Olanzapine and Warfarin Interaction
Olanzapine does not interact with warfarin and can be safely used together without dose adjustments or additional INR monitoring beyond standard care. 1
Evidence from FDA Drug Labeling
The FDA-approved prescribing information for olanzapine explicitly addresses this combination:
- Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics 1
- Single doses of olanzapine did not affect the pharmacokinetics of warfarin 1
- In vitro studies demonstrate that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A, making it unlikely to cause clinically important drug interactions mediated by these enzymes 1
Mechanistic Rationale
The lack of interaction is explained by the metabolic pathways involved:
- Warfarin is primarily metabolized by CYP2C9 (for the more potent S-enantiomer) and CYP3A4 (for the R-enantiomer) 2
- Olanzapine does not inhibit or induce CYP2C9, the critical enzyme for warfarin metabolism 1
- Unlike other psychotropics that potentiate warfarin (quetiapine, valproic acid, SSRIs), olanzapine lacks CYP450 inhibitory effects 2
Contrast with Other Psychotropics
It is important to distinguish olanzapine from other psychotropic medications that DO interact with warfarin:
- SSRIs more than double the risk of bleeding when combined with warfarin, particularly fluvoxamine and fluoxetine which inhibit CYP2C9 2, 3, 4
- Quetiapine potentiates warfarin via CYP450 enzyme inhibition 2
- Valproic acid increases warfarin effects through CYP450 inhibition 2
Clinical Management Recommendations
When prescribing olanzapine to patients on warfarin:
- No warfarin dose adjustment is required when initiating or discontinuing olanzapine 1
- Continue standard INR monitoring as per usual warfarin management protocols; no additional monitoring is needed specifically for this combination 1
- Be aware of orthostatic hypotension risk from olanzapine, which may be relevant if the patient is also taking antihypertensive medications 1
Important Caveats
While olanzapine itself does not interact with warfarin, clinicians should remain vigilant about:
- Other concurrent medications that may interact with warfarin, as polypharmacy increases bleeding risk 5, 6
- NSAIDs (including COX-2 inhibitors) double the bleeding risk and should be avoided in warfarin-treated patients 2, 7
- Acetaminophen doses >2g/day significantly increase INR by an average of 0.7 within 3 days 2, 8
- Antimicrobials (particularly azoles, macrolides, and quinolones) significantly increase INR and bleeding risk 2, 7