What is the risk of bleeding associated with Duloxetine (Cymbalta)?

From the Guidelines

Duloxetine (Cymbalta) is associated with an increased risk of bleeding, particularly when used with anticoagulants.

Key Points

• The recommended dosage of Duloxetine is 20-30 mg once daily, with a maximum dosage of 120 mg/d 1.
• The increased bleeding risk is a precaution that needs to be considered when prescribing Duloxetine, especially in patients taking anticoagulants 1.
• Other precautions include the risk of serotonin syndrome and withdrawal syndromes with abrupt discontinuation, as well as caution with hepatic failure 1.
• It is essential to carefully weigh the benefits and risks of Duloxetine in patients with a history of bleeding or those taking anticoagulants, and to monitor them closely for signs of bleeding 1.

From the FDA Drug Label

Drugs that interfere with serotonin reuptake inhibition, including duloxetine delayed-release capsules, may increase the risk of bleeding events. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine delayed-release capsules. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk.

Increased Risk of Bleeding — Caution patients about the concomitant use of duloxetine delayed-release capsules and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding

abnormal bleeding: Duloxetine delayed-release capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

The risk of bleeding associated with Duloxetine (Cymbalta) includes:

• Gastrointestinal bleeding
• Postpartum hemorrhage
• Ecchymoses
• Hematomas
• Epistaxis
• Petechiae
• Life-threatening hemorrhages This risk may be increased with concomitant use of:
• Aspirin
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Warfarin
• Other anti-coagulants Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine delayed-release capsules and these agents 2, 2.

From the Research

Risk of Bleeding Associated with Duloxetine

The risk of bleeding associated with duloxetine (Cymbalta) has been evaluated in several studies.

• A study published in 2013 3 found that the combination of duloxetine and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a statistically significantly higher incidence of bleeding-related treatment-emergent adverse events (TEAEs) compared with duloxetine alone.
• Another study published in 2019 4 found that serotonin reuptake inhibitors (SRIs), including duloxetine, increase the risk of bleeding by 1.16- to 2.36-fold, and that the risk is synergistic between SRIs and NSAIDs.
• A study published in 2014 5 found that duloxetine was detected in 34 cases of death, and that many of these deaths involved the concomitant use of numerous other medications, including NSAIDs, antipsychotics, and benzodiazepines.

Factors Influencing Bleeding Risk

Several factors can influence the risk of bleeding associated with duloxetine, including:

• Concomitant use of NSAIDs: The combination of duloxetine and NSAIDs has been shown to increase the risk of bleeding-related TEAEs 3, 4.
• Dose of duloxetine: One study found that there was no significant difference in the incidence of bleeding-related TEAEs between patients treated with duloxetine 60 mg once daily and those treated with 120 mg once daily 3.
• Use of other medications: The use of other medications, such as antipsychotics and benzodiazepines, may also increase the risk of bleeding-related TEAEs 5.

Management of Bleeding Risk

To manage the risk of bleeding associated with duloxetine, clinicians should:

• Be aware of the risk of bleeding with SRI use, especially for patients taking NSAIDs 4.
• Consider alternative antidepressants with low or no affinity for the serotonin transporter, such as bupropion or mirtazapine, for patients at risk of bleeding 4.
• Educate patients about the risk of bleeding and the importance of monitoring for signs of bleeding 4.