Drug products: Arkolamyl, Olanzapin Actavis, Olanzapin Bluefish, Olanzapin Ebb, Olanzapin Lilly, Olanzapin Orifarm, Olanzapin Orion, Olanzapin Ranbaxy, Olanzapin Sandoz, Olanzapin STADA, Olanzapin SUN, Olanzapine Accord, Olanzapine Glenmark, Olanzapine Glenmark Europe, Olanzapine Mylan, Olanzapine Teva, Zalasta®, Zyprexa®, Zyprexa® Velotab
ATC code: N05AH03
A lower starting dose should be considered for women as pharmacokinetic data show lower clearance of olanzapine in women.
An observational study found that older demented men treated with olanzapine developed Parkinsonism twice as often as old, demented women with the same treatment.
One study has shown the risk of women having vertigo as an adverse event is higher than for men.
The lowest effective dose should always be considered and a lower starting dose should be considered in women.
The pharmacokinetics of single-dose olanzapine differ from steady state conditions. A pooled analysis of two single-dose randomized cross-over bioequivalence trials in healthy Caucasian volunteers (33 men, 30 women) reported no sex differences in pharmacokinetics after adjusting for weight . In addition to this, a single-dose randomized cross-over study of 5 mg olanzapine in healthy volunteers (10 men, 10 women) found no sex differences in pharmacokinetics of olanzapine .
In contrast to these two studies and an unpublished company research file, a single-dose study (44 men, 5 women) showed the half-life of olanzapine to be 12% longer in women than in men (36.7 h versus 32.3 h) and the clearance to be 31% lower in women than in men (18.9 l/h versus 27.3 l/h). The authors stated that this is an effect of the slower drug metabolism through CYP1A2 isoenzymes in women .In a pooled analysis of two double-blind randomized clinical trials in patients with schizophrenia or Alzheimer’s disease (total 332 men, 191 women) men had a 27% higher clearance of olanzapine than women .
In a therapeutic drug monitoring (TDM) study in patients with schizophrenia or other psychoses (77 men, 44 women) men had 35% lower concentration/dose ratio than women at steady state conditions . In a retrospective TDM study in patients with schizophrenia, affective disorders or dementia (39 men, 28 women) men had 55% lower concentration/dose ratio or 34% lower weight-corrected concentration/dose ratio than women .In retrospective TDM study at steady state in pediatric psychiatric patients age 10-21 years (74 boys, 48 girls) girls had higher olanzapine/N-desmethyl-olanzapine ratio and concentration/dose ratio for 2-OH-olanzapine. The ratio between olanzapine and the inactive metabolites is correlated to the lower clearance of olanzapine in girls .In a pharmacokinetic fixed dose study, patients with treatment-resistant schizophrenia (20 men, 7 women) were treated with 25 mg olanzapine daily during 8 weeks. Steady state was reached by three and five weeks in men and women, respectively. Women had higher plasma concentrations of olanzapine, 63% and 85% after five and eight weeks, respectively. In this study 71% of the women and 10% of the men had plasma concentrations > 50 ng/ml . Suggested therapeutic interval is 20-40 ng/mL and there is some evidence that adverse effects are more likely above 80 ng/mL .
According to the manufacturer’s Prescribing Information the recommended starting dose is 5-10 mg and in some populations, e.g. nonsmoking women ≥65 years of age, recommended starting dose is 5 mg and dose escalation should be performed with caution .
A double blind randomized parallel clinical trial in 1336 patients with schizophrenia and treatment with olanzapine 5-20 mg/day over a 14 month period reported no differences in drug efficacy between men and women .
In a randomized double-blind parallel clinical trial during 6 weeks in patients with schizophrenia treated with olanzapine (868 men on daily dose 14.1 mg, 467 women on daily dose 12.5 mg) women had a better treatment response after four to five weeks than men (Brief Psychiatric Rating Scale total scores). Premenopausal women had better treatment response than postmenopausal women regardless of chronicity .
In a prospective observational study of patients with schizophrenia (2528 men, 1861 women) treatment response measured by physicians as Clinical Global Impression showed no difference between men and women. However, the women reported greater improvements in quality of life (EQ-VAS) [16, 17].
A randomized double-blind parallel clinical trial during 14 months in 1336 patients with schizophrenia treated with olanzapine 5-20 mg/day showed no clinically sex differences in prolactin elevation or weight change . In contrast to this, a randomized, double-blind clinical trial of patients with schizophrenia (870 men, 467 women) treated with either 13.2 mg olanzapine/day or haloperidol during 6 weeks men on olanzapine had a greater increase in weight (+2,2 kg) and BMI (+0.7) than women on olanzapine (weight +1.6 kg, BMI +0.6) .
Two single-dose pharmacokinetic studies in healthy volunteers (total 62 men, 58 women) showed that women had 33-37% higher prolactin Cmax increase from baseline and 46-47% higher prolactin AUC increase from baseline than men respectively [4, 19].In a randomized clinical trial of patients with schizophrenia (24 men, 26 women) treated with 10 mg olanzapine during four weeks women had a more pronounced prolactin elevation than men. Premenopausal (16) and postmenopausal women (8) had similar plasma concentrations of the drug as well as of prolactin .In a clinical trial in Japanese drug-naïve schizophrenic patients (10 men, 10 women) treated with olanzapine women had a greater increase in plasma prolactin levels than men 8 weeks after initiation of olanzapine treatment .A pooled analysis of four single-dose pharmacokinetic phase I clinical trials in healthy volunteers (29 men, 28 women) showed that women carrying the DRD2 A1+receptor gene had a higher increase in prolactin compared to baseline in Cmax and AUC .
A pooled analysis of two single-dose randomized cross-over bioequivalence trials of 5 mg olanzapine in healthy Caucasian volunteers (33 men, 30 women) showed that women had a higher frequency of dizziness than men (40% vs. 12%). There was no sex difference in QT prolongation 2 h and 5 h after dosing . A retrospective observational cohort study of 51,878 elderly patients with dementia treated with risperidone, quetiapine, or olanzapine found men to have an overall 2.3 times higher risk than women for developing Parkinsonism in all treatment groups. The most pronounced sex difference in hazard ratio for developing Parkinsonism was found in the high dose quetiapine group .In a clinical trial patients with early psychosis were randomized to treatment with olanzapine (101 men, 32 women), quetiapine (92 men, 42 women), or risperidone (99 men, 34 women) during 52 weeks. Men in all treatment groups were more likely than women to increase in BMI and weight after 12 and 52 weeks of treatment . This is in contrast to the findings from a prospective analysis of a randomized, double-blind, placebo-controlled trial in elderly patients with Alzheimer’s disease (186 men, 235 women). In this study, women treated with olanzapine, quetiapine, risperidone, or placebo during 36 weeks showed an increase in BMI while men did not .In a randomized controlled study in patients with psychotic depression (93 men, 166 women) during 12 weeks treatment with a mean dose of olanzapine 14.3 mg daily showed that men had lower total cholesterol (−16.4 mg/dl), HDL and LDL levels (−10.4 mg/dl) than women .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
In an eight week clinical trial of twenty female schizophrenia patients with menstrual disturbances, galactorrhea and/or sexual dysfunction switching from risperidone to olanzapine lowered prolactin serum concentration and improved menstrual and sexual functioning .
In a single-dose clinical trial healthy volunteers (7 men, 6 women) received 10 mg olanzapine. In women but not in men, sleep latency, actual sleep time and slow wave sleep increased while the relative amount of REM-sleep decreased which indicates that the effective dose olanzapine to induce sleep may be lower in women . A similar result has been found in another study .
Date of litterature search: 2015-05-03
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson