OLANZAPINE

OLANZAPINE

Olanzapine

What’s of Interest:

• US FDA warned that olanzapine is associated with a rare but serious skin condition known as Drug Reaction with Eosinophilia (DRESS). DRESS may begin as a rash but can progress to others parts of the body and can include symptoms such as fever, swollen lymph nodes, swollen face, inflammation of organs, and an increase in white blood cells known as eosinophilia. In some cases, DRESS can lead to death. Clinicians prescribing olanzapine should inform patients about the risk of DRESS; patients who develop a fever with rash and swollen lymph nodes or swollen face should seek medical care. Patients are not advised to stop their medication without consulting their prescribing clinician.

Brands

• Zyprexa, Zyprexa Relprevv, Olasek, other

Class

• Atypical antipsychotic (serotonin-dopamine antagonist; second-generation antipsychotic; also a mood stabilizer)

Approved For:

• Schizophrenia (ages 13 and older)
• Maintaining response in schizophrenia
• Acute agitation associated with schizophrenia (intramuscular)
• Acute mania/mixed mania (monotherapy and adjunct to lithium or valproate) (ages 13 and older)
• Bipolar maintenance
• Acute agitation associated with bipolar I mania (intramuscular)
• Bipolar depression [in combination with fluoxetine (Symbyax)]
• Treatment-resistant depression [in combination with fluoxetine (Symbyax)]

Dosing

Formulation:

• Tablets 2.5 mg, 5 mg, 7.5mg, 10 mg, 15 mg, 20 mg
• Orally disintegrating tablets 5 mg, 10 mg, 15 mg, 20 mg
• Intramuscular formulation 5 mg/mL, each vial contains 10 mg (available in some countries)
• Depot 210 mg, 300 mg, 405 mg
• Olanzapine-fluoxetine combination capsule (mg equivalent olanzapine/mg equivalent fluoxetine) 6 mg/25 mg, 6 mg/50 mg, 12mg/25 mg, 12 mg/50 mg

Dosage range:

• 10–20 mg/day (oral or intramuscular)
• 6–12 mg olanzapine /25–50 mg fluoxetine (olanzapine-fluoxetine combination)
• 210–300 mg/2 weeks (depot)

Dosing Tips–Oral:

• Initial 5–10 mg once daily orally; increase by 5 mg/day once a week until desired efficacy is reached; maximum approved dose is 20 mg/day
• More may be more: raising usual dose above 15 mg/day can be useful for acutely ill and agitated patients and some treatment-resistant patients, gaining efficacy without many more side effects
• Some heroic uses for patients who do not respond to other antipsychotics can occasionally justify dosing over 30 mg/day and short-term up to 90 mg/day
• For high doses in treatment-resistant or violent patients, monitor therapeutic drug levels and target generally higher than the usual range of 5–75 mg/mL (i.e., greater than 125 mg/mL), but keep below the toxic range associated with QTc prolongation (700–800 mg/mL)
• Rather than raise the dose above these levels in acutely agitated patients requiring acute antipsychotic actions, consider augmentation with a benzodiazepine or conventional antipsychotic, either orally or intramuscularly
• Rather than raise the dose above these levels in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate or lamotrigine
• Clearance of olanzapine is slightly reduced in women compared to men, so women may need lower doses than men
• Children and elderly should generally be dosed at the lower end of the dosage spectrum
• Treatment should be suspended if absolute neutrophil count falls below 1,000/mm³

Dosage Tips–Depot:

• Initial dose: 210–300 mg/2 weeks (depends on stabilizing oral dose)
• Maintenance dose: 210–300 mg/2 weeks (depends on stabilizing oral dose)
• Maximum recommended dose 300 mg every 2 weeks or 405 mg every 4 weeks
• Conversion from oral dose: if stable on 10 mg/day, then 210 mg LAI every 2 weeks or 405 mg LAI every 4 weeks for the first 8 weeks, then 150 mg LAI every 2 weeks or 300 mg LAI every 4 weeks
• If stable on oral 15 mg/day, then 300 mg LAI every 2 weeks for the first 8 weeks, then 210 mg LAI every 2 weeks or 405 mg LAI every 4 weeks
• If stable on oral 20 mg/day, then 300 mg LAI every 2 weeks
• Injection site: intramuscular gluteal
• Needle gauge: 19
• Injection volume: 150 mg/mL; range 1.0–2.7 mL
• Dosing schedule: 2 weeks, 4 weeks
• No oral supplementation required
• No leading required
• 3-hour post-injection monitoring required due to risk (0.2%) of post-injection delirium from vascular breach

Pearls

• Recent landmark head to head study in schizophrenia suggests greater effectiveness (i.e., lower dropouts of all causes) at moderately high doses compared to some other atypical and conventional antipsychotics at moderate doses
• Same recent head to head study in schizophrenia suggests greater efficacy but greater metabolic side effects compared to some other atypical and conventional antipsychotics
• Well accepted for use in schizophrenia and bipolar disorder, including difficult cases
• Documented utility in treatment-refractory cases, especially at higher doses
• Documented efficacy as augmenting agent to SSRIs (fluoxetine) in nonpsychotic treatment-resistant major depressive disorder
• Documented efficacy in bipolar depression, especially in combination with fluoxetine
• More weight gain than many other antipsychotics—does not mean every patient gains weight
• Motor side effects unusual at low-to-mid doses
• Less sedation than for some other antipsychotics, more than for others
• Controversial as to whether olanzapine has more risk of diabetes and dyslipidemia than other antipsychotics
• Cigarette smoke can decrease olanzapine levels and patients may require a dose increase if they begin or increase smoking
• A short-acting intramuscular dosage formulation is available
• A long-acting intramuscular dosage formulation is also approved
• Patients with inadequate responses to atypical antipsychotics may benefit from determination of plasma drug levels and, if low, a dosage increase even beyond the usual prescribing limits
• For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring
• In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic
• Patients with inadequate responses to atypical antipsychotics may also benefit from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic
• However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either
• Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

 Children and adolescents:

• Approved for use in schizophrenia and manic/mixed episodes (ages 13 and older for both)
• Clinical experience and early data suggest olanzapine is probably safe and effective for behavioral disturbances in children and adolescents
• Children and adolescents using olanzapine may need to be monitored more often than adults
• Intramuscular formulation has not been studied in patients under 18 and is not recommended for use in this population

 Pregnancy:

• Controlled studies have not been conducted in pregnant women
• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding
• Psychotic symptoms may worsen during pregnancy, and some form of treatment may be necessary
• Early findings of infants exposed to olanzapine in utero currently do not show adverse consequences
• Olanzapine may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy
• National Pregnancy Registry for Atypical Antipsychotics: 1-866-961-2388 or http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

Side Effects

Weight gain:

Sedation:

 Notable or dangerous side effects:

• Probably increases risk for diabetes mellitus and dyslipidemia
• Dizziness, sedation, weakness
• Dry mouth, constipation, dyspepsia, weight gain
• Peripheral edema
• Joint pain, back pain, chest pain, extremity pain, abnormal gait, ecchymosis
• Tachycardia
• Orthostatic hypotension, usually during initial dose titration
• Rare tardive dyskinesia (much reduced risk compared to conventional antipsychotics)
• Rare rash on exposure to sunlight
• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics
• Rare but serious skin condition known as Drug Reaction with Eosinophilia (DRESS)
• Rare neuroleptic malignant syndrome (much reduced risk compared to conventional antipsychotics)
• Rare seizures
• Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis

 Drug interactions:

• May increase effect of antihypertensive agents
• May antagonize levodopa, dopamine agonists
• Dose may need to be lowered if given with CYP450 1A2 inhibitors (e.g., fluvoxamine); raised if given in conjunction with CYP450 1A2 inducers (e.g., cigarette smoke, carbamazepine)

 Cardiac impairment:

• Should be used with caution because of risk of orthostatic hypotension

 Renal impairment:

• No dose adjustment required for oral formulation
• Not removed by hemodialysis
• For intramuscular formulation, consider lower starting dose (5 mg)

 Hepatic impairment:

• May need to lower dose
• Patients with liver disease should have liver function tests a few times a year
• For moderate to severe hepatic impairment, starting oral dose 5 mg; increase with caution
• For intramuscuar formulation, consider lower starting dose (5 mg)