Usual Adult Dose for Bipolar Disorder

Monotherapy:

• Initial dose: 10 or 15 mg orally once a day
• Dose adjustments: If indicated, dose adjustments should occur at intervals of at least 24 hours in 5 mg increments/decrements.
• Maintenance dose: 5 to 20 mg orally once a day
• Maximum dose: 20 mg/day

Adjunctive Treatment with Lithium or Valproate:

• Initial dose: 10 mg orally once a day
• Maintenance dose: 5 to 20 mg orally once a day
• Maximum dose: 20 mg/day

Treatment of Depressive Episodes Associated with Bipolar I Disorder (In Combination with Fluoxetine):

• Initial dose: 5 mg orally once a day (with fluoxetine)
• Dose adjustments: Should be made with the individual components within the dose range of 5 to 12.5 mg as indicated according to efficacy and tolerability.
• Maximum dose: 18 mg/day (with fluoxetine)

Uses:

• Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder
• Treatment of manic or mixed episode associated with bipolar disorder as an adjunct to lithium or valproate
• Treatment of depressive episodes associated with bipolar I disorder when used in combination with fluoxetine

Usual Adult Dose for Schizophrenia

Oral:

• Initial dose: 5 to 10 mg orally once a day
• Target dose: 10 mg orally once a day within the first several days; further dose adjustments, if needed, should occur at intervals of not less than 1 week in 5 mg increments/decrements.
• Maximum dose: 20 mg orally once a day

Oral Formulations Comments:

• Efficacy has been demonstrated in doses of 10 to 15 mg per day; doses above 10 mg per day were not demonstrated as more efficacious.
• Dose increases above 10 mg per day should occur only after a clinical assessment.

Parenteral:
Dosing for Extended-release Injectable Suspension (Based on Corresponding Oral Doses):
If the target oral olanzapine dose is 10 mg/day:

• Initial dose: 210 mg IM every 2 weeks OR 405 mg IM every 4 weeks for the first 8 weeks
• Maintenance dose: 150 mg IM every 2 weeks OR 300 mg IM every 4 weeks

If the target oral olanzapine dose is 15 mg/day:

• Initial dose: 300 mg IM every 2 weeks for the first 8 weeks
• Maintenance dose: 210 mg IM every 2 weeks OR 405 mg IM every 4 weeks

If the target oral olanzapine dose is 20 mg/day:

• Initial dose: 300 mg IM every 2 weeks for the first 8 weeks
• Maintenance dose: 300 mg IM every 2 weeks

Parenteral Formulations Comments:

• Tolerability should be established with oral formulations prior to initiating IM extended-release therapy.
• Efficacy has been demonstrated with doses from 150 to 300 mg IM every 2 weeks and 405 mg IM every 4 weeks.

Use: Treatment of schizophrenia

Usual Adult Dose for Depression

Treatment of Depressive Episodes Associated with Bipolar I Disorder (In Combination with Fluoxetine):

• Initial dose: 5 mg orally once a day (with fluoxetine)
• Dose adjustments: Should be made with the individual components within the dose range of 5 to 20 mg as indicated according to efficacy and tolerability
• Maximum dose: 18 mg/day (with fluoxetine)

Comments:

• The safety of co-administration of doses above 18 mg has not been evaluated in clinical studies.
• Monotherapy is not indicated for treatment resistant depression.

Use: 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

Usual Adult Dose for Agitated State

Immediate-release Injection:

• Initial dose: 10 mg IM once
• Dose range: 2.5 to 10 mg
• Subsequent doses up to 10 mg may be given every 2 hours for agitation that persists following the initial dose
• Maximum number of doses: 3 doses in 24 hours; additional doses in patients with clinically significant postural hypotension are not recommended

Comments:

• The efficacy of repeated doses in agitated patients has not been systematically evaluated in controlled clinical trials.
• The safety of total daily dose 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) has not been evaluated in clinical trials; maximal dosing may be associated with significant orthostatic hypotension.
• If ongoing therapy is clinically indicated, oral olanzapine may be initiated in a range of 5 to 20 mg per day as soon as clinically appropriate.

Use: For the treatment of acute agitation associated with schizophrenia and bipolar I mania

Usual Geriatric Dose for Agitated State

Immediate-release Injection:

• Initial dose: 5 mg IM once
• Subsequent doses may be given for agitation that persists following the initial dose
• Maximum dose: 10 mg IM 2 to 4 hours apart; additional doses in patients with clinically significant postural hypotension are not recommended

Comments:

• The efficacy of repeated doses in agitated patients has not been systematically evaluated in controlled clinical trials.
• The safety of total daily dose 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) has not been evaluated in clinical trials; maximal dosing may be associated with significant orthostatic hypotension.
• If ongoing therapy is clinically indicated, oral olanzapine may be initiated in a range of 5 to 20 mg per day as soon as clinically appropriate.

Use: For the treatment of acute agitation associated with schizophrenia and bipolar I mania

Usual Pediatric Dose for Schizophrenia

Oral:
13 to 17 years:

• Initial dose: 2.5 to 5 mg orally once a day
• Target dose: 10 mg orally once a day; further dose adjustments, if needed, should occur at intervals of not less than 1 week in 2.5 to 5 mg increments/decrements.
• Maximum dose: 20 mg orally/day

Comments:

• Efficacy has been demonstrated in the range of 2.5 to 20 mg per day; a mean modal dose of 12.5 mg per day (mean dose 11.1 mg per day) was demonstrated in adolescent schizophrenia efficacy trials.
• Medication therapy for adolescents should be initiated only after a thorough diagnostic evaluation and careful consideration given to the risks associated with treatment; medication treatment should be part of a total treatment program that includes psychological, educational, and social interventions.
• When deciding among the alternative treatments, clinicians should consider the increased potential for weight gain and dyslipidemia in this population compared to adults.

Use: Treatment of schizophrenia

Usual Pediatric Dose for Bipolar Disorder

Treatment of Depressive Episodes Associated with Bipolar I Disorder (In Combination with Fluoxetine):
10 to 17 years:

• Initial dose: 2.5 mg orally once a day (with fluoxetine)
• Dose adjustments: Should be made with the individual components within the dose range of 5 to 12.5 mg as indicated according to efficacy and tolerability.
• Maximum dose: 12.5 mg/day (with fluoxetine)

Comments:

• Medication therapy for adolescents should be initiated only after a thorough diagnostic evaluation and careful consideration given to the risks associated with treatment; medication treatment should be part of a total treatment program that includes psychological, educational, and social interventions.
• When deciding among the alternative treatments, clinicians should consider the increased potential for weight gain and dyslipidemia in this population compared to adults.

Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder:
13 to 17 years:

• Initial dose: 2.5 to 5 mg orally once a day
• Target dose: 10 mg orally once a day; dose adjustments, if needed, should occur at intervals of not less than 1 week in 2.5 to 5 mg increments/decrements.
• Maximum dose: 20 mg/day

Comment: Efficacy has been demonstrated in the range of 2.5 to 20 mg per day; a mean modal dose of 10.7 mg per day (mean dose 8.9 mg per day) was demonstrated in adolescent clinical trials.

Uses:

• Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder
• Treatment of depressive episodes associated with bipolar I disorder when used in combination with fluoxetine

Usual Pediatric Dose for Depression

Treatment of Depressive Episodes Associated with Bipolar I Disorder (In Combination with Fluoxetine):
10 to 17 years:

• Initial dose: 2.5 mg orally once a day (with fluoxetine)
• Dose adjustments: Should be made with the individual components within the dose range of 3 to 12 mg as indicated according to efficacy and tolerability
• Maximum dose: 12 mg/day (with fluoxetine)

Comments:

• The safety of co-administration of doses above 12 mg has not been evaluated in clinical studies.
• Monotherapy is not indicated for treatment resistant depression.

Use: 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

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

Data not available

Dose Adjustments

Dose modifications are generally not necessary for age, gender, or smoking status; however, dose modification may be necessary in patients exhibiting a combination of these factors.

Initial dose adjustments should be considered in the following patients:

• Those with a predisposition to hypotensive reactions
• Those who exhibit a combination of factors that may slow the metabolism (e.g., female gender, geriatric age, nonsmokers)
• Those who may be pharmacodynamically sensitive (see Warnings)
• Those who are debilitated

Oral:

• Initial dose: 5 mg orally per day
• In combination with fluoxetine: Initial dose: 2.5 to 5 mg orally per day
• Dose escalation should be performed with caution

Parenteral:
Immediate-release IM: Initial dose: 2.5 mg IM
Extended-release IM suspension: Initial dose: 150 mg IM every 4 weeks

• Dose escalation should be performed with caution

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Zyprexa Relprevv. It includes a medication guide, communication plan, elements to assure safe use, and implementation system. For additional information: www.fda.gov/REMS

US BOXED WARNINGS:
POST-INJECTION DELIRIUM/SEDATION SYNDROME:

• Adverse events with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections. This drug must be administered in a registered healthcare facility with ready access to emergency response services. After each injection, patients must be observed at the healthcare facility by a healthcare professional for at least 3 hours. Because of this risk, this drug is only available through a restricted distribution program call ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment.

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 17 placebo-controlled trials (modal duration of 10 weeks) in patients largely 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 atypical 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 characteristics(s) of the patients is not clear. This drug is not approved for the treatment of patients with dementia-related psychosis.
• When using olanzapine and fluoxetine in combination, refer to the Boxed Warning for this combination drug.

Safety and efficacy of the extended-release injection have not been established in patients younger than 18 years.
Safety and efficacy of oral olanzapine have not been established in patients younger than 13 years.
Safety and efficacy of combination oral olanzapine-fluoxetine have not been established in patients younger than 10 years.

Consult WARNINGS section for additional precautions.

Dialysis

No data available

Other Comments

Administration advice:

• Take orally once a day without regard to meals.
• In combination with fluoxetine, take once daily in the evening.
• Tolerance should be established with oral formulations prior to beginning extended-release IM treatment.
• Extended-release IM formulations: This formulation should be given via deep intramuscular gluteal use only; subcutaneous and intravascular administration should be avoided.

Orally disintegrating tablets:

• At the time of administration, open sachet and peel back foil; do not push tablet through foil.
• With dry hands, immediately remove the tablet and place in mouth; tablet disintegration occurs rapidly in saliva and can be swallowed with or without liquid.
• Alternatively, some experts state that the wafer/tablet may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk, or coffee) immediately before administration; do not disperse in cola beverages.

Immediate-release IM injection:

• Inject slowly and deep into muscle mass.

Extended-release IM injection:

• Should be administered by a healthcare professional in a healthcare facility with ready access to emergency response services; patients should be continuously monitored for post-injection delirium/sedation syndrome for at least 2 to 3 hours following each injection.
• Administer by deep IM gluteal injection using a 19-gauge, 1.5 inch needle; inject at a steady, continuous pressure; do not massage the injection site.
• After inserting needle into muscle, but prior to injection, aspiration should be maintained for several seconds to ensure that no blood is drawn into the syringe; if any blood is aspirated, discard syringe and start over with fresh drug from a new kit.
• After at least 2 to 3 hours postinjection, patients may be discharged if they are alert, oriented, and absent of any signs and symptoms of post-injection delirium/sedation syndrome; for the remainder of the day, they should not drive or operate heavy machinery and should be vigilant for symptoms of post-injection delirium/sedation syndrome.

Storage requirements:

• Tablets and oral disintegrating tablets: Protect from light and moisture
• Immediate-release injection: Protect from light, do not freeze

Reconstitution/preparation techniques:
Immediate-release IM injection:

• Reconstitute with 2.1 mL of sterile water to provide a concentration of 5 mg/mL; used within 1 hour after reconstitution; discard unused portion.

Extended-release IM suspension:

• The manufacturer product information should be consulted.
• Once the drug is suspended in solution, it may be held at room temperature for 24 hours, the vial should be agitated immediately prior to product withdrawal; once suspension is into the syringe, it should be used immediately.

IV compatibility:

• This drug should not be mixed in the same syringe as diazepam, lorazepam, or haloperidol.

General:

• There are 2 IM formulations with different dosages, dosing frequencies, and indications; these products should not be interchanged and should not be administered IV or subcutaneously.
• Initial improvement may take days to weeks; patients should be monitored closely during this time.
• Patients should be periodically reevaluated as to the long-term usefulness of this drug in their condition.
• This drug is not indicated as monotherapy for the treatment of depressive episodes associated with bipolar I disorder.

Monitoring:

• Post-injection delirium/sedation syndrome: Continuously observe patients at a healthcare facility with ready access to emergency response services for at least 2 to 3 hours following each extended-release IM injection
• Cardiovascular: Patients requiring repeated immediate-release IM injections should be assessed for orthostatic hypotension prior to the administration of subsequent doses
• Hematologic: CBC frequently during the first few months in patients with preexisting low WBC and/or a prior history of drug-induced leukopenia or neutropenia
• Metabolic: Monitor for increases in blood sugar, weight, and lipids
• Psychiatric: Monitor for clinical worsening and suicidality; close supervision of high-risk patients should accompany drug therapy

Patient advice:

• Patients, families, and caregivers should be advised that post-injection delirium/sedation syndrome may occur shortly after each IM administration; patients should not drive or operate heavy machinery for the remainder of the day of each injection.
• Patients should be told that this drug may impair judgment, thinking, or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
• Inform patients that this drug may cause dizziness upon arising; it is best to get up slowly form a seated or lying position.
• Advise patients to speak to physician or health care professional if they are pregnant, intend to become pregnant, or are breastfeeding.
• Advise patients that this drug may cause metabolic changes such as increases in blood sugar, body weight and lipids.
• Patients should be made aware of the signs/symptoms associated with drug reaction with eosinophilia and systemic symptoms (DRESS). Tell patients to immediately report any signs/symptoms of DRESS.
• Patients should avoid overheating and dehydration.