Zyprexa Relprevv

Zyprexa Relprevv uses

• Warning: increased mortality in elderly patients with dementia-related psychosis
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Zyprexa Relprevv reviews

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Zyprexa Relprevv (olanzapine) is not approved for the treatment of patients with dementia-related psychosis .

When using Zyprexa Relprevv and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Zyprexa Relprevv is not approved for the treatment of patients with dementia-related psychosis. (5.1, 5.14, 17.2)
  

  When using Zyprexa Relprevv and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

None.

1 INDICATIONS AND USAGE

Zyprexa Relprevv^® is an atypical antipsychotic indicated:

As oral formulation for the:

• Treatment of schizophrenia. (1.1)
  • Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. (14.1)
  • Adolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia (14.1). The increased potential (in adolescents compared with adults) for weight gain and hyperlipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.1)
• Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. (1.2)
  • Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial. (14.2)
  • Adolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder (14.2). The increased potential (in adolescents compared with adults) for weight gain and hyperlipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (1.2)
• Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks. (1.3)
• Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. (1.2)
  • Efficacy was established in two 6-week clinical trials in adults (14.2). Maintenance efficacy has not been systematically evaluated.

As Zyprexa Relprevv IntraMuscular for the:

• Treatment of acute agitation associated with schizophrenia and bipolar I mania. (1.4)
  • Efficacy was established in three 1-day trials in adults. (14.3)

As Zyprexa Relprevv and Fluoxetine in Combination for the:

• Treatment of depressive episodes associated with bipolar I disorder. (1.5)
  • Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.
• 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). (1.6)
  • Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.

1.1 Schizophrenia

Oral Zyprexa Relprevv 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 .

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 .

1.2 Bipolar I Disorder

Monotherapy - Oral Zyprexa Relprevv is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment 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- to 4-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 .

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 .

Adjunctive Therapy to Lithium or Valproate - Oral Zyprexa Relprevv is indicated for the treatment of manic or mixed episodes associated with bipolar I 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 evaluated in controlled trials .

1.3 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, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

1.4 Zyprexa Relprevv IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania

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

Efficacy was demonstrated in 3 short-term placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolar I disorder (manic or mixed episodes) .

“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 Relprevv and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

Oral Zyprexa Relprevv and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies in adult patients. When using Zyprexa Relprevv 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.

1.6 Zyprexa Relprevv and Fluoxetine in Combination: Treatment Resistant Depression

Oral Zyprexa Relprevv 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 Relprevv 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

• Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. (2.1)
• Zyprexa Relprevv may be given without regard to meals. (2.1)

Zyprexa Relprevv and Fluoxetine in Combination:

• Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (2.5, 2.6)
• Zyprexa Relprevv monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. (2.5, 2.6)
• Safety of co-administration of doses above 18 mg Zyprexa Relprevv with 75 mg fluoxetine has not been evaluated. (2.5, 2.6)

2.1 Schizophrenia

Adults

Dose Selection - Oral Zyprexa Relprevv 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 Zyprexa Relprevv would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/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 demonstrated to 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) is recommended only after clinical assessment. Zyprexa Relprevv 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 hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of Zyprexa Relprevv (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to Zyprexa Relprevv . When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment - The effectiveness of oral Zyprexa Relprevv, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on Zyprexa Relprevv for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial . The physician who elects to use Zyprexa Relprevv for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Adolescents

Dose Selection - Oral Zyprexa Relprevv should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 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 in clinical 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/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 .

Maintenance Treatment - The efficacy of Zyprexa Relprevv for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of Zyprexa Relprevv 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

Adults

Dose Selection for Monotherapy - Oral Zyprexa Relprevv should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. 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 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/day has not been evaluated in clinical trials .

Maintenance Monotherapy - The benefit of maintaining bipolar I patients on monotherapy with oral Zyprexa Relprevv at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial . The physician who elects to use Zyprexa Relprevv 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 Zyprexa Relprevv dosing should generally begin 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 . The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Adolescents

Dose Selection - Oral Zyprexa Relprevv should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 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 dose range 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 .

Maintenance Treatment - The efficacy of Zyprexa Relprevv for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of Zyprexa Relprevv 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 Relprevv ZYDIS

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 Relprevv ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

2.4 Zyprexa Relprevv 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 Zyprexa Relprevv for injection in controlling agitation 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 or 7.5 mg may be considered when clinical factors warrant . If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular Zyprexa Relprevv for injection in agitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections 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 Zyprexa Relprevv (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension . 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 Zyprexa Relprevv 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 Zyprexa Relprevv therapy is clinically indicated, oral Zyprexa Relprevv may be initiated in a range of 5-20 mg/day as soon as clinically appropriate .

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 more pharmacodynamically sensitive to Zyprexa Relprevv .

Administration of Zyprexa Relprevv IntraMuscular - Zyprexa Relprevv 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 Relprevv IntraMuscular with Sterile Water for Injection - Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of Zyprexa Relprevv. The resulting solution should appear clear and yellow. Zyprexa Relprevv 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 Zyprexa Relprevv for injection reconstituted with Sterile Water for Injection.

Physical Incompatibility Information - Zyprexa Relprevv IntraMuscular should be reconstituted only with Sterile Water for Injection. Zyprexa Relprevv 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 Relprevv IntraMuscular as this combination results in a delayed reconstitution time. Zyprexa Relprevv IntraMuscular should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade Zyprexa Relprevv over time.

2.5 Zyprexa Relprevv and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

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

Oral Zyprexa Relprevv should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral Zyprexa Relprevv and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral Zyprexa Relprevv 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with Zyprexa Relprevv and fluoxetine in combination in adult patients with a dose range of Zyprexa Relprevv 6 to 12 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of Zyprexa Relprevv and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of Zyprexa Relprevv 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 Relprevv 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 Relprevv 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 chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

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

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

2.6 Zyprexa Relprevv and Fluoxetine in Combination: Treatment Resistant Depression

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

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

Safety and efficacy of Zyprexa Relprevv in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax. 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 Relprevv 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 Relprevv 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 different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

Safety of co-administration of doses above 18 mg Zyprexa Relprevv 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 2 antidepressants of adequate dose and duration in the current episode).

2.7 Zyprexa Relprevv and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral Zyprexa Relprevv 2.5-5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of Zyprexa Relprevv or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to Zyprexa Relprevv. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Zyprexa Relprevv and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients <18 years of age .

3 DOSAGE FORMS AND STRENGTHS

The Zyprexa Relprevv 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 are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. Tablets are not scored. The tablets are available as follows:

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

Zyprexa Relprevv IntraMuscular is available in 10 mg vial (1s).

• Tablets (not scored): 2.5, 5, 7.5, 10, 15, 20 mg (3)
• Orally Disintegrating Tablets (not scored): 5, 10, 15, 20 mg (3)
• Intramuscular Injection: 10 mg vial (3)

4 CONTRAINDICATIONS

• None with Zyprexa Relprevv monotherapy.
• When using Zyprexa Relprevv 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.

• None with Zyprexa Relprevv monotherapy.
• When using Zyprexa Relprevv and fluoxetine in combination, also refer to the Contraindications section of the package insert for Symbyax^®. (4)
• When using Zyprexa Relprevv in combination with lithium or valproate, refer to the Contraindications section of the package inserts for those products. (4)

5 WARNINGS AND PRECAUTIONS

When using Zyprexa Relprevv 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 risk of death and increased incidence of cerebrovascular adverse events. (5.1)
• 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 drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax. (5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
• Hyperglycemia: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking Zyprexa Relprevv. Patients taking Zyprexa Relprevv should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.4)
• Hyperlipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment. (5.5)
• Weight Gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight. (5.6)
• Tardive Dyskinesia: Discontinue if clinically appropriate. (5.7)
• Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses. (5.8)
• Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including Zyprexa Relprevv. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Zyprexa Relprevv should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.9)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. (5.11)
• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery. (5.12)
• Hyperprolactinemia: May elevate prolactin levels. (5.15)
• Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate. (5.16)
• Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment. (5.17)

5.1 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 Relprevv is not approved for the treatment of patients with dementia-related psychosis .

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly 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 Zyprexa Relprevv 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 Zyprexa Relprevv compared to patients treated with placebo. Zyprexa Relprevv is not approved for the treatment of patients with dementia-related psychosis .

5.2 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 drug therapy. Prescriptions for Zyprexa Relprevv should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3 Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Zyprexa Relprevv. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated 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 clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central 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 treatments are 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. The patient should be carefully monitored, since recurrences of NMS have been reported .

5.4 Hyperglycemia

Physicians should consider the risks and benefits when prescribing Zyprexa Relprevv to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level. Patients taking Zyprexa Relprevv should be monitored regularly for worsening of glucose control. Patients starting treatment with Zyprexa Relprevv should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug .

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Zyprexa Relprevv. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and Zyprexa Relprevv 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 Zyprexa Relprevv in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received Zyprexa Relprevv (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 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.

Zyprexa Relprevv Monotherapy in Adults - In an analysis of 5 placebo-controlled adult Zyprexa Relprevv monotherapy studies with a median treatment duration of approximately 3 weeks, Zyprexa Relprevv was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between Zyprexa Relprevv 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 glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c 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-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult Zyprexa Relprevv monotherapy studies.

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 of Zyprexa Relprevv therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Zyprexa Relprevv Monotherapy in Adolescents - The safety and efficacy of Zyprexa Relprevv have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled Zyprexa Relprevv monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), Zyprexa Relprevv 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 shows short-term and long-term changes in fasting blood glucose from adolescent Zyprexa Relprevv monotherapy studies.

5.5 Hyperlipidemia

Undesirable alterations in lipids have been observed with Zyprexa Relprevv use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Zyprexa Relprevv, is recommended .

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

Zyprexa Relprevv Monotherapy in Adults - In an analysis of 5 placebo-controlled Zyprexa Relprevv 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, and 20.8 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 between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related 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 of 5.6 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 who completed 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, or changes 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.

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

Zyprexa Relprevv Monotherapy in Adolescents - The safety and efficacy of Zyprexa Relprevv have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled Zyprexa Relprevv monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides 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 LDL cholesterol 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, no clinically 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 of 5.5 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 in fasting lipids values in adolescents.

5.6 Weight Gain

Potential consequences of weight gain should be considered prior to starting Zyprexa Relprevv. Patients receiving Zyprexa Relprevv should receive regular monitoring of weight .

Zyprexa Relprevv Monotherapy in Adults - In an analysis of 13 placebo-controlled Zyprexa Relprevv monotherapy studies, olanzapine-treated patients gained an average 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% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to 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 patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to 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 Zyprexa Relprevv pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Zyprexa Relprevv Monotherapy in Adolescents - The safety and efficacy of Zyprexa Relprevv have not been established in patients under the age of 13 years. Mean increase 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.

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 of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent 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 24 weeks of exposure.

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

5.7 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence 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 potential to 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 the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, Zyprexa Relprevv should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic 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 chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on Zyprexa Relprevv, drug discontinuation should be considered. However, some patients may require treatment with Zyprexa Relprevv 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.

5.8 Orthostatic Hypotension

Zyprexa Relprevv may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α₁-adrenergic antagonistic properties .

For oral Zyprexa Relprevv therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD . 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 Zyprexa Relprevv for injection. In an open-label clinical pharmacology study in nonagitated patients with schizophrenia in which the safety and tolerability of intramuscular Zyprexa Relprevv were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) . Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral Zyprexa Relprevv studies and in 0.3% (2/722) of olanzapine-treated patients with agitation in the intramuscular Zyprexa Relprevv for injection studies. Three normal volunteers in phase 1 studies with intramuscular Zyprexa Relprevv experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the reactions occurred on intramuscular Zyprexa Relprevv, and in 1 case, on oral Zyprexa Relprevv). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For intramuscular Zyprexa Relprevv 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.

Zyprexa Relprevv 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, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression . Concomitant administration of intramuscular Zyprexa Relprevv and parenteral benzodiazepine is not recommended due to the potential for excessive sedation and cardiorespiratory depression.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect - In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including Zyprexa Relprevv. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Zyprexa Relprevv should be considered at the first sign of a 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 such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³) should discontinue Zyprexa Relprevv and have their WBC followed until recovery.

5.10 Dysphagia

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

5.11 Seizures

During premarketing testing, seizures occurred in 0.9% of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Zyprexa Relprevv should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Zyprexa Relprevv 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.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with Zyprexa Relprevv treatment, occurring at an incidence of 26% in Zyprexa Relprevv patients compared to 15% in placebo patients. This adverse reaction was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since Zyprexa Relprevv 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 Relprevv therapy does not affect them adversely .

5.13 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 prescribing Zyprexa Relprevv 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 .

5.14 Use in Patients with Concomitant Illness

Clinical experience with Zyprexa Relprevv in patients with certain concomitant systemic illnesses is limited .

Zyprexa Relprevv exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with Zyprexa Relprevv, Zyprexa Relprevv was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations from Zyprexa Relprevv, but Zyprexa Relprevv should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus or related conditions.

In 5 placebo-controlled studies of Zyprexa Relprevv in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with Zyprexa Relprevv than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with Zyprexa Relprevv are at an increased risk of death compared to placebo. Zyprexa Relprevv is not approved for the treatment of patients with dementia-related psychosis .

Zyprexa Relprevv has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with Zyprexa Relprevv, caution should be observed in cardiac patients .

5.15 Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, Zyprexa Relprevv 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 reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased 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 importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the Zyprexa Relprevv carcinogenicity studies conducted in mice and rats . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration 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 Zyprexa Relprevv clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with Zyprexa Relprevv as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with Zyprexa Relprevv, 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 Zyprexa Relprevv monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with Zyprexa Relprevv, potentially associated clinical manifestations included menstrual-related events¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events³ (2% [3/168] of females, 2% [7/286] of males) .

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, and sexual dysfunction.

³ Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate

When using Zyprexa Relprevv and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax. When using Zyprexa Relprevv in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate .

5.17 Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended .

6 ADVERSE REACTIONS

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

Most common adverse reactions associated with:

Oral Zyprexa Relprevv Monotherapy:

• Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia (6.1)
• Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth (6.1)
• Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor (6.1)
• Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity (6.1)

Combination of Zyprexa Relprevv and Lithium or Valproate:

• Manic or Mixed Episodes, Bipolar I Disorder (Adults) – dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia (6.1)

Zyprexa Relprevv and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for Symbyax. (6)

Zyprexa Relprevv IntraMuscular for Injection:

• Agitation with Schizophrenia and Bipolar I Mania (Adults) – somnolence (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 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 directly compared 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 Zyprexa Relprevv is derived from a clinical trial database for Zyprexa Relprevv consisting of 8661 adult patients with approximately 4165 patient-years of exposure to oral Zyprexa Relprevv and 722 patients with exposure to intramuscular Zyprexa Relprevv for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral Zyprexa Relprevv 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 Zyprexa Relprevv premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral Zyprexa Relprevv trial of patients having various psychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure; (4) 5788 patients from 88 additional oral Zyprexa Relprevv clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular Zyprexa Relprevv for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia. In addition, information from the premarketing 6-week clinical study database for Zyprexa Relprevv 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-years of exposure, is included below.

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

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 I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and agitation.

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 grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary 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 of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with Zyprexa Relprevv, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of Zyprexa Relprevv.

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 usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence 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 Zyprexa Relprevv for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials, and (2) intramuscular Zyprexa Relprevv 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 Zyprexa Relprevv vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral Zyprexa Relprevv vs 0% for placebo).

Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy - Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral Zyprexa Relprevv vs 2% for placebo).

Agitation - Overall, there was no difference in the incidence of discontinuation due to adverse reactions (0.4% for intramuscular Zyprexa Relprevv for injection vs 0% for placebo).

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

Bipolar I Disorder (Manic or Mixed Episodes), Zyprexa Relprevv as Adjunct to Lithium or Valproate - In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral Zyprexa Relprevv with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral Zyprexa Relprevv and lithium 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 Zyprexa Relprevv (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

Zyprexa Relprevv Intramuscular - There was 1 adverse reaction (somnolence) observed at an incidence of 5% or greater among intramuscular Zyprexa Relprevv for injection-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 agitated patients with schizophrenia or bipolar I mania was 6% for intramuscular Zyprexa Relprevv 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 treated with oral Zyprexa Relprevv (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.

Commonly Observed Adverse Reactions in Short-Term Trials of Oral Zyprexa Relprevv 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 the combination of Zyprexa Relprevv and lithium or valproate (incidence of ≥5% and at least twice placebo) were:

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

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of Zyprexa Relprevv (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials.

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

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

Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 1% or more of patients treated with intramuscular Zyprexa Relprevv 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.

Additional Findings Observed in Clinical Trials

Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials

Extrapyramidal Symptoms: The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral Zyprexa Relprevv at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

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

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

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular Zyprexa Relprevv for injection with placebo in agitation. Patients in each dose group could receive up to 3 injections during the trials . Patient assessments were conducted during the 24 hours following the initial dose of intramuscular Zyprexa Relprevv for injection.

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

Dystonia, Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days 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 high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with Zyprexa Relprevv use.

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

Differences among Fixed-Dose Groups Observed in Other Zyprexa Relprevv Clinical Trials

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 Zyprexa Relprevv in patients with schizophrenia or schizoaffective disorder, differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. Mean baseline to endpoint 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. Incidence of treatment-emergent prolactin elevation >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%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Zyprexa Relprevv

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral Zyprexa Relprevv (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 rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 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: nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.
• Hemic and Lymphatic System - Infrequent: leukopenia, thrombocytopenia.
• Metabolic and Nutritional Disorders - Infrequent: alkaline phosphatase increased, 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 their seriousness.

² Adjusted for gender.

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

Following is a list of treatment-emergent adverse reactions reported by patients treated with intramuscular Zyprexa Relprevv 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) 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) for which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions 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 Zyprexa Relprevv Short-Term, Placebo-Controlled Trials

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

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 Zyprexa Relprevv (doses ≥2.5 mg) reported with an incidence of 2% or more and greater than placebo are listed in Table 22.

6.2 Vital Signs and Laboratory Studies

Vital Sign Changes - Oral Zyprexa Relprevv was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular Zyprexa Relprevv for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials .

Laboratory Changes

Zyprexa Relprevv Monotherapy in Adults: An assessment of the premarketing experience for Zyprexa Relprevv revealed an association with asymptomatic increases in ALT, 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 transient changes that tended to normalize while Zyprexa Relprevv treatment was continued.

In placebo-controlled Zyprexa Relprevv 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 Zyprexa Relprevv compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with Zyprexa Relprevv or discontinued Zyprexa Relprevv. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's Rule.

Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period.

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

Zyprexa Relprevv administration was also associated with increases in serum prolactin , with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

Zyprexa Relprevv Monotherapy in Adolescents: In placebo-controlled clinical trials of adolescent patients with schizophrenia or bipolar I disorder (manic or mixed 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%); elevated GGT (10% vs 1%); and elevated prolactin (47% vs 7%).

In placebo-controlled Zyprexa Relprevv monotherapy studies in adolescents, clinically significant ALT elevations (change from <3 times ULN at baseline to ≥3 times ULN) were observed in 12% (22/192) of patients exposed to Zyprexa Relprevv compared to 2% (2/109) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 4% (8/192) of olanzapine-treated patients, compared to 1% (1/109) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with Zyprexa Relprevv or discontinued Zyprexa Relprevv. No adolescent 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 Zyprexa Relprevv and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc (Fridericia corrected), and PR intervals. Zyprexa Relprevv 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 inducing orthostatic changes .

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zyprexa Relprevv. Because these reactions are reported voluntarily from a population 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 Relprevv therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea or vomiting), jaundice, neutropenia, pancreatitis, priapism, rash, rhabdomyolysis, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.

7 DRUG INTERACTIONS

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

• Diazepam: May potentiate orthostatic hypotension.
• Alcohol: May potentiate orthostatic hypotension. (7.1)
• Carbamazepine: Increased clearance of Zyprexa Relprevv. (7.1)
• Fluvoxamine: May increase Zyprexa Relprevv levels. (7.1)
• Zyprexa Relprevv and Fluoxetine in Combination: Also refer to the Drug Interactions section of the package insert for Symbyax. (7.1)
• CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol. (7.2)
• Antihypertensive Agents: Enhanced antihypertensive effect. (7.2)
• Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists. (7.2)
• Lorazepam (IM): Increased somnolence with IM Zyprexa Relprevv. (7.2)
• Other Concomitant Drug Therapy: When using Zyprexa Relprevv in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products. (7.2)

7.1 Potential for Other Drugs to Affect Zyprexa Relprevv

Diazepam - The co-administration of diazepam with Zyprexa Relprevv potentiated the orthostatic hypotension observed with Zyprexa Relprevv .

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

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

Alcohol - Ethanol (45 mg/70 kg single dose) did not have an effect on Zyprexa Relprevv pharmacokinetics. The co-administration of alcohol (i.e., ethanol) with Zyprexa Relprevv potentiated the orthostatic hypotension observed with Zyprexa Relprevv .

Inhibitors of CYP1A2

Fluvoxamine: Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of Zyprexa Relprevv. This results in a mean increase in Zyprexa Relprevv Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in Zyprexa Relprevv AUC is 52% and 108%, respectively. Lower doses of Zyprexa Relprevv 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 of Zyprexa Relprevv and a small (mean 16%) decrease in Zyprexa Relprevv clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using Zyprexa Relprevv and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Warfarin - Warfarin (20 mg single dose) did not affect Zyprexa Relprevv pharmacokinetics .

Inducers of CYP1A2 or Glucuronyl Transferase - Omeprazole and rifampin may cause an increase in Zyprexa Relprevv clearance.

Charcoal - The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral Zyprexa Relprevv by about 60%. As peak Zyprexa Relprevv levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for Zyprexa Relprevv overdose.

7.2 Potential for Zyprexa Relprevv to Affect Other Drugs

CNS Acting Drugs - Given the primary CNS effects of Zyprexa Relprevv, caution should be used when Zyprexa Relprevv is taken in combination with other centrally acting drugs and alcohol.

Antihypertensive Agents - Zyprexa Relprevv, because of its potential for inducing hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists - Zyprexa Relprevv may antagonize the effects of levodopa and dopamine agonists.

Lorazepam (IM) - Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular Zyprexa Relprevv for injection (5 mg) did not significantly affect the pharmacokinetics of Zyprexa Relprevv, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular Zyprexa Relprevv for injection added to the somnolence observed with either drug alone .

Lithium - Multiple doses of Zyprexa Relprevv (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant Zyprexa Relprevv administration does not require dosage adjustment of lithium .

Valproate - Zyprexa Relprevv (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant Zyprexa Relprevv administration does not require dosage adjustment of valproate .

Effect of Zyprexa Relprevv on Drug Metabolizing Enzymes - In vitro studies utilizing human liver microsomes suggest that Zyprexa Relprevv has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, Zyprexa Relprevv is unlikely to cause clinically important drug interactions mediated by these enzymes.

Imipramine - Single doses of Zyprexa Relprevv did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Warfarin - Single doses of Zyprexa Relprevv did not affect the pharmacokinetics of warfarin .

Diazepam - Zyprexa Relprevv did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam. However, diazepam co-administered with Zyprexa Relprevv increased the orthostatic hypotension observed with either drug given alone .

Alcohol - Multiple doses of Zyprexa Relprevv did not influence the kinetics of ethanol .

Biperiden - Multiple doses of Zyprexa Relprevv did not influence the kinetics of biperiden.

Theophylline - Multiple doses of Zyprexa Relprevv did not affect the pharmacokinetics of theophylline or its metabolites.

8 USE IN SPECIFIC POPULATIONS

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

• Pregnancy: Zyprexa Relprevv should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Nursing Mothers: Breast-feeding is not recommended. (8.3)
• Pediatric Use: Safety and effectiveness of Zyprexa Relprevv in children <13 years of age have not been established. (8.4)

8.1 Pregnancy

Teratogenic Effects, Pregnancy Category C - 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 maximum recommended human daily oral dose on a mg/m² basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m² basis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/m² basis). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Placental transfer of Zyprexa Relprevv occurs in rat pups.

There are no adequate and well-controlled trials with Zyprexa Relprevv in pregnant females. Seven pregnancies were observed during clinical trials with Zyprexa Relprevv, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion.

Nonteratogenic Effects - Neonates exposed to antipsychotic drugs (including Zyprexa Relprevv), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Zyprexa Relprevv should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The effect of Zyprexa Relprevv on labor and delivery in humans is unknown. Parturition in rats was not affected by Zyprexa Relprevv.

8.3 Nursing Mothers

In a study in lactating, healthy women, Zyprexa Relprevv was excreted in breast milk. Mean infant dose at steady state was estimated to be 1.8% of the maternal Zyprexa Relprevv dose. It is recommended that women receiving Zyprexa Relprevv should not breast-feed.

8.4 Pediatric Use

The safety and effectiveness of oral Zyprexa Relprevv in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term studies in adolescents. Use of Zyprexa Relprevv in adolescents is supported by evidence from adequate and well-controlled studies of Zyprexa Relprevv in which 268 adolescents received Zyprexa Relprevv in a range of 2.5 to 20 mg/day . Recommended starting dose for adolescents is lower than that for adults . Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels . 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 .

Safety and effectiveness of Zyprexa Relprevv in children <13 years of age have not been established .

Safety and effectiveness of Zyprexa Relprevv and fluoxetine in combination in children and adolescents <18 years of age have not been established.

8.5 Geriatric Use

Of the 2500 patients in premarketing clinical studies with oral Zyprexa Relprevv, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of Zyprexa Relprevv in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with Zyprexa Relprevv are at an increased risk of death compared to placebo. In placebo-controlled studies of Zyprexa Relprevv in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with Zyprexa Relprevv compared to patients treated with placebo. Zyprexa Relprevv is not approved for the treatment of patients with dementia-related psychosis. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to Zyprexa Relprevv should lead to consideration of a lower starting dose for any geriatric patient .

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

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

In studies prospectively designed to assess abuse and dependence potential, Zyprexa Relprevv was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the maximum recommended human daily oral dose (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dose on a mg/m² basis.

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

10 OVERDOSAGE

10.1 Human Experience

In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of Zyprexa Relprevv was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.

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

10.2 Management of Overdose

The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral Zyprexa Relprevv by about 60%. As peak Zyprexa Relprevv levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for Zyprexa Relprevv overdose.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to Zyprexa Relprevv. Therefore, appropriate supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Close medical supervision and monitoring should continue until the patient recovers.

For specific information about overdosage with lithium or valproate, refer to the Overdosage section of the package inserts for these products. For specific information about overdosage with Zyprexa Relprevv and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.

11 DESCRIPTION

Zyprexa Relprevv (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:

Zyprexa Relprevv is a yellow crystalline solid, which is practically insoluble in water.

Zyprexa Relprevv tablets are intended for oral administration only.

Each tablet contains Zyprexa Relprevv 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 Relprevv ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration only.

Each orally disintegrating tablet contains Zyprexa Relprevv 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 Relprevv ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben, and sodium propyl paraben.

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

Each vial provides for the administration of 10 mg (32 μmol) Zyprexa Relprevv 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.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Zyprexa Relprevv, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 antagonism. The mechanism of action of Zyprexa Relprevv in the treatment of acute manic or mixed episodes associated with bipolar I disorder is unknown.

12.2 Pharmacodynamics

Zyprexa Relprevv 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). Zyprexa Relprevv is an antagonist with moderate affinity binding for serotonin 5HT₃ (K_i=57 nM) and muscarinic M_1-5 (K_i=73, 96, 132, 32, and 48 nM, respectively). Zyprexa Relprevv binds weakly to GABA_A, BZD, and β-adrenergic receptors (K_i>10 μM).

Antagonism at receptors other than dopamine and 5HT₂ may explain some of the other therapeutic and side effects of Zyprexa Relprevv. Olanzapine's antagonism of muscarinic M_1-5 receptors may explain its anticholinergic-like effects. Olanzapine's antagonism of histamine H₁ receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic α₁ receptors may explain the orthostatic hypotension observed with this drug.

12.3 Pharmacokinetics

Oral Administration, Monotherapy - Zyprexa Relprevv is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of Zyprexa Relprevv absorption. Pharmacokinetic studies showed that Zyprexa Relprevv tablets and Zyprexa Relprevv ZYDIS (olanzapine orally disintegrating tablets) dosage forms of Zyprexa Relprevv are bioequivalent.

Zyprexa Relprevv displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).

Administration of Zyprexa Relprevv once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of Zyprexa Relprevv may vary between individuals on the basis of smoking status, gender, and age.

Zyprexa Relprevv is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α₁-acid glycoprotein.

Metabolism and Elimination - Following a single oral dose of ¹⁴C labeled Zyprexa Relprevv, 7% of the dose of Zyprexa Relprevv was recovered in the urine as unchanged drug, indicating that Zyprexa Relprevv is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, Zyprexa Relprevv accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of Zyprexa Relprevv, and 4′-N-desmethyl Zyprexa Relprevv, present at steady state at 31% of the concentration of Zyprexa Relprevv. Both metabolites lack pharmacological activity at the concentrations observed.

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

Intramuscular Administration - Zyprexa Relprevv 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 Zyprexa Relprevv for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral Zyprexa Relprevv. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.

Specific Populations

Renal Impairment - Because Zyprexa Relprevv is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of Zyprexa Relprevv. The pharmacokinetic characteristics of Zyprexa Relprevv were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, Zyprexa Relprevv 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 Zyprexa Relprevv, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of Zyprexa Relprevv.

Geriatric - In a study involving 24 healthy subjects, the mean elimination half-life of Zyprexa Relprevv was about 1.5 times greater in elderly (≥65 years) than in nonelderly subjects (<65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity .

Gender - Clearance of Zyprexa Relprevv is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Smoking Status - Zyprexa Relprevv clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Race - In vivo studies have shown that exposures are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race are, therefore, not recommended.

Combined Effects - The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of Zyprexa Relprevv .

Adolescents (ages 13 to 17 years) - In clinical studies, most adolescents were nonsmokers and this population had a lower average body weight, which resulted in higher average Zyprexa Relprevv exposure compared to adults.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis - Oral carcinogenicity studies were conducted in mice and rats. Zyprexa Relprevv was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily oral dose on a mg/m² basis). 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 maximum recommended human daily oral dose on a mg/m² basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice dosed at 8 mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/m² basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2-5 times the maximum recommended human daily oral dose on a mg/m² basis); 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 and adenocarcinomas 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 maximum recommended human daily oral dose on a mg/m² basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the Zyprexa Relprevv carcinogenicity studies; however, measurements during subchronic toxicity studies showed that Zyprexa Relprevv elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown .

Mutagenesis - No evidence of genotoxic potential for Zyprexa Relprevv was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse 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 dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). Discontinuance of Zyprexa Relprevv treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended human daily oral dose on a mg/m² basis). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on a mg/m² basis); therefore Zyprexa Relprevv may produce a delay in ovulation.

13.2 Animal Toxicology and/or Pharmacology

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

14 CLINICAL STUDIES

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

14.1 Schizophrenia

Adults

The efficacy of oral Zyprexa Relprevv in the treatment of schizophrenia was established in 2 short-term controlled trials of adult inpatients who met DSM 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 compare these 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), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed Zyprexa Relprevv doses of 1 and 10 mg/day (once daily schedule), Zyprexa Relprevv, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.

(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of Zyprexa Relprevv (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest Zyprexa Relprevv dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest Zyprexa Relprevv dose group was superior to placebo on the SANS. There was no clear advantage 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 Zyprexa Relprevv during open-label treatment for at least 8 weeks were randomized to continuation on their current Zyprexa Relprevv doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to Zyprexa Relprevv relapses, and Zyprexa Relprevv was superior to placebo on time to relapse, the primary outcome for this study. Thus, Zyprexa Relprevv was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.

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

Adolescents

The efficacy of oral Zyprexa Relprevv 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 and confirmed 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 Rating Scale for Children (BPRS-C) total score.

In this flexible-dose trial, Zyprexa Relprevv 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 the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the Zyprexa Relprevv 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 Relprevv should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of Zyprexa Relprevv pharmacokinetic parameters in adult and adolescent patients. 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.

14.2 Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Monotherapy - The efficacy of oral Zyprexa Relprevv 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 patients with or without psychotic features and with or without a rapid-cycling course.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:

(1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of Zyprexa Relprevv (5-20 mg/day, once daily, starting at 10 mg/day), Zyprexa Relprevv was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, Zyprexa Relprevv demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.

(2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of Zyprexa Relprevv (5-20 mg/day, once daily, starting at 15 mg/day), Zyprexa Relprevv was 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-label treatment phase for about 2 weeks, on average, to Zyprexa Relprevv 5 to 20 mg/day were randomized to either continuation of Zyprexa Relprevv at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the Zyprexa Relprevv group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the 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 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued Zyprexa Relprevv experienced a significantly longer time to relapse.

Adjunct to Lithium or Valproate - The efficacy of oral Zyprexa Relprevv with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:

(1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either Zyprexa Relprevv or placebo, in combination with their original therapy. Zyprexa Relprevv (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 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 mixed symptoms (Y-MRS ≥16) were randomized to receive either Zyprexa Relprevv or placebo, in combination with their original therapy. Zyprexa Relprevv (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 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 Zyprexa Relprevv in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed 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) total score.

In this flexible-dose trial, Zyprexa Relprevv 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 the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the Zyprexa Relprevv 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 Relprevv should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of Zyprexa Relprevv pharmacokinetic parameters in adult and adolescent patients. 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.

14.3 Agitation Associated with Schizophrenia and Bipolar I Mania

The efficacy of intramuscular Zyprexa Relprevv 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 trials included 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 treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least 1 individual item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS Excited Component 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 these trials 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 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. 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 Zyprexa Relprevv for injection doses 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 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and 10 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 Zyprexa Relprevv for injection dose of 10 mg was evaluated. Zyprexa Relprevv 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 mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular Zyprexa Relprevv for injection dose of 10 mg was evaluated. Zyprexa Relprevv for injection was 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

The Zyprexa Relprevv 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 are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number. The tablets are available as follows:

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

Zyprexa Relprevv IntraMuscular is available in:

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

16.2 Storage and Handling

Store Zyprexa Relprevv tablets, Zyprexa Relprevv ZYDIS, and Zyprexa Relprevv IntraMuscular vials (before reconstitution) at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Reconstituted Zyprexa Relprevv IntraMuscular may be stored at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP] for up to 1 hour if necessary. Discard any unused portion of reconstituted Zyprexa Relprevv IntraMuscular. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature 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 Relprevv tablets and Zyprexa Relprevv ZYDIS from light and moisture. Protect Zyprexa Relprevv IntraMuscular from light, do not freeze.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide for the oral formulations.

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

17.1 Information on Medication Guide

Prescribers or other health professionals should inform patients, their families, and their caregivers about the potential benefits and potential risks associated with treatment with Zyprexa Relprevv, and should counsel them in its appropriate use. A patient Medication Guide is available for Zyprexa Relprevv. Prescribers or other health professionals should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. When using Zyprexa Relprevv and fluoxetine in combination, also refer to the Medication Guide for Symbyax.

17.2 Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events, Including Stroke

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

Zyprexa Relprevv is not approved for elderly patients with dementia-related psychosis .

17.3 Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including Zyprexa Relprevv. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) .

17.4 Hyperglycemia

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking Zyprexa Relprevv .

17.5 Hyperlipidemia

Patients should be counseled that hyperlipidemia has occurred during treatment with Zyprexa Relprevv. Patients should have their lipid profile monitored regularly .

17.6 Weight Gain

Patients should be counseled that weight gain has occurred during treatment with Zyprexa Relprevv. Patients should have their weight monitored regularly .

17.7 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 of concomitant drugs that may potentiate the orthostatic effect of Zyprexa Relprevv, e.g., diazepam or alcohol . 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 orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.

17.8 Potential for Cognitive and Motor Impairment

Because Zyprexa Relprevv 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 Relprevv therapy does not affect them adversely .

17.9 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 if they 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, feeling thirsty, not able to produce urine .

17.10 Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, Symbyax. Patients should also be advised to inform their physicians if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions .

17.11 Alcohol

Patients should be advised to avoid alcohol while taking Zyprexa Relprevv .

17.12 Phenylketonurics

Zyprexa Relprevv ZYDIS contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively) .

17.13 Use in Specific Populations

Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Zyprexa Relprevv .

Nursing Mothers - Patients should be advised not to breast-feed an infant if they are taking Zyprexa Relprevv .

Pediatric Use - Zyprexa Relprevv is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic aminotransferase levels. Patients should be counseled about the potential long-term risks associated with Zyprexa Relprevv and advised that these risks may lead them to consider other drugs first . Safety and effectiveness of Zyprexa Relprevv in patients under 13 years of age have not been established. Safety and effectiveness of Zyprexa Relprevv and fluoxetine in combination in patients <18 years of age have not been established .

17.14 Need for Comprehensive Treatment Program in Pediatric Patients

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

Literature revised June 2, 2011

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

Copyright © 1997, 2011, Eli Lilly and Company. All rights reserved.

PV 6249 AMP

Medication Guide

Zyprexa Relprevv^® (zy-PREX-a)

(olanzapine)

Tablet

Zyprexa Relprevv^® ZYDIS^® (zy-PREX-a ZY-dis)

(olanzapine)

Tablet, Orally Disintegrating

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

What is the most important information I should know about Zyprexa Relprevv?

Zyprexa Relprevv may cause serious side effects, including:

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis).
• High blood sugar (hyperglycemia).
• High fat levels in your blood (increased cholesterol and triglycerides), especially in teenagers age 13 to 17.
• Weight gain, especially in teenagers age 13 to 17.

These serious side effects are described below.

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). Zyprexa Relprevv is not approved for treating psychosis in elderly people with dementia.
• High blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes. High blood sugar could 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 Relprevv and during treatment. In people who do not have diabetes, sometimes high blood sugar goes away when Zyprexa Relprevv is stopped. People with diabetes and some people who did not have diabetes before taking Zyprexa Relprevv need to take medicine for high blood sugar even after they stop taking Zyprexa Relprevv.
  

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

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

  • 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
• High fat levels in your blood (cholesterol and triglycerides). High fat levels may happen in people treated with Zyprexa Relprevv, especially in teenagers (13 to 17 years old). You may not have any symptoms, so your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking Zyprexa Relprevv and during treatment.
• Weight gain. Weight gain is very common in people who take Zyprexa Relprevv. Teenagers (13 to 17 years old) are more likely to gain weight and to gain more weight than adults. Some people may gain a lot of weight while taking Zyprexa Relprevv, so you and your doctor should check your weight regularly. Talk to your doctor about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.

What is Zyprexa Relprevv?

Zyprexa Relprevv 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 adults.
• 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 Relprevv has not been approved for use in children under 13 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, racing thoughts, 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, decreased concentration, 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 Relprevv?

Zyprexa Relprevv may not be right for you. Before starting Zyprexa Relprevv, 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 Relprevv 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 Relprevv will harm your unborn baby.
• are breast-feeding or plan to breast-feed. Zyprexa Relprevv can pass into your breast milk and may harm your baby. You should not breast-feed while taking Zyprexa Relprevv. Talk to your doctor about the best way to feed your baby if you take Zyprexa Relprevv.

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. If you 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 Relprevv 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 it is safe to take Zyprexa Relprevv with your other medicines. Do not start or stop any medicine while taking Zyprexa Relprevv without talking to your doctor first.

How should I take Zyprexa Relprevv?

• Take Zyprexa Relprevv exactly as prescribed. Your doctor may need to change (adjust) the dose of Zyprexa Relprevv until it is right for you.
• If you miss a dose of Zyprexa Relprevv, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of Zyprexa Relprevv at the same time.
• To prevent serious side effects, do not stop taking Zyprexa Relprevv suddenly. If you need to stop taking Zyprexa Relprevv, your doctor can tell you how to safely stop taking it.
• If you take too much Zyprexa Relprevv, call your doctor or poison control center at 1-800-222-1222 right away, or get emergency treatment.
• Zyprexa Relprevv can be taken with or without food.
• Zyprexa Relprevv is usually taken one time each day.
• Take Zyprexa Relprevv 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 Relprevv.

What should I avoid while taking Zyprexa Relprevv?

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

What are the possible side effects of Zyprexa Relprevv?

Serious side effects may happen when you take Zyprexa Relprevv, including:

• See “What is the most important information I should know about Zyprexa Relprevv?”, which describes the increased risk of death in elderly people with 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 Relprevv 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 Relprevv. NMS can cause death and must be treated in a hospital. Call your doctor right away if you become severely ill and have any of these symptoms:
  • high fever
  • excessive sweating
  • rigid muscles
  • confusion
  • changes in your breathing, heartbeat, and blood pressure.
• Tardive Dyskinesia: This condition causes body movements that keep happening and that you can not control. These movements usually affect the face and tongue. Tardive dyskinesia may not go away, even if you stop taking Zyprexa Relprevv. It may also start after you stop taking Zyprexa Relprevv. Tell your doctor 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 Relprevv.
• 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 is important for you to drink water to avoid dehydration. Call your doctor right away if you become severely ill and have any of these symptoms of dehydration:
  • sweating too much or not at all
  • dry mouth
  • feeling very hot
  • feeling thirsty
  • not able to produce urine.

Common side effects of Zyprexa Relprevv 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 Relprevv. 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 Relprevv?

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

Keep Zyprexa Relprevv and all medicines out of the reach of children.

General information about Zyprexa Relprevv

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

This Medication Guide summarizes the most important information about Zyprexa Relprevv. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zyprexa Relprevv that was written for healthcare professionals. For more information about Zyprexa Relprevv call 1-800-Lilly-Rx (1-800-545-5979) or visit www.zyprexa.com.

What are the ingredients in Zyprexa Relprevv?

Active ingredient: Zyprexa Relprevv

Inactive ingredients:

Tablets - carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. 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.

Medication Guide revised June 21, 2011

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

www.zyprexa.com

Copyright © 2009, 2011, Eli Lilly and Company. All rights reserved.

PV 6924 AMP

Zyprexa Relprevv pharmaceutical active ingredients containing related brand and generic drugs:

• Olanzapine Pamoate

Zyprexa Relprevv available forms, composition, doses:

• Injectable; Injection; Olanzapine Pamoate 210 mg
• Injectable; Injection; Olanzapine Pamoate 300 mg
• Injectable; Injection; Olanzapine Pamoate 405 mg

Zyprexa Relprevv destination | category:

• Human:
• Atypical antipsychotics

Zyprexa Relprevv Anatomical Therapeutic Chemical codes:

• N05AH03 - Olanzapine

Zyprexa Relprevv pharmaceutical companies:

• Eli Lilly

References

1. Dailymed."ZYPREXA RELPREVV (OLANZAPINE PAMOATE) KIT [ELI LILLY AND COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."FLUOXETINE HYDROCHLORIDE; OLANZAPINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "olanzapine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Zyprexa Relprevv after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zyprexa Relprevv not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology