Amitriptyline and Fluoxetine Interaction
Drug interaction information between Amitriptyline and Fluoxetine.
Amitriptyline and Fluoxetine have a documented minor interaction in FDA labeling.
FDA drug labeling documents a minor-severity interaction between Amitriptyline and Fluoxetine. Major interactions are generally avoided, moderate ones may need monitoring or a dose adjustment, and minor ones are usually low-risk. This page shows the documented mechanism and guidance. Label-documented interactions are not a complete safety review, so always confirm your own medications with a pharmacist or doctor. Educational information, not medical advice.
How They Interact
Fluoxetine blocks the liver from breaking down amitriptyline and stays in the body for a very long time. This can cause amitriptyline levels to become too high even after you stop taking fluoxetine.
What To Do
You should wait at least five weeks after stopping fluoxetine before you start taking amitriptyline.
FDA Label Information
While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Amitriptyline Also Interacts With
- Risperidone major
- Sertraline minor
- Paroxetine minor
- Disulfiram minor
- Flecainide minor
Fluoxetine Also Interacts With
- Aspirin major
- Warfarin major
- Olanzapine major
- Pimozide major
- Thioridazine major
Frequently Asked Questions
Can I take Amitriptyline and Fluoxetine together?
This is a minor interaction. You should wait at least five weeks after stopping fluoxetine before you start taking amitriptyline.
How serious is the interaction between Amitriptyline and Fluoxetine?
This interaction is classified as "minor" severity by the FDA. Minor interactions are unlikely to cause significant problems but should still be mentioned to your healthcare provider.
Why do Amitriptyline and Fluoxetine interact?
Fluoxetine blocks the liver from breaking down amitriptyline and stays in the body for a very long time. This can cause amitriptyline levels to become too high even after you stop taking fluoxetine.
Understanding the Amitriptyline and Fluoxetine Interaction
FDA-approved prescribing information for these two drugs flags their combination as a minor-severity interaction. Amitriptyline belongs to the Tricyclic Antidepressant (TCA) class and Fluoxetine belongs to the Selective Serotonin Reuptake Inhibitor (SSRI) class - two categories that can collide when co-prescribed. The mechanism described in FDA labeling is: Fluoxetine blocks the liver from breaking down amitriptyline and stays in the body for a very long time. Severity tiers matter: major flags generally advise avoidance, moderate flags often require monitoring or dose adjustment, and minor flags may only call for awareness.
Context around a specific patient determines real-world impact. Amitriptyline has 21 total documented interactions on file in this dataset, and Fluoxetine has 68. Each additional medication compounds the interaction surface, which is why pharmacists run full-profile checks rather than evaluating one pair at a time. FDA-derived guidance for this pair is: You should wait at least five weeks after stopping fluoxetine before you start taking amitriptyline. Timing of doses, renal and hepatic function, age, and other concurrent prescriptions all shape whether a labeled interaction matters clinically.
An interaction flag is not a verdict. A large share of labeled interactions are managed routinely in clinical practice, the fix may be as simple as spacing doses or adding a monitoring test. Others require the prescriber to choose a different medication entirely. This page surfaces FDA-sourced labeling and openFDA data for educational purposes only; it is not medical advice and cannot account for your full clinical picture. Never start, stop, or adjust either Amitriptyline or Fluoxetine based on a web page, speak with your prescriber or pharmacist before making any change.
Sources: FDA Drug Labels (SPL) via openFDA (2026). This is for informational purposes only and is not medical advice. Always consult your healthcare provider about drug interactions.
Read our methodology - how this data is sourced, computed, and verified.