Tamoxifen with Paroxetine Interaction Details

Brand Names Associated with Tamoxifen

Brand Names Associated with Paroxetine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Dec 18, 2023

Interaction Effect

Reduced tamoxifen and tamoxifen active metabolite exposure, reduced efficacy of tamoxifen and its active metabolite and an increased risk of QT interval prolongation

Interaction Summary

Coadministration of PARoxetine and tamoxifen decreases the plasma concentration of the major active metabolite of tamoxifen but large retrospective studies have reported conflicting clinical results, with either no significant impact of antidepressants, including PARoxetine, on the risk of subsequent breast cancer  or an increased risk of death from breast cancer with concomitant use of tamoxifen and PARoxetine, but not with other SSRIs . Therefore, when concomitant antidepressant therapy is necessary, alternatives to PARoxetine with little or no CYP2D6 inhibition should be considered .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Coadministration of PARoxetine and tamoxifen may decrease the plasma concentration of 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), the major active metabolite of tamoxifen and may reduce the clinical benefit of tamoxifen, particularly if used together over an extended time . When concomitant antidepressant therapy is necessary, consider alternatives to PARoxetine with little or no CYP2D6 inhibition .

Mechanism Of Interaction

Irreversible inhibition of CYP2D6-mediated tamoxifen metabolism; additive QT interval prolongation

Literature Reports

A) The risk of subsequent breast cancer was not significantly increased with concurrent use of antidepressants in a retrospective review of 16,887 insured women receiving tamoxifen for at least 6 months following a diagnosis of Stage 0 to II breast cancer. The median duration of tamoxifen use was 2.7 years. Of the 8089 patients who were prescribed antidepressants, the median days of overlap between antidepressant and tamoxifen use was 144 days. After a median follow-up of 6 years, 17.4% of all patients developed a subsequent breast cancer. Of the 10.6% of patients who received PARoxetine, 25%, 50%, and 75% increases in overlapping use during the first year of tamoxifen were associated with the highest increases in the risk of subsequent breast cancer (6%, 13%, and 20%, respectively), but these increases were not significant and diminished over time. FLUoxetine was the most common antidepressant prescribed (19.9%) and was associated with a 0%, 1%, and 3% nonsignificant increase in the risk of subsequent breast cancer for the corresponding 25%, 50%, and 75% increases in overlapping use during the first year of tamoxifen. Other agents tested were grouped into categories of other SSRIs, tricyclics, and other types that included venlafaxine, traZODone, buPROPion, and tetracyclics .

B) Results from a retrospective study demonstrated that concomitant use of PARoxetine and tamoxifen is associated with an increased risk of death from breast cancer that is directly related to the duration of concomitant therapy, while the risk is not increased with other SSRIs. Participants in the study included females at least 66 years old who were newly treated with tamoxifen for breast cancer and who also received a single SSRI antidepressant. Of the 2430 participants, 2025 initiated tamoxifen within 1 year of being diagnosed with breast cancer and the median duration of tamoxifen therapy was 4 years. PARoxetine was the most common SSRI prescribed (n=630) while others consisted of sertraline (n=541), citalopram (n=467), venlafaxine (n=365), FLUoxetine (n=253), and fluvoxaMINE (n=174). After a mean follow-up of 2.38 years, 374 women died of breast cancer. Absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen concomitantly with PARoxetine were associated with significant increases of 24%, 54%, and 91% in the risk of death from breast cancer, respectively. No other SSRI was associated with an increased risk of breast cancer mortality when administered during tamoxifen therapy .

C) Concomitant use of PARoxetine, a potent inhibitor of CYP2D6, and tamoxifen, which requires activation by CYP2D6 enzymes to the antiestrogenic metabolite (endoxifen), results in substantially reduced plasma concentrations of endoxifen. Eighty newly diagnosed breast cancer patients taking tamoxifen 20 mg/day were genotyped for the common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. After 1 and 4 months of tamoxifen treatment, plasma concentrations of tamoxifen and endoxifen were measured. After 4 months of tamoxifen, plasma endoxifen concentrations were significantly lower in those with a CYP2D6 homozygous variant genotype (20 nM) or a heterozygous genotype (43.1 nM) than those with a homozygous wild-type genotype (78 nM). The mean plasma endoxifen concentration for subjects with a homozygous wild-type genotype who were taking CYP2D6 inhibitors was 58% lower than those not taking such inhibitors (38.6 nM versus 91.4 nM). Concomitant use of venlafaxine, a weak inhibitor of CYP2D6, resulted in slightly reduced plasma concentrations of endoxifen, while the use of PARoxetine, a potent inhibitor of CYP2D6, resulted in substantial reductions in endoxifen concentrations. Plasma concentrations of tamoxifen and metabolites were not altered significantly by genetic variations of CYP2C9, CYP3A5 or SULT1A1 .

D) In a prospective clinical trial involving 12 women of known CYP2D6 genotype with breast cancer taking adjuvant tamoxifen, coadministration of PARoxetine decreased the plasma concentration of the tamoxifen active metabolite, endoxifen (4-hydroxy-N-desmethyl-tamoxifen). Each patient was maintained on tamoxifen 20 mg/day during treatment with PARoxetine 10 mg/day for 4 weeks. Plasma concentrations of endoxifen significantly decreased from a pre-PARoxetine mean of 12.4 ng/mL to 5.5 ng/mL after PARoxetine administration. When analyzed by genotype, reduced levels of endoxifen were more pronounced in women who carried the wild-type CYP2D6, while those with the variant genotype experienced no significant effect of PARoxetine on endoxifen levels .

Tamoxifen Overview

• Tamoxifen is used to treat breast cancer that has spread to other parts of the body in men and women. It is used to treat early breast cancer in women who have already been treated with surgery, radiation, and/or chemotherapy. It is used to reduce the risk of developing a more serious type of breast cancer in women who have had ductal carcinoma in situ (DCIS; a type of breast cancer that does not spread outside of the milk duct where it forms) and who have been treated with surgery and radiation. It is used to reduce the risk of breast cancer in women who are at high risk for the disease due to their age, personal medical history, and family medical history.

• Tamoxifen is in a class of medications known as antiestrogens. It blocks the activity of estrogen (a female hormone) in the breast. This may stop the growth of some breast tumors that need estrogen to grow.

Paroxetine Overview

• Paroxetine tablets, suspension (liquid), and extended-release (long-acting) tablets are used to treat depression, panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks), and social anxiety disorder (extreme fear of interacting with others or performing in front of others that interferes with normal life). Paroxetine tablets and suspension are also used to treat obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over), generalized anxiety disorder (GAD; excessive worrying that is difficult to control), and posttraumatic stress disorder (disturbing psychological symptoms that develop after a frightening experience). Paroxetine extended-release tablets are also used to treat premenstrual dysphoric disorder (PMDD, physical and psychological symptoms that occur before the onset of the menstrual period each month). Paroxetine capsules (Brisdelle) are used to treat hot flashes (sudden feelings of warmth, especially in the face, neck, and chest) in women who are experiencing menopause (stage of life when menstrual periods become less frequent and stop and women may experience other symptoms and body changes). Paroxetine is in a class of medications called selective serotonin-reuptake inhibitors (SSRIs). It treats depression and other mental illnesses by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance. There is not enough information available at this time to know how paroxetine works to treat hot flashes.

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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.