1 INDICATIONS AND USAGE

1.1 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 (14.1)].

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].

1.2 Bipolar I Disorder (Manic or Mixed Episodes)

Monotherapy — Oral ZYPREXA is indicated for the acute treatment of manic or mixed episodes associated with bipolarI disorder and maintenance treatment of bipolarI disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolarI disorder (ages 13-17), efficacy was established in one 3-week trial [see Clinical Studies (14.2)].

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].

Adjunctive Therapy to Lithium or Valproate — Oral ZYPREXA is indicated for the treatment of manic or mixed episodes associated with bipolarI disorder as 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 eva luated in controlled trials [see Clinical Studies (14.2)].

1.3 Special Considerations in Treating Pediatric Schizophrenia and BipolarI Disorder

Pediatric schizophrenia and bipolarI disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolarI disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolarI disorder be initiated only after a thorough diagnostic eva luation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolarI disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

1.4 ZYPREXA IntraMuscular: Agitation Associated with Schizophrenia and BipolarI Mania

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

Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolarI disorder (manic or mixed episodes) [see Clinical Studies (14.3)].

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often 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.

1.5 ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with BipolarI Disorder

Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolarI disorder, 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 depressive episodes associated with bipolarI disorder.

1.6 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 do not 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.

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Adults

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10mg initially, with a target dose of 10mg/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, dose increments/decrements of 5mgQD are recommended.

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

Dosing in Special Populations — The recommended starting dose is 5mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment — The effectiveness of oral olanzapine, 10mg/day to 20mg/day, in maintaining treatment response in schizophrenic patients who had 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 (14.1)]. The physician who elects to use ZYPREXA for extended periods should periodically reeva luate the long-term usefulness of 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 or 5mg, with a target dose of 10mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20mg/day in clinical trials, with a mean modal dose of 12.5mg/day (mean dose of 11.1mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5mg are recommended.

The safety and effectiveness of doses above 20mg/day have not been eva luated in clinical trials [see Clinical Studies (14.1)].

Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of schizophrenia in the adolescent population has not been systematically eva luated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, 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.

2.2 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 10 or 15mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5mgQD are recommended.

Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5mg to 20mg/day in clinical trials. The safety of doses above 20mg/day has not been eva luated in clinical trials [see Clinical Studies (14.2)].

Maintenance Monotherapy — The benefit of maintaining bipolarI patients on monotherapy with oral ZYPREXA at a dose of 5 to 20mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies (14.2)]. The physician who elects to use ZYPREXA for extended periods should periodically reeva luate 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 generally begin with 10mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in a dose range of 5mg to 20mg/day in clinical trials [see Clinical Studies (14.2)]. The safety of doses above 20mg/day has not been eva luated 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 or 5mg, with a target dose of 10mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20mg/day in clinical trials, with a mean modal dose of 10.7mg/day (mean dose of 8.9mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5mg are recommended.

The safety and effectiveness of doses above 20mg/day have not been eva luated in clinical trials [see Clinical Studies (14.2)].

Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of bipolar I disorder in the adolescent population has not been eva luated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, 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.

2.3 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 and place entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

2.4 ZYPREXA IntraMuscular: Agitation Associated with Schizophrenia and BipolarI Mania

Dose Selection for Agitated Adult Patients with Schizophrenia and BipolarI Mania— The efficacy of intramuscular olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5mg to 10mg. The recommended dose in these patients is 10mg. A lower dose of 5 or 7.5mg may be considered when clinical factors warrant [see Clinical Studies (14.3)]. If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically eva luated in controlled clinical trials. Also, the safety of total daily doses greater than 30mg, or 10mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been eva luated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., 3 doses of 10mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension [see Warnings and Precautions (5.8)]. Thus, it is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of an additional 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 5-20mg/day as soon as clinically appropriate [see Dosage and Administration (2.1, 2.2)].

Intramuscular Dosing in Special Populations — A dose of 5mg/injection should be considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5mg/injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Administration of ZYPREXA IntraMuscular — ZYPREXA IntraMuscular is intended for intramuscular use only. Do not administer intravenously or subcutaneously. 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 container permit.

Directions for Preparation of ZYPREXA IntraMuscular with Sterile Water for Injection — Dissolve the contents of the vial using 2.1mL of Sterile Water for Injection to provide a solution containing approximately 5mg/mL 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 for Injection.

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

2.5 ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with BipolarI Disorder

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 5mg of oral olanzapine and 20mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5mg and fluoxetine 20 to 50mg. Antidepressant efficacy was demonstrated with ZYPREXA and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12mg and fluoxetine 25 to 50mg.

Safety and efficacy of ZYPREXA and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of ZYPREXA and fluoxetine). Symbyax is dosed between 3mg/25mg (olanzapine/fluoxetine) per day and 12mg/50mg (olanzapine/fluoxetine) per day. The following table 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 bipolarI disorder, including the depressive episodes associated with bipolarI disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

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

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

2.6 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 5mg of oral olanzapine and 20mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20mg and fluoxetine 20 to 50mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18mg and fluoxetine 25 to 50mg.

Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3mg/25mg (olanzapine/fluoxetine) per day and 12mg/50mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the a