Does trazodone increase the risk of bleeding?

Does Trazodone Increase Risk of Bleeding?

Trazodone can increase the risk of bleeding, particularly when used with anticoagulants or antiplatelet medications, as explicitly stated in the FDA drug label.

Mechanism and Evidence

The FDA drug label for trazodone clearly states that "drugs that interfere with serotonin reuptake inhibition, including Trazodone Hydrochloride Tablets, increase the risk of bleeding events" 1. This warning is included in the official prescribing information, making it a high-priority consideration in clinical practice.

The mechanism behind this increased bleeding risk appears to be related to serotonin reuptake inhibition. According to the FDA label, bleeding events associated with drugs that interfere with serotonin reuptake can range from minor manifestations (ecchymosis, hematoma, epistaxis, petechiae) to life-threatening hemorrhages 1.

Interaction with Anticoagulants

The interaction between trazodone and warfarin is particularly noteworthy:

• A case series published in the Annals of Pharmacotherapy documented clinically significant interactions between trazodone and warfarin 2
• In this series, initiation of trazodone led to decreased PT/INR values, while discontinuation led to increased PT/INR values 2
• The 2022 guidelines on drug interactions affecting oral anticoagulant use mention that trazodone may induce CYP450 enzymes, potentially requiring higher doses of warfarin to maintain therapeutic INR 3

This interaction is particularly concerning because it could lead to subtherapeutic anticoagulation, increasing thrombotic risk when trazodone is added, or excessive anticoagulation with bleeding risk when trazodone is discontinued.

Clinical Recommendations

When prescribing trazodone:

1. Inform patients about bleeding risk when using trazodone with antiplatelet agents or anticoagulants 1
2. Monitor coagulation indices carefully when initiating, titrating, or discontinuing trazodone in patients taking warfarin 1
3. Avoid using trazodone on an as-needed basis in patients receiving warfarin due to the difficulty in maintaining therapeutic anticoagulation 2
4. Consider alternative antidepressants in patients at high risk for bleeding or those on multiple antithrombotic medications

Special Considerations

High-Risk Populations

Patients at particularly high risk for bleeding complications when taking trazodone include:

• Those on dual antiplatelet therapy or anticoagulants
• Elderly patients
• Patients with history of GI bleeding
• Those concurrently using NSAIDs
• Patients with hepatic or renal impairment

Monitoring Recommendations

For patients on trazodone and anticoagulants:

• More frequent INR monitoring when starting or stopping trazodone
• Vigilance for signs of bleeding (bruising, epistaxis, melena, hematuria)
• Consideration of dose adjustments for anticoagulants when trazodone therapy changes

Conclusion

While trazodone may have advantages over tricyclic antidepressants in terms of cardiovascular side effects and safety in overdose 4, 5, its effect on bleeding risk through serotonin reuptake inhibition and potential drug interactions with anticoagulants should not be overlooked. Clinicians should be aware of this risk and take appropriate precautions when prescribing trazodone, particularly in patients already on antithrombotic therapy.