`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ZYPREXA safely and effectively. See full prescribing information
`
`
`for ZYPREXA.
`
`ZYPREXA (olanzapine) Tablet for Oral use
`
`ZYPREXA ZYDIS (olanzapine) Tablet, Orally Disintegrating for
`
`
`Oral use
`ZYPREXA IntraMuscular (olanzapine) Injection, Powder, For
`
`Solution for Intramuscular use
`
`Initial U.S. Approval: 1996
`
`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 is not approved for the treatment of patients with
`
`
`dementia-related psychosis. (5.1, 5.14, 17.2)
`
`When using ZYPREXA and fluoxetine in combination, also
`
`
`refer to the Boxed Warning section of the package insert for
`Symbyax.
`
`
`
`
`MM/YYYY
`
`
`
`MM/YYYY
`
`--------------------------- RECENT MAJOR CHANGES --------------------------
`
`
`
`Indications and Usage, ZYPREXA and Fluoxetine in
`
`
`Combination:
`Depressive Episodes Associated with Bipolar I
`
`Disorder (1.5)
`
`Dosage and Administration, ZYPREXA and Fluoxetine
`
`in Combination:
`Depressive Episodes Associated with Bipolar I
`
`Disorder (2.5)
`
`MM/YYYY
`Dosing in Special Populations (2.7)
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`
`
`ZYPREXA® (olanzapine) 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 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 and Fluoxetine in Combination for the:
`
`•
`
`•
`
`Reference ID: 3347923
`
`•
`
`•
`
`1
`
`Treatment of depressive episodes associated with bipolar I
`disorder. (1.5)
`
`• Efficacy was established with Symbyax (olanzapine and
`
`fluoxetine in combination); refer to the product label for
`Symbyax.
`
`Treatment of treatment resistant depression. (1.6)
`
`• Efficacy was established with Symbyax (olanzapine and
`
`fluoxetine in combination) in adults; refer to the product label
`for Symbyax.
`
`------------------------ DOSAGE AND ADMINISTRATION -----------------------
`
`
`
`Schizophrenia in adults (2.1)
`Oral: Start at 5-10 mg once daily;
`
`Target: 10 mg/day within several
`days
`
`Oral: Start at 2.5-5 mg once daily;
`Target: 10 mg/day
`
`Oral: Start at 10 or 15 mg once daily
`
`Schizophrenia in adolescents
`(2.1)
`
`Bipolar I Disorder (manic or
`mixed episodes) in adults (2.2)
`
`Bipolar I Disorder (manic or
`mixed episodes) in
`adolescents (2.2)
`
`Bipolar I Disorder (manic or
`mixed episodes) with lithium or
`valproate in adults (2.2)
`
`Agitation associated with
`Schizophrenia and Bipolar I
`Mania in adults (2.4)
`
`
`Depressive Episodes
`associated with Bipolar I
`Disorder in adults (2.5)
`
`Depressive Episodes
`associated with Bipolar I
`Disorder in children and
`adolescents (2.5)
`
`Treatment Resistant
`Depression in adults (2.6)
`
`
`Oral: Start at 2.5-5 mg once daily;
`Target: 10 mg/day
`
`
`Oral: Start at 10 mg once daily
`
`
`IM: 10 mg (5 mg or 7.5 mg when
`
`clinically warranted)
`
`Assess for orthostatic hypotension
`prior to subsequent dosing (max. 3
`doses 2-4 hrs apart)
`
`Oral in combination with fluoxetine:
`Start at 5 mg of oral olanzapine and
`20 mg of fluoxetine once daily
`
`Oral in combination with fluoxetine:
`Start at 2.5 mg of oral olanzapine
`and 20 mg of fluoxetine once daily
`
`
`Oral in combination with fluoxetine:
`Start at 5 mg of oral olanzapine and
`20 mg of fluoxetine once daily
`
`
`
`•
`
`•
`
`•
`
`•
`
`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)
`
`•
`Olanzapine may be given without regard to meals. (2.1)
`
`
`ZYPREXA and Fluoxetine in Combination:
`Dosage adjustments, if indicated, should be made with the
`•
`
`individual components according to efficacy and tolerability. (2.5,
`2.6)
`
`Olanzapine 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 olanzapine with
`75 mg fluoxetine has not been evaluated in adults. (2.5, 2.6)
`
`Safety of co-administration of doses above 12 mg olanzapine with
`50 mg fluoxetine has not been evaluated in children and
`adolescents ages 10 to 17. (2.5)
`
` ---------------------- DOSAGE FORMS AND STRENGTHS---------------------
`
`
`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)
`
` ------------------------------- CONTRAINDICATIONS ------------------------------
`
`
`None with ZYPREXA monotherapy.
`•
`
`• When using ZYPREXA and fluoxetine in combination, also refer
`to the Contraindications section of the package insert for
`Symbyax®. (4)
`• When using ZYPREXA in combination with lithium or valproate,
`refer to the Contraindications section of the package inserts for
`
`those products. (4)
`
`
`------------------------ WARNINGS AND PRECAUTIONS -----------------------
`
`

`

`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`Elderly Patients with Dementia-Related Psychosis: Increased risk
`of death and increased incidence of cerebrovascular adverse
`events (e.g., stroke, transient ischemic attack). (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 olanzapine. Patients taking olanzapine 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. 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 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)
`
` ------------------------------- ADVERSE REACTIONS ------------------------------
`
`Most common adverse reactions (≥5% and at least twice that for
`placebo) associated with:
`
`Oral Olanzapine Monotherapy:
`•
` Schizophrenia (Adults) – postural hypotension, constipation,
`weight gain, dizziness, personality disorder, akathisia (6.1)
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`
`INDICATIONS AND USAGE
`
`1
`1.1
` Schizophrenia
`1.2
`Bipolar I Disorder (Manic or Mixed Episodes)
`1.3
`Special Considerations in Treating Pediatric
`
`Schizophrenia and Bipolar I Disorder
`
`
`ZYPREXA IntraMuscular: Agitation Associated with
`Schizophrenia and Bipolar I Mania
`ZYPREXA and Fluoxetine in Combination: Depressive
`Episodes Associated with Bipolar I Disorder
`
`ZYPREXA and Fluoxetine in Combination: Treatment
`Resistant Depression
`
`1.4
`
`1.5
`
`1.6
`
`Reference ID: 3347923
`
`2
`
`•
`
`•
`
`•
`•
`
`•
`•
`
`•
`•
`
`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 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 and Fluoxetine in Combination: Also refer to the Adverse
`Reactions section of the package insert for Symbyax. (6)
`
`ZYPREXA 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
` ------------------------------- DRUG INTERACTIONS ------------------------------
`
`
`Diazepam: May potentiate orthostatic hypotension. (7.1, 7.2)
`•
`
`
`Alcohol: May potentiate orthostatic hypotension. (7.1)
`•
`
`Carbamazepine: Increased clearance of olanzapine. (7.1)
`•
`
`
`Fluvoxamine: May increase olanzapine levels. (7.1)
`•
`•
`ZYPREXA 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 olanzapine. (7.2)
`
`
`Other Concomitant Drug Therapy: When using olanzapine in
`combination with lithium or valproate, refer to the Drug
`Interactions sections of the package insert for those products.
`(7.2)
`
` ------------------------ USE IN SPECIFIC POPULATIONS -----------------------
`Pregnancy: ZYPREXA should be used during pregnancy only if
`•
`the potential benefit justifies the potential risk to the fetus. (8.1)
`
`Nursing Mothers: Breast-feeding is not recommended. (8.3)
`
`Pediatric Use: Safety and effectiveness of ZYPREXA in children
`<13 years of age have not been established. Safety and
`effectiveness of ZYPREXA and fluoxetine in combination in
`children <10 years of age have not been established. (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide
`
`
`Revised: MM/YYYY
`
`
`
`2
`
` DOSAGE AND ADMINISTRATION
`
`
` Schizophrenia
`2.1
`2.2
`Bipolar I Disorder (Manic or Mixed Episodes)
`2.3
`Administration of ZYPREXA ZYDIS (olanzapine orally
`
`disintegrating tablets)
`ZYPREXA IntraMuscular: Agitation Associated with
`Schizophrenia and Bipolar I Mania
`ZYPREXA and Fluoxetine in Combination: Depressive
`Episodes Associated with Bipolar I Disorder
`
`ZYPREXA and Fluoxetine in Combination: Treatment
`Resistant Depression
`ZYPREXA and Fluoxetine in Combination: Dosing in
`Special Populations
`3 DOSAGE FORMS AND STRENGTHS
`
`
`2.4
`
`2.5
`
`2.6
`
`2.7
`
`

`

`
` 4 CONTRAINDICATIONS
`
` 5 WARNINGS AND PRECAUTIONS
`
`Elderly Patients with Dementia-Related Psychosis
`5.1
`
` Suicide
`5.2
`
`Neuroleptic Malignant Syndrome (NMS)
`5.3
`
` Hyperglycemia
`5.4
` Hyperlipidemia
`5.5
`
` Weight Gain
`5.6
` Tardive Dyskinesia
`5.7
`5.8
` Orthostatic Hypotension
`5.9
`Leukopenia, Neutropenia, and Agranulocytosis
` Dysphagia
`5.10
`
`5.11
` Seizures
`5.12 Potential for Cognitive and Motor Impairment
`
`5.13 Body Temperature Regulation
`
`5.14 Use in Patients with Concomitant Illness
`5.15
` Hyperprolactinemia
`5.16 Use in Combination with Fluoxetine, Lithium, or Valproate
`
` Laboratory Tests
`5.17
`
`6 ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`6.2
`Vital Signs and Laboratory Studies
` Postmarketing Experience
`6.3
`
`7 DRUG INTERACTIONS
`
`Potential for Other Drugs to Affect Olanzapine
`7.1
`
`Potential for Olanzapine to Affect Other Drugs
`7.2
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
`Labor and Delivery
` Nursing Mothers
`8.3
`
`8.4
` Pediatric Use
` Geriatric Use
`8.5
`
`9 DRUG ABUSE AND DEPENDENCE
`
` Dependence
`9.3
`
`10 OVERDOSAGE
`
` Human Experience
`10.1
` Management of Overdose
`10.2
`
`
`11 DESCRIPTION
`
`
`3
`
`
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
` Pharmacodynamics
`12.3
` Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
` Schizophrenia
`14.1
`14.2 Bipolar I Disorder (Manic or Mixed Episodes)
`14.3 Agitation Associated with Schizophrenia and Bipolar I
`Mania
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` How Supplied
`16.1
`16.2 Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`Information on Medication Guide
`17.1
`17.2 Elderly Patients with Dementia-Related Psychosis:
`Increased Mortality and Cerebrovascular Adverse Events
`(CVAE), Including Stroke
`
`17.3 Neuroleptic Malignant Syndrome (NMS)
`
` Hyperglycemia
`17.4
`
` Hyperlipidemia
`17.5
` Weight Gain
`17.6
`
` Orthostatic Hypotension
`17.7
`17.8 Potential for Cognitive and Motor Impairment
`
`17.9 Body Temperature Regulation
`
`17.10 Concomitant Medication
`17.11 Alcohol
`17.12 Phenylketonurics
`17.13 Use in Specific Populations
`
`17.14 Need for Comprehensive Treatment Program in Pediatric
`
`Patients
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`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 (olanzapine) is not approved for the
`treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1, 5.14) and Patient
`Counseling Information (17.2)].
`When using ZYPREXA and fluoxetine in combination, also refer to the Boxed Warning section of the
`package insert for Symbyax.
`
`1
`1.1
`
`INDICATIONS AND USAGE
`Schizophrenia
`Oral ZYPREXA is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in
`adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia
`(ages 13-17), efficacy was established in one 6-week trial [see Clinical Studies (14.1)].
`When deciding among the alternative treatments available for adolescents, clinicians should consider the
`
`increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should
`
`Reference ID: 3347923
`
`

`

`4
`
`consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider
`prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].
`
`Bipolar I Disorder (Manic or Mixed Episodes)
`1.2
`Monotherapy — Oral ZYPREXA 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 [see Clinical Studies (14.2)].
`When deciding among the alternative treatments available for adolescents, clinicians should consider the
`
`increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should
`consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider
`prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].
`Adjunctive Therapy to Lithium or Valproate — Oral ZYPREXA is indicated for the treatment of manic or mixed
`
`episodes associated with 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 [see Clinical Studies (14.2)].
`
`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 IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania
`
`ZYPREXA IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and
`bipolar I mania.
`Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult
`inpatients with: schizophrenia or bipolar I disorder (manic or mixed episodes) [see Clinical Studies (14.3)].
`
`“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner
`
`tension.” Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g.,
`threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the
`
`use of intramuscular antipsychotic medications to achieve immediate control of the agitation.
`
`
`
`ZYPREXA and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder
`1.5
`Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of depressive episodes associated with
`bipolar I disorder, based on clinical studies. When using ZYPREXA and fluoxetine in combination, refer to the Clinical
`Studies section of the package insert for Symbyax.
`ZYPREXA monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I
`
`disorder.
`ZYPREXA and Fluoxetine in Combination: Treatment Resistant Depression
`1.6
`Oral ZYPREXA and fluoxetine in combination is indicated for the treatment of treatment resistant depression
`(major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate
`dose and duration in the current episode), based on clinical studies in adult patients. When using ZYPREXA and
`
`fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.
`
`ZYPREXA monotherapy is not indicated for the treatment of treatment resistant depression.
`
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Schizophrenia
`
`Adults
`Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals,
`generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage
`
`adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine
`would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, 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.
`Olanzapine is not indicated for use in doses above 20 mg/day.
`Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who
`
`have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower
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`Reference ID: 3347923
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`5
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`metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more
`pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical
`
`Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.
`Maintenance Treatment — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment
`response in schizophrenic patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed
`for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to
`use ZYPREXA for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual
`patient.
`
`
`Adolescents
`Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with
`a recommended starting dose of 2.5 or 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 [see Clinical
`Studies (14.1)].
`Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of schizophrenia in the
`adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from
`adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is
`generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed
`
`to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
`
`Bipolar I Disorder (Manic or Mixed Episodes)
`2.2
`
`Adults
`
`Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule without
`regard to meals, generally beginning with 10 or 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 [see Clinical Studies (14.2)].
`Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral ZYPREXA 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 [see Clinical Studies (14.2)]. The physician who elects to use ZYPREXA for extended periods should
`periodically reevaluate the long-term usefulness of the drug for the individual patient.
`Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral
`
`olanzapine dosing should 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 [see Clinical Studies
`
`(14.2)]. The safety of doses above 20 mg/day has not been evaluated in clinical trials.
`
`
`Adolescents
`Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with
`a recommended starting dose of 2.5 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 [see Clinical
`Studies (14.2)].
`
`Maintenance Treatment — The efficacy of ZYPREXA for the maintenance treatment of bipolar I disorder in the
`
`adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along
`with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally
`recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to
`maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
`
`Administration of ZYPREXA ZYDIS (olanzapine orally disintegrating tablets)
`2.3
`After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the
`blister, using dry hands, remove tablet and place entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs
`
`rapidly in saliva so it can be easily swallowed with or without liquid.
`ZYPREXA IntraMuscular: Agitation Associated with Schizophrenia and Bipolar I Mania
`2.4
`Dose Selection for Agitated Adult Patients with Schizophrenia and Bipolar I Mania — The efficacy of intramuscular
`olanzapine 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
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`6
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`warrant [see Clinical Studies (14.3)]. 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 olanzapine
`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 olanzapine (e.g., 3 doses
`of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic
`hypotension [see Warnings and Precautions (5.8)]. Thus, it is recommended that patients requiring subsequent
`intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of
`intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically significant
`
`
`postural change in systolic blood pressure is not recommended.
`If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as
`soon as clinically appropriate [see Dosage and Administration (2.1, 2.2)].
`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 olanzapine
`[see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].
`Administration of ZYPREXA IntraMuscular — ZYPREXA IntraMuscular is intended for intramuscular use only. Do
`
`not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit.
`Directions for Preparation of ZYPREXA IntraMuscular with Sterile Water for Injection