Fluoxetine with Clopidogrel Interaction Details

Brand Names Associated with Fluoxetine

Brand Names Associated with Clopidogrel

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 11, 2023

Interaction Effect

Reduced plasma concentrations of the active metabolite of clopidogrel and an increased risk of bleeding

Interaction Summary

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of clopidogrel and FLUoxetine (a moderate CYP2C19 inhibitor) may reduce clopidogrel active metabolite concentrations and reduce platelet inhibition. Additionally, concomitant use may increase the risk of bleeding, as the release of serotonin by platelets is important for maintaining hemostasis. If concomitant use is required, use caution . Consider treatment with an SSRI that is not a CYP2C19 inhibitor . In a meta-analysis, there was a significant 11% increased risk of ischemic events when coadministered .

Severity

Major

Onset

Unspecified

Evidence

Established

How To Manage Interaction

Use caution with the concomitant use of clopidogrel and FLUoxetine, as an increased risk of bleeding has been demonstrated with the concomitant use of some SSRIs and antiplatelet drugs. Concomitant use of clopidogrel and FLUoxetine also has the potential for reduced clopidogrel active metabolite concentrations and reduced platelet inhibition . Consider treatment with an SSRI that is not a CYP2C19 inhibitor, such as citalopram, escitalopram, PARoxetine, and sertraline .

Mechanism Of Interaction

Inhibition of CYP2C19-mediated clopidogrel metabolism to its active metabolite by FLUoxetine; additive effects on hemostasis

Literature Reports

A) Initiation of clopidogrel in patients receiving a CYP2C19-inhibiting SSRI (n=9281; 97.5% FLUoxetine; 2.5% fluvoxamine) resulted in a small but significant 12% increased risk of any ischemic event (95% CI, 1.01 to 1.24) compared with non-CYP2C19-inhibiting SSRIs (n=44,278) in a propensity-score matched cohort study. CYP2C19-inhibiting SSRIs were also associated with a significant 18% increased risk of a stent procedure, and at 17% increased risk of PTCA. In patients 65 years or older, there was a nonsignificant 22% increased risk of any ischemic event, a significant 39% increased risk of stenting, and a significant 38% increased risk of PTCA . Initiation of a CYP2C19-inhibiting SSRI (n=2350; 98% FLUoxetine; 2% fluvoxamine) in patients receiving clopidogrel resulted in a nonsignificant 7% (95% CI, 0.82 to 1.4) increased risk of any ischemic event compared with non-CYP2C19-inhibiting SSRIs (n=16,115) in a propensity-score matched cohort study. In a meta-analysis of pooled results regardless of the order of drug initiation, there was a significant 11% (95% CI, 1.01 to 1.22) increased risk of any ischemic event and no significant difference in the composite bleeding outcome .

B) SSRI use was associated with a significant 55% increase in the risk of developing an upper GI bleed according to a meta-analysis of 22 studies (6 cohort and 16 case-control studies, involving more than 1,073,000 patients). Subgroup analyses reported concurrent antiplatelet drug use resulted in a 2.48-fold increase in upper GI bleed risk. PARoxetine, sertraline, FLUoxetine, citalopram, and escitalopram significantly increased risk while fluvoxaMINE and venlafaxine did not. Using acid suppressing drugs may reduce this risk .

C) FLUoxetine reduced the pharmacological activity of clopidogrel in healthy volunteers in an open-label crossover study (N=8). The AUC and Cmax of the active metabolite of clopidogrel was 20.6% and 25.3% lower after coadministration of FLUoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values were 13.9% to 22.4% lower and the platelet reactivity index was 36.8% lower when clopidogrel was administered in conjunction with FLUoxetine. Overall, the antiplatelet effect of clopidogrel was decreased by approximately 25% .

D) Case reports and epidemiological studies (case-control and cohort studies) have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages .

Fluoxetine Overview

• Fluoxetine is used to treat depression, obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over), some eating disorders, and panic attacks (sudden, unexpected attacks of extreme fear and worry about these attacks). Fluoxetine is also used to relieve the symptoms of premenstrual dysphoric disorder, including mood swings, irritability, bloating, and breast tenderness. It is also used along with olanzapine (Zyprexa) to treat depression that did not respond to other medications and episodes of depression in people with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Fluoxetine is in a class of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.

Clopidogrel Overview

• Clopidogrel is used alone or with aspirin to prevent serious or life-threatening problems with the heart and blood vessels in people who have had a stroke, heart attack, or severe chest pain. This includes people who have percutaneous coronary intervention (PCI; angioplasty; a type of heart surgery) that may involve inserting coronary stents (metal tubes surgically placed in clogged blood vessels to improve blood flow) or who have coronary artery bypass grafting (CABG; a type of heart surgery). Clopidogrel is also used to prevent serious or life-threatening problems with the heart and blood vessels in people who have peripheral arterial disease (poor circulation in the blood vessels that supply blood to the legs). Clopidogrel is in a class of medications called antiplatelet medications. It works by preventing platelets (a type of blood cell) from collecting and forming clots that may cause a heart attack or stroke.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.