Olandus 5/Olandus 10: Given the primary CNS effects of Olanzapine, caution should be used when Olanzapine tablets are taken in combination with other centrally acting drugs and alcohol. Because of its potential for inducing hypotension, Olanzapine tablets may enhance the effects of certain antihypertensive agents. Olanzapine may antagonize the effects of levodopa and dopamine agonists. The metabolism of Olanzapine is mediated to some extent by the cytochrome P450 isozyme CYP1A2. Concomitant administration of drugs which inhibit or act as a substrate to this isozyme may affect plasma concentrations of Olanzapine. The clearance of Olanzapine is increased by tobacco smoking.
Olandus ODT 15: Given the primary central nervous system effects of Olanzapine, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. As it exhibits in vitro dopamine antagonism, Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Caution should be exercised when Olanzapine is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval.
Potential for other medicines to affect Olanzapine: Single-doses of antacids (containing aluminium and magnesium) or cimetidine do not affect the oral bioavailability of Olanzapine. The concomitant administration of activated charcoal reduces the oral bioavailability of Olanzapine by 50 to 60%.
Fluoxetine (60 mg single dose or 60 mg daily for 8 days) caused a 16% increase in the maximum plasma concentration of Olanzapine and a 16% decrease in Olanzapine clearance. The magnitude of this is small in comparison to the overall variability between individuals and therefore dose modification is not routinely recommended.
The metabolism of Olanzapine may be induced by concomitant smoking (the clearance of olanzapine is 33% lower and the terminal elimination half-life is 21% longer in non-smokers compared to smokers) or carbamazepine therapy (clearance is increased 44% and the terminal elimination half-life is reduced by 20% when administered with carbamazepine). Smoking and carbamazepine therapy induce P450-1A2 activity. The pharmacokinetics of theophylline, which is metabolised by P450-1A2, is not altered by olanzapine.
Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of Olanzapine. This results in a mean increase in Olanzapine Cmax following fluvoxamine of 54% in female non-smokers and 77% in male smokers. The mean increase in Olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine or any other P450-1A2 inhibitor, such as ciprofloxacin.
Potential for Olanzapine to affect other medicines: In clinical trials with single doses of olanzapine, no inhibition of the metabolism of imipramine/ desipramine (P450-2D6, P450- 3A or P450-1A2), warfarin (P450-2C19), theophylline (P450-1A2) or diazepam (P450-3A4 and P450-2C19) was evident. Olanzapine showed no interaction when coadministered with lithium or biperiden. The in vitro ability of Olanzapine to inhibit metabolism by five principle cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 mcM), 2C9 (751 mcM), 1A2 (36 mcM), 2C19 (920 mcM), 2D6 (89 mcM) that compared to Olanzapine plasma concentrations of approximately 0.2 mcM, would mean maximum inhibition of these P450 systems by Olanzapine would be less than 0.7%. The clinical relevance of these findings is unknown.
Steady state concentrations of Olanzapine had no effect on the pharmacokinetics of ethanol (45 mg/70 kg). However, additive pharmacological effects such as increased sedation may occur when ethanol is ingested together with Olanzapine.
Studies in vitro using human liver microsomes showed that Olanzapine has little potential to inhibit the major metabolic pathway of valproate, which is glucuronidation. Further, valproate was found to have little effect on the oxidative metabolism of Olanzapine in vitro. Daily concomitant in vivo administration of 10 mg Olanzapine for 2 weeks did not affect steady state plasma concentrations of valproate. Therefore, concomitant Olanzapine administration does not require dosage adjustment of valproate.