Bipolar I Disorder

Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptomprofiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It isrecommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has beenperformed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia andbipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

ZYPREXA IntraMuscular: Agitation Associated With Schizophrenia And Bipolar I Mania

ZYPREXA IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and bipolar I mania.

Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolar Idisorder (manic or mixed episodes) [see Clinical Studies] .

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitationoften manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation.

ZYPREXA And Fluoxetine In Combination: Depressive Episodes Associated With Bipolar I Disorder

Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinicalstudies. When using ZYPREXA and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

ZYPREXA And Fluoxetine In Combination

Treatment Resistant Depression

Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who donot respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients.When using ZYPREXA and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

ZYPREXA monotherapy is not indicated for the treatment of treatment resistant depression.

Dosage for Zyprexa

Schizophrenia

Adults

Dose Selection

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially,with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week,since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, doseincrements/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstratedto be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) isrecommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day.

Dosing in Special Populations

The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensivereactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 yearsof age), or who may be more pharmacodynamically sensitive to olanzapine [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY] . When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment

The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients whohad been stable on ZYPREXA for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies] . The healthcare provider who elects to use ZYPREXA for extended periods should periodically reevaluate the long-term usefulnessof the drug for the individual patient.

Adolescents

Dose Selection

Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day inclinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrementsof 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies] .

Maintenance Treatment

The efficacy of ZYPREXA for the maintenance treatment of schizophrenia in the adolescent population has not beensystematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokineticparameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at thelowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Bipolar I Disorder (Manic Or Mixed Episodes)

Adults

Dose Selection for Monotherapy

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlledtrials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/dayhas not been evaluated in clinical trials [see Clinical Studies] .

Maintenance Monotherapy

The benefit of maintaining bipolar I patients on monotherapy with oral ZYPREXA at a dose of 5 to 20 mg/day, afterachieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies] . The healthcareprovider who elects to use ZYPREXA for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dose Selection for Adjunctive Treatment

When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generallybegin with 10 mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies] . The safety of doses above20 mg/day has not been evaluated in clinical trials.

Adolescents

Dose Selection

Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible doserange of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary,dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies] .

Maintenance Treatment

The efficacy of ZYPREXA for the maintenance treatment of bipolar I disorder in the adolescent population has not beenevaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adultand adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose neededto maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Administration Of ZYPREXA ZYDIS (Olanzapine Orally Disintegrating Tablets)

After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister, using dry hands, remove tablet andplace entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

ZYPREXA IntraMuscular: Agitation Associated With Schizophrenia And Bipolar I Mania

Dose Selection For Agitated Adult Patients With Schizophrenia And Bipolar I Mania

The efficacy of intramuscular olanzapine for injection in controllingagitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is 10 mg. A lower dose of 5 or7.5 mg may be considered when clinical factors warrant [see Clinical Studies] . If agitation warranting additional intramuscular doses persistsfollowing the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection inagitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mginjections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significantorthostatic hypotension [see WARNINGS AND PRECAUTIONS] . Thus, it is recommended that patients requiring subsequent intramuscular injections beassessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of anadditional dose to a patient with a clinically significant postural change in systolic blood pressure is not recommended.

If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as soon as clinically appropriate [see Schizophrenia, Bipolar I Disorder (Manic Or Mixed Episodes)] .

Intramuscular Dosing In Special Populations

A dose of 5 mg/injection should be considered for geriatric patients or when other clinical factors warrant.A lower dose of 2.5 mg/injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be morepharmacodynamically sensitive to olanzapine [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY] .

Administration Of ZYPREXA IntraMuscular

ZYPREXA IntraMuscular is intended for intramuscular use only. Do not administer intravenously orsubcutaneously. Inject slowly, deep into the muscle mass.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and containerpermit.

Directions For Preparation Of ZYPREXA IntraMuscular With Sterile Water For Injection

Dissolve the contents of the vial using 2.1 mL of Sterile Waterfor Injection to provide a solution containing approximately 5 mg/m²L of olanzapine. The resulting solution should appear clear and yellow. ZYPREXA IntraMuscular reconstituted with Sterile Water for Injection should be used immediately (within 1 hour) after reconstitution. Discard any unused portion.

The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water forInjection.

Dose, mg Olanzapine	Volume of Injection, mL
10	Withdraw total contents of vial
7.5	1.5
5	1
2.5	0.5

Physical Incompatibility Information

ZYPREXA IntraMuscular should be reconstituted only with Sterile Water for Injection. ZYPREXA IntraMuscularshould not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed. Lorazepam injection should notbe used to reconstitute ZYPREXA IntraMuscular as this combination results in a delayed reconstitution time. ZYPREXA IntraMuscular should not becombined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.

ZYPREXA And Fluoxetine In Combination: Depressive Episodes Associated With Bipolar I Disorder

When using ZYPREXA and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Adults

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mgof oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oralolanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with ZYPREXA and fluoxetine in combination in adultpatients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mgfluoxetine has not been evaluated in clinical studies.

Children And Adolescents (10-17 Years Of Age)

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mgof oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

Safety and efficacy of ZYPREXA and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combinationof ZYPREXA and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day.The following table demonstrates the appropriate individual component doses of ZYPREXA and fluoxetine versus Symbyax. Dosage adjustments, ifindicated, should be made with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax^a and the Combination of ZYPREXA and Fluoxetine

For ZYPREXA (mg/day)	Use in Combination
	ZYPREXA (mg/day)	Fluoxetine (mg/day)
3 mg olanzapine/25 mg fluoxetine	2.5	20
6 mg olanzapine/25 mg fluoxetine	5	20
6 mg olanzapine/25 mg fluoxetine	10+2.5	20
6 mg olanzapine/50 mg fluoxetine	5	40+10
12 mg olanzapine/50 mg fluoxetine	10+2.5	40+10
a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of ZYPREXA and fluoxetine

While there is no body of evidence to answer the question of how long a patient treated with ZYPREXA and fluoxetine in combination should remain on it,it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronictreatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

ZYPREXA And Fluoxetine In Combination: Treatment Resistant Depression

When using ZYPREXA and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mgof oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oralolanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adultpatients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combinationof olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day.Table 1 above demonstrates the appropriate individual component doses of ZYPREXA and fluoxetine versus Symbyax. Dosage adjustments, if indicated,should be made with the individual components according to efficacy and tolerability.

While there is no body of evidence to answer the question of how long a patient treated with ZYPREXA and fluoxetine in combination should remain on it,it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of differentantidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider shouldperiodically reexamine the need for continued pharmacotherapy.

Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

ZYPREXA monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2antidepressants of adequate dose and duration in the current episode).

ZYPREXA And Fluoxetine In Combination: Dosing In Special Populations

The starting dose of oral olanzapine 2.5-5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patientswith hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (femalegender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may benecessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution inthese patients. ZYPREXA and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under 10 yearsof age [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY] .

HOW SUPPLIED

Dosage Forms And Strengths

The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets areelliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. Tablets arenot scored. The tablets are available as follows:

	TABLET STRENGTH
	2.5 mg	5 mg	7.5 mg	10 mg	15 mg	20 mg
Tablet No.	4112	4115	4116	4117	4415	4420
Identification	LILLY 4112	LILLY 4115	LILLY 4116	LILLY 4117	LILLY 4415	LILLY 4420

ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. Tablets are not scored. The tablets areavailable as follows:

ZYPREXA ZYDIS Tablets	TABLET STRENGTH
	5mg	10 mg	15 mg	20 mg
Tablet No.	4453	4454	4455	4456
Debossed	5	10	15	20

ZYPREXA IntraMuscular is available as single-dose 10 mg vial (1s).

The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets areelliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. Thetablets are available as follows:

	TABLET STRENGTH
	2.5 mg	5 mg	7.5 mg	10 mg	15 mg	20 mg
Tablet No.	4112	4115	4116	4117	4115	4420
Tablet No.	LILLY 4112	LILLY 4115	LILLY 4116	LILLY 4117	LILLY 4115	LILLY 4420
NDC Codes: Bottles 30	NDC 0002-4112-30	NDC 0002-4112-30	NDC 0002-4115-30	NDC 0002-4117-30	NDC 0002-4415-30	NDC 0002-4420-30

ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed with the tablet strength. The tablets are available as follows:

	TABLET STRENGTH
	5 mg	10 mg	15 mg	20 mg
Tablet No.	4453	4454	4455	4456
Debossed	5	10	15	20
NDC Codes: Dose Pack 30 (Child Resistant)	NDC 0002-4453-85	NDC 0002-4455-85	NDC 0002-4455-85	NDC 0002-4456-85

ZYPREXA IntraMuscular is available in:

NDC 0002-7597-01 (No. VL7597) – 10 mg single-dose vial (1s)

Storage And Handling

Store ZYPREXA tablets, ZYPREXA ZYDIS, and ZYPREXA IntraMuscular vials (before reconstitution) at controlled room temperature, 20° to 25°C (68°to 77°F) [ see USP]. Reconstituted ZYPREXA IntraMuscular may be stored at controlled room temperature, 20° to 25°C (68° to 77°F) [ see USP] for up to 1hour if necessary.Discard any unused portion of reconstituted ZYPREXA IntraMuscular. The USP defines controlled room temperature as a temperaturemaintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetictemperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies,hospitals, and warehouses.

Protect ZYPREXA tablets and ZYPREXA ZYDIS from light and moisture. Protect ZYPREXA IntraMuscular from light, do not freeze.

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Feb 2021.

Side Effects for Zyprexa

When using ZYPREXA and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Clinical Trials In Adults

The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765patient-years of exposure to olanzapine plus 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patientswho participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes)trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having variouspsychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure; (4) 5788 additional patients from 88oral olanzapine clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011; and (6) 722patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic ormixed episodes), or dementia. Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-yearsof exposure.

The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases ofstudies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed bycollecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologicexaminations.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes,weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar Idisorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) andagitation.

Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing.Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first groupingsimilar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTARTDictionary terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction ofthe type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baselineevaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labelingmay not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarilycaused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usualmedical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannotbe compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, doprovide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactionsincidence in the population studied.

Incidence Of Adverse Reactions In Short-Term, Placebo-Controlled And Combination Trials

The following findings are based on premarketing trials of (1) oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequenttrial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and (2) intramuscularolanzapine for injection in agitated patients with schizophrenia or bipolar I mania.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Schizophrenia

Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo).However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo).

Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy

Overall, there was no difference in the incidence of discontinuation due to adversereactions (2% for oral olanzapine vs 2% for placebo).

Agitation

Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular olanzapine for injectionvs 0% for placebo).

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials

Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate

In a study of patients who were already tolerating eitherlithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium orvalproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine andlithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%).

Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials

The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalentincidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA

Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine (N=248)	Placebo (N=118)
Postural hypotension	5	2
Constipation	9	3
Weight gain	6	1
Dizziness	11	4
Personality disordera	8	4
Akathisia	5	1
a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior.

Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar IDisorder (Manic or Mixed Episodes)

Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine (N=125)	Placebo (N=129)
Asthenia	15	6
Dry mouth	22	7
Constipation	11	5
Dyspepsia	11	5
Increased appetite	6	3
Somnolence	35	13
Dizziness	18	6
Tremor	6	3

Olanzapine Intramuscular

There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular olanzapine forinjection-treated patients and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo)during the placebo-controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitatedpatients with schizophrenia or bipolar I mania was 6% for intramuscular olanzapine for injection and 3% for placebo.

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treatedwith oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine

Body System/Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine (N=532)	Placebo (N=294)
Body as a Whole
Accidental injury	12	8
Asthenia	10	9
Fever	6	2
Back pain	5	2
Chest pain	3	1
Cardiovascular System
Postural hypotension	3	1
Tachycardia	3	1
Hypertension	2	1
Digestive System
Dry mouth	9	5
Constipation	9	4
Dyspepsia	7	5
Vomiting	4	3
Increased appetite	3	2
Hemic and Lymphatic System
Ecchymosis	5	3
Metabolic and Nutritional Disorders
Weight gain	5	3
Peripheral edema	3	1
Musculoskeletal System
Extremity pain (other than joint)	5	3
Joint pain	5	3
Nervous System
Somnolence	29	13
Insomnia	12	11
Dizziness	11	4
Abnormal gait	6	1
Tremor	4	3
Akathisia	3	2
Hypertonia	3	2
Articulation impairment	2	1
Respiratory System
Rhinitis	7	6
Cough increased	6	3
Pharyngitis	4	3
Special Senses
Amblyopia	3	2
Urogenital System
Urinary incontinence	2	1
Urinary tract infection	2	1

Dose Dependency of Adverse Reactions

A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder,incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see WARNINGS AND PRECAUTIONS] .

The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oralolanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The datawere analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was atrend.

Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups andPlacebo

Adverse Reaction	Percentage of Patients Reporting Event
	Placebo (N=68)	Olanzapine 5 ± 2.5 mg/day (N=65)	Olanzapine 10 ± 2.5 mg/day (N=64)	Olanzapine 15 ± 2.5 mg/day (N=69)
Asthenia	15	8	9	20
Dry mouth	4	3	5	13
Nausea	9	0	2	9
Somnolence	16	20	30	39
Tremor	3	0	5	7

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate

In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with thecombination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium orValproate Trials — Bipolar I Disorder (Manic or Mixed Episodes)

Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine with lithium or valproate (N=229)	Placebo with lithium or valproate (N=115)
Dry mouth	32	9
Weight gain	26	7
Increased appetite	24	8
Dizziness	14	7
Back pain	8	4
Constipation	8	4
Speech disorder	7	1
Increased salivation	6	2
Amnesia	5	2
Paresthesia	5	2

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine as Adjunct toLithium or Valproate

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treatedwith the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participatedin the acute phase of placebo-controlled combination trials.

Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct toLithium or Valproate

Body System/Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine with lithium or valproate (N=229)	Placebo with lithium or valproate (N=115)
Body as a Whole
Asthenia	18	13
Back pain	8	4
Accidental injury	4	2
Chest pain	3	2
Cardiovascular System
Hypertension	2	1
Digestive System
Dry mouth	32	9
Increased appetite	24	8
Thirst	10	6
Constipation	8	4
Increased salivation	6	2
Metabolic and Nutritional Disorders
Weight gain	26	7
Peripheral edema	6	4
Edema	2	1
Nervous System
Somnolence	52	27
Tremor	23	13
Depression	18	17
Dizziness	14	7
Speech disorder	7	1
Amnesia	5	2
Paresthesia	5	2
Apathy	4	3
Confusion	4	1
Euphoria	3	2
Incoordination	2	0
Respiratory System
Pharyngitis	4	1
Dyspnea	3	1
Skin and Appendages
Sweating	3	1
Acne	2	0
Dry skin	2	0
Special Senses
Amblyopia	9	5
Abnormal vision	2	0
Urogenital System
Dysmenorrheaa	2	0
Vaginitisa	2	0
a Denominator used was for females only (olanzapine, N=128; placebo, N=51).

For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts forthese other products.

Adverse Reactions Occurring at an Incidence of 1% or More among Intramuscular Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials

Table 15 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treatedwith intramuscular olanzapine for injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who participated in the short-term,placebo-controlled trials in agitated patients with schizophrenia or bipolar I mania.

Table 15: Treatment-Emergent Adverse Reactions: Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials with IntramuscularOlanzapine for Injection in Agitated Patients with Schizophrenia or Bipolar I Mania

Body System/Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine (N=415)	Placebo (N=150)
Body as a Whole
Asthenia	2	1
Cardiovascular System
Hypotension	2	0
Postural hypotension	1	0
Nervous System
Somnolence	6	3
Dizziness	4	2
Tremor	1	0

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formalrating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a6-week trial.

Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-ControlledClinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase

	Percentage of Patients Reporting Event
	Placebo	Olanzapine 5 ± 2.5 mg/day	Olanzapine 10 ± 2.5 mg/day	Olanzapine 15 ± 2.5 mg/day
Parkinsonisma	15	14	12	14
Akathisiab	23	16	19	27
a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reportedadverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment ofschizophrenia in a 6-week trial.

Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-ControlledClinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase

	Percentage of Patients Reporting Event
	Placebo (N=68)	Olanzapine 5 ± 2.5 mg/day (N=65)	Olanzapine 10 ± 2.5 mg/day (N=64)	Olanzapine 15 ± 2.5 mg/day (N=69)
Dystonic eventsa	1	3	2	3
Parkinsonism eventsb	10	8	14	20
Akathisia eventsc	1	5	11	10
Dyskinetic eventsd	4	0	2	1
Residual eventse	1	2	5	1
Any extrapyramidal event	16	15	25	32
a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies,tremor. c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneouslyreported adverse reactions during acute therapy (dose range: 2.5 to 20 mg/day).

Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of OralOlanzapine in Schizophrenia and Bipolar I Disorder — Adolescents

Categoriesa	Percentage of Patients Reporting Event
	Placebo (N=89)	Olanzapine (N=179)
Dystonic events	0	1
Parkinsonism events	2	1
Akathisia events	4	6
Dyskinetic events	0	1
Nonspecific events	0	4
Any extrapyramidal event	6	10
a Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formalrating scales during controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with placebo in agitation. Patients in each dosegroup could receive up to 3 injections during the trials [see Clinical Studies] . Patient assessments were conducted during the 24 hours following theinitial dose of intramuscular olanzapine for injection.

Table 19: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dose, Placebo-Controlled Clinical Trialof Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia

	Percentage of Patients Reporting Event
	Placebo	Olanzapine IM 2.5 mg	Olanzapine IM 5 mg	Olanzapine IM 7.5 mg	Olanzapine IM 10 mg
Parkinsonismaa	0	0	0	0	3
Akathisiab	0	0	5	0	0
a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reportedadverse reactions in the same controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with placebo in agitated patients with schizophrenia.

Table 20: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dose, Placebo-Controlled ClinicalTrial of Intramuscular Olanzapine for Injection in Agitated Patients with Schizophrenia

	Percentage of Patients Reporting Event
	Placebo (N=45)	Olanzapine IM 2.5 mg (N=48)	Olanzapine IM 5 mg (N=45)	Olanzapine IM 7.5 mg (N=46)	Olanzapine IM 10 mg (N=46)
Dystonic eventsa	0	0	0	0	0
Parkinsonism eventsb	0	4	2	0	0
Akathisia eventsc	0	2	0	0	0
Dyskinetic eventsd	0	0	0	0	0
Residual eventse	0	0	0	0	0
Any extrapyramidal events	0	4	2	0	0
a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies,tremor. c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

Dystonia, Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first fewdays of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty,difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with highpotency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger agegroups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials.This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote,(3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rateequal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in atleast 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole- Infrequent: chills, face edema, photosensitivity reaction, suicide attempt¹ ; Rare: chills and fever, hangover effect, sudden death¹.

Cardiovascular System- Infrequent: cerebrovascular accident, vasodilatation.

Digestive System-Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System-Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders-Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System- Rare: osteoporosis.

Nervous System- Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System- Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages- Infrequent: alopecia.

Special Senses- Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System- Infrequent: amenorrhea², breast pain, decreased menstruation, impotence², increased menstruation², menorrhagia², metrorrhagia², polyuria², urinary frequency, urinary retention, urinary urgency, urination impaired.

¹ These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of theirseriousness.
² Adjusted for gender.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Intramuscular Olanzapine for Injection

Following is a list of treatment-emergent adverse reactions reported by patients treated with intramuscular olanzapine for injection (at 1 or more doses≥2.5 mg/injection) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) forwhich a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications,or (5) for which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adversereactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients.

Body as a Whole- Frequent: injection site pain.

Cardiovascular System- Infrequent: syncope.

Digestive System- Infrequent: nausea.

Metabolic and Nutritional Disorders- Infrequent: creatine phosphokinase increased.

Clinical Trials in Adolescent Patients (age 13 to 17 years)

Commonly Observed Adverse Reactions in Oral Olanzapine Short-Term, Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 5% or more and reported at least twiceas frequently as placebo-treated patients are listed in Table 21 .

Table 21: Treatment-Emergent Adverse Reactions of ≥5% Incidence among Adolescents (13-17 Years Old) with Schizophrenia or Bipolar IDisorder (Manic or Mixed Episodes)

Adverse Reactions	Percentage of Patients Reporting Event
	6 Week Trial % Schizophrenia Patients		3 Week Trial % Bipolar Patients
	Olanzapine (N=72)	Placebo (N=35)	Olanzapine (N=107)	Placebo (N=54)
Sedationa	39	9	48	9
Weight increased	31	9	9	4
Headache	17	6	17	17
Increased appetite	17	9	29	4
Dizziness	8	3	7	2
Abdominal painbb	6	3	6	7
Pain in extremity	6	3	5	0
Fatigue	3	3	14	6
Dry mouth	4	0	7	0
a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. b Patients with the following MedDRA terms were counted in this category: abdominal pain, abdominal pain lower, abdominal pain upper.

Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term (3-6 weeks), Placebo-Controlled Trials

Adverse reactions in adolescent patients treated with oral olanzapine (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placeboare listed in Table 22 .

Table 22: Treatment-Emergent Adverse Reactions of ≥2% Incidence among Adolescents (13-17 Years Old) (Combined Incidence from Short-Term, Placebo-Controlled Clinical Trials of Schizophrenia or Bipolar I Disorder [Manic or Mixed Episodes])

Adverse Reaction	Percentage of Patients Reporting Event
	Olanzapine (N=179)	Placebo (N=89)
Sedationa	44	9
Weight increased	30	6
Increased appetite	24	6
Headache	17	12
Fatigue	9	4
Dizziness	7	2
Dry mouth	6	0
Pain in extremity	5	1
Constipation	4	0
Nasopharyngitis	4	2
Diarrhea	3	0
Restlessness	3	2
Liver enzymes increasedb	8	1
Dyspepsia	3	1
Epistaxis	3	0
Respiratory tract infectionc	3	2
Sinusitis	3	0
Arthralgia	2	0
Musculoskeletal stiffness	2	0
a Patients with the following MedDRA terms were counted in this category: hypersomnia, lethargy, sedation, somnolence. b The terms alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic enzyme were combined under liver enzymes. c Patients with the following MedDRA terms were counted in this category: lower respiratory tract infection, respiratory tract infection, respiratory tract infection viral,upper respiratory tract infection, viral upper respiratory tract infection.

Vital Signs And Laboratory Studies

Vital Sign Changes

Oral olanzapine was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular olanzapine for injectionwas associated with bradycardia, hypotension, and tachycardia in clinical trials [see WARNINGS AND PRECAUTIONS] .

Laboratory Changes

Olanzapine Monotherapy in Adults

An assessment of the premarketing experience for olanzapine revealed an association with asymptomatic increases inALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transientchanges that tended to normalize while olanzapine treatment was continued.

In placebo-controlled olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal[ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed toplacebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treatedpatients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine ordiscontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGTlevels were recorded in ≥1% (88/5245) of patients.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limitedhepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Olanzapine administration was also associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS] , with an asymptomatic elevation ofthe eosinophil count in 0.3% of patients, and with an increase in CPK.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uricacid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adolescents

In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic ormixed episodes), greater frequencies for the following treatment-emergent findings, at anytime, were observed in laboratory analytes compared to placebo:elevated ALT (≥3X ULN in patients with ALT at baseline <3X ULN), (12% vs 2%); elevated AST (28% vs 4%); low total bilirubin (22% vs 7%); elevatedGGT (10% vs 1%); and elevated prolactin (47% vs 7%).

In placebo-controlled olanzapine monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times ULN at baseline to ≥3times ULN) were observed in 12% (22/192) of patients exposed to olanzapine compared to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned tonormal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. Noadolescent patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

ECG Changes

In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placeboin the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals.Olanzapine use was associated with a mean increase in heart rate compared to placebo (adults: +2.4 beats per minute vs no change with placebo;adolescents: +6.3 beats per minute vs -5.1 beats per minute with placebo). This increase in heart rate may be related to olanzapine's potential for inducingorthostatic changes [see WARNINGS AND PRECAUTIONS] .

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZYPREXA. Because these reactions are reported voluntarily from apopulation of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include thefollowing: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabeticketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis,jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering¹, and venousthromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceridelevels of ≥1000 mg/dL have been reported. Stuttering was only studied in oral and long acting injection (LAI) formulations.

¹ Stuttering was only studied in oral and long acting injection (LAI) formulations.

Drug Interactions for Zyprexa

The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies.

Potential For Other Drugs To Affect Olanzapine

Diazepam

The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Potential For Olanzapine To Affect Other Drugs] .

Cimetidine And Antacids

Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability ofolanzapine.

Inducers Of CYP1A2

Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of olanzapine. This increase is likelydue to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase inolanzapine clearance.

Alcohol

Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The co-administration of alcohol (i.e., ethanol) witholanzapine potentiated the orthostatic hypotension observed with olanzapine [see Potential For Olanzapine To Affect Other Drugs ] .

Inhibitors Of CYP1A2

Fluvoxamine

Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax followingfluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower dosesof olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

Inhibitors Of CYP2D6

Fluoxetine

Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration ofolanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overallvariability between individuals, and therefore dose modification is not routinely recommended. When using ZYPREXA and fluoxetine in combination, alsorefer to the Drug Interactions section of the package insert for Symbyax.

Warfarin

Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics [see Potential For Olanzapine To Affect Other Drugs] .

Inducers Of CYP1A2 Or Glucuronyl Transferase

Omeprazole and rifampin may cause an increase in olanzapine clearance.

Charcoal

The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are nottypically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Anticholinergic Drugs

Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severegastrointestinal adverse reactions related to hypomotility. ZYPREXA should be used with caution in patients receiving medications having anticholinergic(antimuscarinic) effects [see WARNINGS AND PRECAUTIONS] .

Potential For Olanzapine To Affect Other Drugs

CNS Acting Drugs

Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrallyacting drugs and alcohol.

Antihypertensive Agents

Olanzapine, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa And Dopamine Agonists

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM)

Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantlyaffect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam andintramuscular olanzapine for injection added to the somnolence observed with either drug alone [see WARNINGS AND PRECAUTIONS] .

Lithium

Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administrationdoes not require dosage adjustment of lithium [see WARNINGS AND PRECAUTIONS] .

Valproate

Olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapineadministration does not require dosage adjustment of valproate [see WARNINGS AND PRECAUTIONS] .

Effect Of Olanzapine On Drug Metabolizing Enzymes

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential toinhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated bythese enzymes.

Imipramine

Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin

Single doses of olanzapine did not affect the pharmacokinetics of warfarin [see Potential For Other Drugs To Affect Olanzapine] .

Diazepam

Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with olanzapine increased the orthostatic hypotension observed with either drug given alone [see Potential For Other Drugs To Affect Olanzapine] .

Alcohol

Multiple doses of olanzapine did not influence the kinetics of ethanol [see Potential For Other Drugs To Affect Olanzapine] .

Biperiden

Multiple doses of olanzapine did not influence the kinetics of biperiden.

Theophylline

Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Drug Abuse And Dependence

Dependence

In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or nopotential of abuse or physical dependence in rats administered oral doses up to 15 times the daily oral MRHD (20 mg) and rhesus monkeys administeredoral doses up to 8 times the daily oral MRHD based on mg/m² body surface area.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did notreveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limitedexperience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluatedcarefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development oftolerance, increases in dose, drug-seeking behavior).

Warnings for Zyprexa

Included as part of the "PRECAUTIONS" Section

Precautions for Zyprexa

When using ZYPREXA and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

Elderly Patients With Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.ZYPREXA is not approved for the treatment of patients with dementia-related psychosis [see BOX WARNING , Use In Specific Populations, and PATIENT INFORMATION] .

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients wassignificantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities,were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is notapproved for the treatment of patients with dementia-related psychosis [see BOX WARNING and PATIENT INFORMATION] .

Suicide

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drugtherapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce therisk of overdose.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association withadministration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status andevidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may includeelevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinicalpresentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs andsymptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primarycentral nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy;2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatmentsare available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. Thepatient should be carefully monitored, since recurrences of NMS have been reported [see PATIENT INFORMATION] .

Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneousreaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis,pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine if DRESS is suspected [see PATIENT INFORMATION] .

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changesmay be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

Hyperglycemia And Diabetes Mellitus

Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, orhaving borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking olanzapine should be monitoredregularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning oftreatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia includingpolydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics shouldundergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, somepatients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see PATIENT INFORMATION] .

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypicalantipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by thepossibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in thegeneral population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treatedwith the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucoselevels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to theaverage of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucoseof 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration ofapproximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline(patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucoselevel ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL). Olanzapine-treated patients had a greater mean HbA_1c increase from baseline of0.04% (median exposure 21 days), compared to a mean HbA_1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergentglycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adultolanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

			Up to 12 weeksexposure		At least 48 weeksexposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High (<100 mg/dL to ≥126 mg/dL)	Olanzapine	543	2.2%	345	12.8%
		Placebo	293	3.4%	NAa	NAa
	Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Olanzapine	178	17.4%	127	26.0%
		Placebo	96	11.5%	NAa	NAa
a Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months ofolanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In ananalysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder(manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo(2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 showsshort-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

			Up to 12 weeksexposure		At least 24 weeksexposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High (<100 mg/dL to ≥126 mg/dL)	Olanzapine	124	0%	108	0.9%
		Placebo	53	1.9%	NAa	NAa
	Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Olanzapine	14	0%	3	23.1%
		Placebo	13	14.3%	NAa	NAa
a Not Applicable.

Dyslipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluationsin patients using olanzapine, is recommended [see PATIENT INFORMATION] .

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest meanincreases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks,olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL,4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed betweenolanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) weregreater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia orrelated adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients whocompleted 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, orchanges in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

			Up to 12 weeksexposure		At least 48 weeksexposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	745	39.6%	487	61.4%
		Placebo	402	26.1%	NAa	NAa
	Normal to High (<150 mg/dL to ≥200 mg/dL)	Olanzapine	457	9.2%	293	32.4%
		Placebo	251	4.4%	NAa	NAa
	Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	135	39.3%	75	70.7%
		Placebo	65	20.0%	NAa	NAa
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	745	21.6%	489	32.9%
		Placebo	402	9.5%	NAa	NAa
	Normal to High (<200 mg/dL to ≥240 mg/dL)	Olanzapine	392	2.8%	283	14.8%
		Placebo	207	2.4%	NAa	NAa
	Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	Olanzapine	222	23.0%	125	55.2%
		Placebo	112	12.5%	NAa	NAa
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	536	23.7%	483	39.8%
		Placebo	304	14.1%	NAa	NAa
	Normal to High (<100 mg/dL to ≥160 mg/dL)	Olanzapine	154	0%	123	7.3%
		Placebo	82	1.2%	NAa	NAa
	Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	Olanzapine	302	10.6%	284	31.0%
		Placebo	173	8.1%	NAa	NAa
a Not Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase intriglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In ananalysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manicor mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, andtriglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDLcholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, noclinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes infasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

			Up to 6 weeks exposure		At least 24 weeksexposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	138	37.0%	122	45.9%
		Placebo	66	15.2%	NAa	NAa
	Normal to High (<90 mg/dL to >130 mg/dL)	Olanzapine	67	26.9%	66	36.4%
		Placebo	28	10.7%	NAa	NAa
	Borderline to High (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)	Olanzapine	37	59.5%	31	64.5%
		Placebo	17	35.3%	NAa	NAa
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	138	14.5%	122	14.8%
		Placebo	66	4.5%	NAa	NAa
	Normal to High (<170 mg/dL to ≥200 mg/dL)	Olanzapine	87	6.9%	78	7.7%
		Placebo	3	2.3%	NAa	NAa
	Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	36	38.9%	33	57.6%
		Placebo	13	7.7%	NAa	NAa
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	137	17.5%	121	22.3%
		Placebo	63	11.1%	NAa	NAa
	Normal to High (<110 mg/dL to ≥130 mg/dL)	Olanzapine	98	5.1%	92	10.9%
		Placebo	44	4.5%	NAa	NAa
	Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	Olanzapine	29	48.3%	21	47.6%
		Placebo	9	0%	NAa	NAa
a Not Applicable.

Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring ofweight [see PATIENT INFORMATION] .

Olanzapine Monotherapy in Adults

In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained anaverage of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% ofolanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a medianexposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation dueto weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patientswho gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation dueto weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients whocompleted treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults

Amount Gained kg (lb)	6 Weeks (N=7465) (%)	6 Months (N=4162) (%)	12 Months (N=1345) (%)	24 Months (N=474) (%)	36 Months (N=147) (%)
≤0	26.2	24.3	20.8	23.2	17.0
0 to ≤5 (0-11 lb)	57.0	36.0	26.0	23.4	25.2
>5 to ≤10 (11-22 lb)	14.9	24.6	24.2	24.1	18.4
>10 to ≤15 (22-33 lb)	1.8	10.9	14.9	11.4	17.0
>15 to ≤20 (33-44 lb)	0.1	.1	8.6	9.3	11.6
>20 to ≤25 (44-55 lb)	0	0.9	3.3	5.1	4.1
>25 to ≤30 (55-66 lb)	0	0.2	1.4	2.3	4.8
>30 (>66 lb)	0	0.1	0.8	1.2	2

Dose group differences with respect to weight gain have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline toendpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Meanincrease in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

	Olanzapine-treated patients	Placebo-treated patients
Mean change in body weight from baseline(median exposure = 3 weeks)	4.6 kg (10.1 lb)	0.3 kg (0.7 lb)
Percentage of patients who gained at least 7% ofbaseline body weight	40.6% (median exposure to 7% = 4 weeks)	9.8% (median exposure to 7% = 8 weeks)
Percentage of patients who gained at least 15% ofbaseline body weight	7.1% (median exposure to 15% = 19 weeks)	2.7% (median exposure to 15% = 8 weeks)

In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179). The percentages ofadolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Amongadolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal(N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients whocompleted treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 monthsof treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents

Amount Gained kg (lb)	6 Weeks (N=243) (%)	6 Months (N=191) (%)
≤0	29.	2.1
0 to ≤5 (0-11 lb)	47.3	24.6
>5 to ≤10 (11-22 lb)	42.4	26.7
>10 to ≤15 (22-33 lb)	5.8	22.0
>15 to ≤20 (33-44 lb)	0.8	12.6
>20 to ≤25 (44-55 lb)	0.8	9.4
>25 to ≤30 (55-66 lb)	0	2.1
>30 to ≤35 (66-77 lb)	0	0
>35 to ≤40 (77-88 lb)	0	0
>40 (>88 lb)	0	0.5

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although theprevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict,at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potentialto cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and thetotal cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, afterrelatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (orpartially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomaticsuppression has upon the long-term course of the syndrome is unknown.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronicantipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and(2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronictreatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continuedtreatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients mayrequire treatment with olanzapine despite the presence of the syndrome. For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

Orthostatic Hypotension

Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during theinitial dose-titration period, probably reflecting its α -adrenergic antagonistic properties [see PATIENT INFORMATION] .

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatichypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see DOSAGE AND ADMINISTRATION] . A more gradual titration to the target dose should be considered if hypotension occurs.

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapinefor injection. In an open-label clinical pharmacology study in nonagitated patients with schizophrenia in which the safety and tolerability of intramuscularolanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patientsexperienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) [see DOSAGE AND ADMINISTRATION] . Syncope wasreported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients withagitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experiencedhypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions occurred on intramuscular olanzapine,and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patientscompared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For intramuscular olanzapine for injection therapy,patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension,bradycardia, and/or hypoventilation.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure,or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, andtreatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increasedmedical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or centralnervous system depression [see DRUG INTERACTIONS] . Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine is notrecommended due to the potential for excessive sedation and cardiorespiratory depression.

Falls

ZYPREXA may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or otherinjuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiatingantipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia, And Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychoticagents, including ZYPREXA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug inducedleukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their completeblood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ZYPREXA should be considered at the first sign ofa clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if suchsymptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³ ) should discontinue ZYPREXA and have their WBCfollowed until recovery.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity andmortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

Seizures

During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributedto the occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients with a history of seizures or with conditions thatpotentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Potential For Cognitive And Motor Impairment

Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patientscompared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in thepremarketing database. Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery,including automobiles, until they are reasonably certain that olanzapine therapy does not affect them adversely [see PATIENT INFORMATION] .

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribingolanzapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously,exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see PATIENT INFORMATION] .

Anticholinergic (Antimuscarinic) Effects

Olanzapine exhibits in vitro muscarinic receptor affinity [see CLINICAL PHARMACOLOGY] . In premarketing clinical trials, Zyprexa was associated withconstipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basisfor discontinuations, but Zyprexa should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significantprostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post marketing experience, the risk for severe adverse reactions(including fatalities) was increased with concomitant use of anticholinergic medications [see DRUG INTERACTIONS] .

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration.Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductivefunction by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have beenreported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead todecreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importanceif the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increaseprolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology] . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronicadministration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adultstreated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated witholanzapine, potentially associated clinical manifestations included menstrual-related events¹ (2% [49/3240] of females), sexual function-related events² (2% [150/8136] of females and males), and breast-related events³ (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixedepisodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treatedpatients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations includedmenstrual-related events¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events (2%[3/168] of females, 2% [7/286] of males) [see Use In Specific Populations] .

¹ Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.
² Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, andsexual dysfunction.
³ Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactinelevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicatedsignificant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

Use In Combination With Fluoxetine, Lithium, Or Valproate

When using ZYPREXA and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert forSymbyax. When using ZYPREXA in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of thepackage inserts for lithium or valproate [see DRUG INTERACTIONS] .

Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Metabolic Changes and PATIENT INFORMATION] .

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION) for the oral formulations.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ZYPREXA as monotherapy or incombination with fluoxetine. If you do not think you are getting better or have any concerns about your condition while taking ZYPREXA, call yourdoctor. When using ZYPREXA and fluoxetine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

Elderly Patients With Dementia-Related Psychosis: Increased Mortality And Cerebrovascular Adverse Events (CVAE), Including Stroke

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk ofdeath. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with ZYPREXA had a significantly higherincidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo.

ZYPREXA is not approved for elderly patients with dementia-related psychosis [see BOX WARNING and WARNINGS AND PRECAUTIONS] .

Neuroleptic Malignant Syndrome (NMS)

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association withadministration of antipsychotic drugs, including ZYPREXA. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, andevidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS] .

Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)

Patients should be advised to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reactionwith Eosinophilia and Systemic Symptoms (DRESS) [see WARNINGS AND PRECAUTIONS] .

Hyperglycemia And Diabetes Mellitus

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucosecontrol. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking ZYPREXA [see WARNINGS AND PRECAUTIONS] .

Dyslipidemia

Patients should be counseled that dyslipidemia has occurred during treatment with ZYPREXA. Patients should have their lipid profile monitored regularly [see WARNINGS AND PRECAUTIONS] .

Weight Gain

Patients should be counseled that weight gain has occurred during treatment with ZYPREXA. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS] .

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use ofconcomitant drugs that may potentiate the orthostatic effect of ZYPREXA, e.g., diazepam or alcohol [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS] . Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint,until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatichypotension: dizziness, fast or slow heartbeat, or fainting.

Potential For Cognitive And Motor Impairment

Because ZYPREXA has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery,including automobiles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS] .

Body Temperature Regulation

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away ifthey become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feelingthirsty, not able to produce urine [see WARNINGS AND PRECAUTIONS] .

Concomitant Medication

Patients should be advised to inform their healthcare providers if they are taking, or plan to take, Symbyax. Patients should also be advised to inform theirhealthcare providers if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, sincethere is a potential for interactions [see DRUG INTERACTIONS] .

Alcohol

Patients should be advised to avoid alcohol while taking ZYPREXA [see DRUG INTERACTIONS] .

Phenylketonurics

ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet,respectively) [see DESCRIPTION] .

Use In Specific Populations

Pregnancy

Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZYPREXA.Advise patients that ZYPREXA may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratorydistress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in womenexposed to ZYPREXA during pregnancy [see Use In Specific Populations] .

Lactation

Advise breastfeeding women using ZYPREXA to monitor infants for excess sedation, irritability, poor feeding and extrapyramidal symptoms(tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use In Specific Populations] .

Infertility

Advise females of reproductive potential that ZYPREXA may impair fertility due to an increase in serum prolactin levels. The effects onfertility are reversible [see Use In Specific Populations] .

Pediatric Use

ZYPREXA is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and havegreater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about thepotential long-term risks associated with ZYPREXA and advised that these risks may lead them to consider other drugs first [see INDICATIONS] . Safety and effectiveness of ZYPREXA in patients under 13 years of age have not been established. Safety and efficacy of ZYPREXA andfluoxetine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar Idisorder. Safety and effectiveness of ZYPREXA and fluoxetine in combination in patients <10 years of age have not been established [see WARNINGS AND PRECAUTIONS and Use In Specific Populations] .

Need For Comprehensive Treatment Program In Pediatric Patients

ZYPREXA is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include othermeasures (psychological, educational, social) for patients with the disorder. Effectiveness and safety of ZYPREXA have not been established in pediatricpatients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary toenvironmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is oftenhelpful. The decision to prescribe atypical antipsychotic medication will depend upon the healthcare provider's assessment of the chronicity and severity ofthe patient's symptoms [see INDICATIONS] .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the daily oral MRHD based on mg/m² body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the daily oral MRHD based on mg/m² body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4,8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the daily oral MRHD based on mg/m² body surface area, respectively). The incidence of liverhemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice at 2 times the daily oral MRHD based on mg/m² bodysurface area. These tumors were not increased in another mouse study in females dosed up to 2-5 times the daily oral MRHD based on mg/m² body surfacearea; in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas andadenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the dailyoral MRHD based on mg/m² body surface area, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents.Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showedthat olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary glandneoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance forhuman risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [see WARNINGS AND PRECAUTIONS] .

Mutagenesis

No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, thechromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test inmouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Impairment Of Fertility

In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a doseof 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the daily oral MRHD based on mg/m² body surface area,respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increasedand the mating index reduced at 5 mg/kg/day (2.5 times the daily oral MRHD based on mg/m² body surface area). Diestrous was prolonged and estrousdelayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m² body surface area); therefore olanzapine may produce a delay in ovulation.

Use In Specific Populations

When using ZYPREXA and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ZYPREXA, duringpregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ZYPREXA, during the third trimester are at risk for extrapyramidal and/or withdrawal symptomsfollowing delivery (see Clinical Considerations) . Overall available data from published epidemiologic studies of pregnant women exposed to olanzapinehave not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to themother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ZYPREXA, during pregnancy (see Clinical Considerations) .

Olanzapine was not teratogenic when administered orally to pregnant rats and rabbits at doses that are 9- and 30-times the daily oral maximumrecommended human dose (MRHD), based on mg/m² body surface area; some fetal toxicities were observed at these doses (see Data) .

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk ofbirth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a directresult of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorderhave been reported in neonates who were exposed to antipsychotic drugs, including ZYPREXA, during the third trimester of pregnancy. These symptomshave varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recoveredwithin hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Placental passage has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% atbirth following exposure during pregnancy. The clinical relevance of this finding is unknown.

Published data from observational studies, birth registries, and case reports that have evaluated the use of atypical antipsychotics during pregnancy do notestablish an increased risk of major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics duringpregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the daily oral MRHD based onmg/m² body surface area, respectively), no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbersof nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the daily oral MRHD based on mg/m² body surface area), and gestation wasprolonged at 10 mg/kg/day (5 times the daily oral MRHD based on mg/m² body surface area). In an oral rabbit teratology study, fetal toxicity manifested asincreased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (30 times the daily oral MRHD based on mg/m² body surface area).

Lactation

Risk Summary

Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormalmuscle movements) in infants exposed to olanzapine through breast milk (see Clinical Considerations) . There is no information on the effects ofolanzapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZYPREXA and any potentialadverse effects on the breastfed child from ZYPREXA or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to ZYPREXA should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormalmuscle movements).

Females And Males Of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of olanzapine (D receptor antagonism), treatment with ZYPREXA may result in an increase in serum prolactin levels,which may lead to a reversible reduction in fertility in females of reproductive potential [see WARNINGS AND PRECAUTIONS] .

Pediatric Use

The safety and effectiveness of oral ZYPREXA in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder wereestablished in short-term studies in adolescents (ages 13 to 17 years). Use of ZYPREXA in adolescents is supported by evidence from adequate and well-controlled studies of ZYPREXA in which 268 adolescents received ZYPREXA in a range of 2.5 to 20 mg/day [see Clinical Studies] .Recommended starting dose for adolescents is lower than that for adults [see DOSAGE AND ADMINISTRATION ] . Compared to patients from adultclinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDLcholesterol, prolactin and hepatic aminotransferase levels [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS ] . When decidingamong the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) forweight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may leadthem to consider prescribing other drugs first in adolescents [see INDICATIONS] .

Safety and effectiveness of olanzapine in children <13 years of age have not been established [see PATIENT INFORMATION] .

Safety and efficacy of ZYPREXA and fluoxetine in combination in children and adolescents (10 to 17 years of age) have been established for the acutetreatment of depressive episodes associated with bipolar I disorder.

Safety and effectiveness of ZYPREXA and fluoxetine in combination in children <10 years of age have not been established.

Geriatric Use

Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there wasno indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients with dementia-relatedpsychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderlypatients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies ofolanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transientischemic attack) in patients treated with olanzapine compared to patients treated with placebo. In 5 placebo-controlled studies of olanzapine in elderlypatients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increasedweight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapinethan placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo.Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see BOX WARNING , WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION] . Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors thatmight decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dosefor any geriatric patient [see BOX WARNING , DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS] .

Clinical studies of ZYPREXA and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether theyrespond differently from younger patients.

Overdose Information for Zyprexa

Human Experience

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limitednumber of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change inlaboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.

In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptomswith ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousnessranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration,cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption ofnormal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly andCompany has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestionof approximately 2 g of oral olanzapine.

Management Of Overdose

There is no specific antidote to an overdose of ZYPREXA. The possibility of multiple drug involvement should be considered. Establish and maintain anairway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuouselectrocardiographic monitoring to detect possible arrhythmias.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the prescribing information for those products. For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax prescribing information.

Contraindications for Zyprexa

• None with ZYPREXA monotherapy.
• When using ZYPREXA and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax.
• For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.

Clinical Pharmacology for Zyprexa

Mechanism Of Action

The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated througha combination of dopamine and serotonin type 2 (5HT₂) antagonism.

Pharmacodynamics

Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C , 5HT₆ (K_i=4, 11, and 5 nM, respectively), dopamine D_1-4 (K_i =11-31 nM), histamine H₁ (K_i =7 nM), and adrenergic α1 receptors (K_i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ (K_i =57 nM) and musscarinic M_1-5 (K_i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA , BZD, and β-adrenergicreceptors (K_i >10 μM).

Pharmacokinetics

Oral Administration, Monotherapy

Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It iseliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does notaffect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that ZYPREXA tablets and ZYPREXA ZYDIS (olanzapine orallydisintegrating 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), andapparent 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 1 week that are approximately twice the concentrations after singledoses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins overthe concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α -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 asunchanged 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. Aftermultiple dosing, the major circulating metabolites were the 10-N-glucuronide, 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 theconcentrations observed.

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest thatCYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be aminor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Intramuscular Administration

ZYPREXA IntraMuscular results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes.Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasmaconcentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curveachieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscularadministration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles afterintramuscular administration are qualitatively similar to metabolic profiles after oral administration.

Specific Populations

Renal Impairment

Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone isunlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients withsevere 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 Impairment

Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect ofimpaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on thepharmacokinetics of olanzapine.

Geriatric

In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years) than innonelderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drugmetabolism 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 andwomen 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 routinelyrecommended.

Race

In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weightdifferences. 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. Theclearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary inpatients who exhibit a combination of factors that may result in slower metabolism of olanzapine [see DOSAGE AND ADMINISTRATION] .

Adolescents (Ages 13 To 17 years)

In clinical studies, most adolescents were nonsmokers and this population had a lower average body weight, whichresulted in higher average olanzapine exposure compared to adults.

Animal Toxicology And/Or Pharmacology

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 timesthe daily oral MRHD based on mg/m² body surface area), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A fewdogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-relateddecreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the daily oral MRHD based on mg/m² body surfacearea) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11times the daily oral MRHD based on mg/m² body surface area) for 3 months or 16 mg/kg (8 times the daily oral MRHD based on mg/m² body surfacearea) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular orhypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

Clinical Studies

When using ZYPREXA and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Schizophrenia

Adults

The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who metDSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not comparethese 2 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), amulti-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 assessingactively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilledobserver, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scaleswere employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and theScale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRSpsychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 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 PANSSNegative subscale, and on CGI Severity.

(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on aonce daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS totalscore, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clearadvantage for the high-dose group over the medium-dose group.

(3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapineduring 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 toplacebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine wassuperior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy inpatients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.

Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Adolescents

The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind,placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR andconfirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).

The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric RatingScale for Children (BPRS-C) total score.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in thetreatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score forpatients in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient treated with ZYPREXA should be maintained,maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescentpatients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.Patients should be periodically reassessed to determine the need for maintenance treatment.

Bipolar I Disorder (Manic Or Mixed Episodes)

Adults

Monotherapy

The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week)placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patientswith 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 11-item clinician-ratedscale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increasedactivity, 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), olanzapinewas superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapinedemonstrated 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), olanzapinewas superior to placebo in 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 I disorder who had responded during an initial open-labeltreatment phase for about 2 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 of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and50% 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 ofthe Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 totalscore to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced asignificantly longer time to relapse.

Adjunct to Lithium or Valproate

The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes wasestablished in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patientswith 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 mixedsymptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose rangeof 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 μg/mL to125 μg/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 mixedsymptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose rangeof 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 μg/mL to125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

Adolescents

Acute Monotherapy

The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) wasestablished in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria formanic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis wasconfirmed by the K-SADS-PL.

The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) totalscore.

In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in thetreatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater meanreduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.

While there is no body of evidence available to answer the question of how long the adolescent patient treated with ZYPREXA should be maintained,maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescentpatients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.Patients should be periodically reassessed to determine the need for maintenance treatment.

Agitation Associated With Schizophrenia And Bipolar I Mania

The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients from 2 diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes). Each of the trialsincluded a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar I mania study).Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatmentwith intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positiveand Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with atleast 1 individual item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS ExcitedComponent score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in thesetrials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections during the 24 hourIM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure wasassessed. The results of the trials follow:

1. In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), 4 fixed intramuscular olanzapine for injectiondoses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hourspost-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and10 mg doses over the 5 mg dose.
2. In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), 1 fixed intramuscular olanzapine forinjection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.
3. In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixedepisode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injectionwas statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Patient Information for Zyprexa

ZYPREXA^®
(zy-PREX-a)
(olanzapine) Tablet

ZYPREXA^®
ZYDIS^®
(zy-PREX-a ZY-dis)
(olanzapine) Tablet, Orally Disintegrating

Read the Medication Guide that comes with ZYPREXA before you start taking it and each time you get a refill. There may be new information. ThisMedication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if thereis something you do not understand or you want to learn more about ZYPREXA.

What is the most important information I should know about ZYPREXA?

ZYPREXA may cause serious side effects, including:

1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).
2. High blood sugar (hyperglycemia).
3. High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17 or when used in combination withfluoxetine in children age 10 to 17.
4. Weight gain, especially in teenagers age 13 to 17 or when used in combination with fluoxetine in children age 10 to 17.

These serious side effects are described below.

1. Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). ZYPREXA is not approved for treating psychosis in elderly people with dementia.
2. High blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugarcould lead to:
   • a build up of acid in your blood due to ketones (ketoacidosis)
   • coma
   • death

Your doctor should do tests to check your blood sugar before you start taking ZYPREXA and during treatment. In people who do not have diabetes,sometimes high blood sugar goes away when ZYPREXA is stopped. People with diabetes and some people who did not have diabetes before takingZYPREXA need to take medicine for high blood sugar even after they stop taking ZYPREXA.

If you have diabetes, follow your doctor's instructions about how often to check your blood sugar while taking ZYPREXA.

Call your doctor if you have any of these symptoms of high blood sugar (hyperglycemia) while taking ZYPREXA:

• feel very thirsty
• need to urinate more than usual
• feel very hungry
• feel weak or tired
• feel sick to your stomach
• feel confused or your breath smells fruity

3. High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with ZYPREXA, especially in teenagers(13 to 17 years old), or when used in combination with fluoxetine in children (10 to 17 years old). You may not have any symptoms, so your doctorshould do blood tests to check your cholesterol and triglyceride levels before you start taking ZYPREXA and during treatment.

4. Weight gain. Weight gain is very common in people who take ZYPREXA. Teenagers (13 to 17 years old) are more likely to gain weight and to gainmore weight than adults. Children (10 to 17 years old) are also more likely to gain weight and to gain more weight than adults when ZYPREXA is usedin combination with fluoxetine. Some people may gain a lot of weight while taking ZYPREXA, so you and your doctor should check your weightregularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

What is ZYPREXA?

ZYPREXA is a prescription medicine used to treat:

• schizophrenia in people age 13 or older.
• bipolar disorder, including:
  • manic or mixed episodes that happen with bipolar I disorder in people age 13 or older.
  • manic or mixed episodes that happen with bipolar I disorder, when used with the medicine lithium or valproate, in adults.
  • long-term treatment of bipolar I disorder in adults.
• episodes of depression that happen with bipolar I disorder, when used with the medicine fluoxetine (Prozac ) in people age 10 or older.
• episodes of depression that do not get better after 2 other medicines, also called treatment resistant depression, when used with the medicine fluoxetine(Prozac), in adults.

ZYPREXA has not been approved for use in children under 13 years of age. ZYPREXA in combination with fluoxetine has not been approved for use inchildren under 10 years of age.

The symptoms of schizophrenia include hearing voices, seeing things that are not there, having beliefs that are not true, and being suspicious or withdrawn.

The symptoms of bipolar I disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racingthoughts, talking fast, impulsive behavior, and a decreased need for sleep.

The symptoms of treatment resistant depression include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreasedconcentration, changes in appetite, and suicidal thoughts or behavior.

Some of your symptoms may improve with treatment. If you do not think you are getting better, call your doctor.

What should I tell my doctor before taking ZYPREXA?

ZYPREXA may not be right for you. Before starting ZYPREXA, tell your doctor if you have or had:

• heart problems
• seizures
• diabetes or high blood sugar levels (hyperglycemia)
• high cholesterol or triglyceride levels in your blood
• liver problems
• low or high blood pressure
• strokes or “mini-strokes” also called transient ischemic attacks (TIAs)
• Alzheimer's disease
• narrow-angle glaucoma
• enlarged prostate in men
• bowel obstruction
• phenylketonuria, because ZYPREXA ZYDIS contains phenylalanine
• breast cancer
• thoughts of suicide or hurting yourself
• any other medical condition
• are pregnant or plan to become pregnant. It is not known if ZYPREXA will harm your unborn baby.
  • If you become pregnant while receiving ZYPREXA, talk to your healthcare provider about registering with the National Pregnancy Registry forAtypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
• are breast-feeding or plan to breast-feed. ZYPREXA passes into your breast milk. Talk to your doctor about the best way to feed your baby if you takeZYPREXA.

Tell your doctor if you exercise a lot or are in hot places often.

The symptoms of bipolar I disorder, treatment resistant depression, or schizophrenia may include thoughts of suicide or of hurting yourself or others. Ifyou have these thoughts at any time, tell your doctor or go to an emergency room right away.

Tell your doctor about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.ZYPREXA and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if itis safe to take ZYPREXA with your other medicines. Do not start or stop any medicine while taking ZYPREXA without talking to your doctor first.

How should I take ZYPREXA?

• Take ZYPREXA exactly as prescribed. Your doctor may need to change (adjust) the dose of ZYPREXA until it is right for you.
• If you miss a dose of ZYPREXA, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose andtake your next dose at the regular time. Do not take two doses of ZYPREXA at the same time.
• To prevent serious side effects, do not stop taking ZYPREXA suddenly. If you need to stop taking ZYPREXA, your doctor can tell you how tosafely stop taking it.
• If you take too much ZYPREXA, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.
• ZYPREXA can be taken with or without food.
• ZYPREXA is usually taken one time each day.
• Take ZYPREXA ZYDIS as follows:
  • Be sure that your hands are dry.
  • Open the sachet and peel back the foil on the blister. Do not push the tablet through the foil.
  • As soon as you open the blister, remove the tablet and put it into your mouth.
  • The tablet will disintegrate quickly in your saliva so that you can easily swallow it with or without drinking liquid.
• Call your doctor if you do not think you are getting better or have any concerns about your condition while taking ZYPREXA.

What should I avoid while taking ZYPREXA?

• ZYPREXA can cause sleepiness and may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavymachinery, or do other dangerous activities until you know how ZYPREXA affects you.
• Avoid drinking alcohol while taking ZYPREXA. Drinking alcohol while you take ZYPREXA may make you sleepier than if you take ZYPREXAalone.

What are the possible side effects of ZYPREXA?

Serious side effects may happen when you take ZYPREXA, including:

• See “What is the most important information I should know about ZYPREXA?”, which describes the increased risk of death in elderly peoplewith dementia-related psychosis and the risks of high blood sugar, high cholesterol and triglyceride levels, and weight gain.
• Increased incidence of stroke or “mini-strokes” called transient ischemic attacks (TIAs) in elderly people with dementia-related psychosis (elderly people who have lost touch with reality due to confusion and memory loss). ZYPREXA is not approved for these patients.
• Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines,including ZYPREXA. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any ofthese symptoms:
  • high fever
  • excessive sweating
  • rigid muscles
  • confusion
  • changes in your breathing, heartbeat, and blood pressure.
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):DRESS can occur with ZYPREXA. Features of DRESS may include rash,fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. DRESS is sometimes fatal; therefore, tell your doctorimmediately if you experience any of these signs.
• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect theface and tongue. Tardive dyskinesia may not go away, even if you stop taking ZYPREXA. It may also start after you stop taking ZYPREXA. Tell yourdoctor if you get any body movements that you can not control.
• Decreased blood pressure when you change positions, with symptoms of dizziness, fast or slow heartbeat, or fainting.
• Difficulty swallowing, that can cause food or liquid to get into your lungs.
• Seizures: Tell your doctor if you have a seizure during treatment with ZYPREXA.
• Problems with control of body temperature: You could become very hot, for instance when you exercise a lot or stay in an area that is very hot. It isimportant for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms ofdehydration:
  • sweating too much or not at all
  • dry mouth
  • feeling very hot
  • feeling thirsty
  • not able to produce urine.

Common side effects of ZYPREXA include: lack of energy, dry mouth, increased appetite, sleepiness, tremor (shakes), having hard or infrequent stools,dizziness, changes in behavior, or restlessness.

Other common side effects in teenagers (13-17 years old) include: headache, stomach-area (abdominal) pain, pain in your arms or legs, or tiredness.Teenagers experienced greater increases in prolactin, liver enzymes, and sleepiness, as compared with adults.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with ZYPREXA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ZYPREXA?

• Store ZYPREXA at room temperature, between 68°F to 77°F (20°C to 25°C).
• Keep ZYPREXA away from light.
• Keep ZYPREXA dry and away from moisture.

Keep ZYPREXA and all medicines out of the reach of children.

General information about ZYPREXA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZYPREXA for a condition for which it was notprescribed. Do not give ZYPREXA to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about ZYPREXA. If you would like more information, talk with your doctor. You canask your doctor or pharmacist for information about ZYPREXA that was written for healthcare professionals. For more information about ZYPREXA call1-800-Lilly-Rx (1-800-545-5979).

What are the ingredients in ZYPREXA?

Active ingredient: olanzapine

Inactive ingredients:

Tablets - carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactiveingredients. The color coating contains: Titanium Dioxide, FD&C Blue No. 2 Aluminum Lake, or Synthetic Red Iron Oxide.

ZYDIS gelatin, mannitol, aspartame, sodium methyl paraben, and sodium propyl paraben.

This Medication Guide has been approved by the U.S. Food and Drug Administration.