DRUG INFORMATION
Class
Second Generation Antipsychotic
Neuroscience-based Nomenclature (NbN)
Pharmacological Target
Dopamine, serotonin
Mode of Action
Receptor Antagonist (D2, 5-HT2)
Brand Name
Zyprexa
Monograph
DOSING AND ADMINISTRATION
Therapeutic Dose Range
Schizophrenia: 10-15 mg/day
Bipolar Disorder Mania: 15 mg/day in monotherapy and 10 mg/day in combination therapy.
Maintenance therapy in Bipolar Disorder: 5-20 mg/day
Augmentation Treatment for Depression: 2.5–10 mg/day
Time of Day
Administered on a once-a-day schedule without regard to meals. Can be taken at bedtime if patient finds it sedating
Effect of Food
May be taken with or without food
Effect of Smoking
Smoking may induce metabolism of olanzapine
ADVERSE EFFECTS
Adverse Effects
Weight gain common
Sedation common
Sexual dysfunction not unusual
Asthenia
Constipation
Dizziness
Dry mouth
Dyspepsia
Serious/Life-Threatening Adverse Effects
Rare cases of serious hyperglycemia, including diabetic ketoacidosis and death
Increased mortality rate vs. placebo when used in elderly patients with dementia
Rare cases of venous thromboembolism
Rare cases of hepatic toxicity
Rare cases of neuroleptic malignant syndrome have been reported
Other
Increased mortality rates vs. placebo have been observed in elderly patients with dementia. Olanzapine should not be used in this population.
Use with caution in patients with cardiovascular or cerebrovascular disease or other conditions that would predispose them to hypotension
Use with caution in patients with a history of seizures or with conditions that lower the seizure threshold
Metabolic parameters should be regularly monitored in all patients
As with all antipsychotics, there is a risk for extrapyramidal side effects and tardive dyskniesia
Smoking
Olanzapine is metabolized, in part, by CYP1A2
Cigarette smoke (polycyclic aromatic hydrocarbons) induces CYP1A2 and may:
Reduce the plasma concentration of olanzapine
Reduce the half-life of olanzapine (by as much as 20-40%)
Increase the clearance of olanzapine (by as much as 33%)
Dosage modifications not routinely recommended but smokers may require higher doses for efficacy. Use caution if patient stops smoking as level of antipsychotic will increase.
Nicotine (including nicotine replacement therapy) does not induce CYP1A2.
PHARMACOKINETICS
Bioavailability
Oral: 87%
Volume of distribution (Vd)
14.3 L/Kg
Protein binding
93%
Elimination half-life
33 hours (range: 21-54 hours). Data from pooled, single dose pharmacokinetic studies
Time to peak (Tmax)
5-8 hours
Metabolism
Primarily hepatic (CYP1A2 & CYP2D6) UGT1A4 (Phase II glucuronide conjugation)
Excretion
Urine: 57% (7% unchanged)
Feces: 30%
Special populations
Renal impairment: no dosage adjustment required for patients with severe renal impairment (CrCl < 30 mL/min)
Hepatic impairment: impaired live function in patients with cirrhosis had little effect on pharmacokinetic parameters.
MORE INFORMATION
Special Populations
Renal impairment: no dosage adjustment required
Hepatic impairment: consider lower dose
Cardiac impairment: use with caution
Elderly: use with caution
Children and adolescents: as with other antidepressants and antidepressant augmentation strategies, careful evaluation of risks vs. benefits and close monitoring for changes in behaviour and/or suicidality are recommended
Other Potential Benefits
Antipsychotic
Augmentation of antidepressant effect in major depressive disorder
DRUG-DRUG INTERACTIONS
Potential for Other Drugs to Affect Olanzapine
CYP1A2 Inducers: Agents that induce CYP1A2 such as omeprazole may increase clearance of olanzapine.
CYP1A2 Inhibitors: Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin or ketoconazole. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Cigarette smoke (polycyclic aromatic hydrocarbons) induces CYP1A2 and may: 1) reduce the plasma concentration of olanzapine, 2) reduce the half-life of olanzpine (by as much as 20-40%), and 3) increase the clearance of olanzapine (by as much as 33%). Dosage modifications not routinely recommended but smokers may require higher doses for efficacy. Use caution if patient stops smoking as level of olanzapine will increase.
Potential for Olanzapine to Affect Other Drugs
Drugs metabolized via P450-CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A: In in vitro studies with human microsomes, olanzapine showed little potential to inhibit cytochromes P450- CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A . Olanzapine is thus unlikely to cause clinically important drug-drug interactions mediated through the metabolic routes outlined above. However, the possibility that olanzapine may alter the metabolism of other drugs, or that other drugs may alter the metabolism of olanzapine, should be considered when prescribing olanzapine.