Tamoxifen with Terbinafine Interaction Details

Brand Names Associated with Tamoxifen

Brand Names Associated with Terbinafine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Jan 04, 2024

Interaction Effect

Decreased plasma concentrations of the active metabolites of tamoxifen

Interaction Summary

Terbinafine is a moderate CYP2D6 inhibitor and tamoxifen is a prodrug metabolized to active metabolites by CYP450 enzymes. Although not studied with terbinafine, concomitant use of tamoxifen and CYP2D6 inhibitors may affect tamoxifen efficacy by inhibiting the formation of endoxifen, an active metabolite of tamoxifen . CYP2D6 drug interactions may result in variations in endoxifen concentrations, which may affect tamoxifen side effects and may reduce its antitumoral efficacy and increase the risk of breast cancer relapse . A retrospective analysis revealed a 1.9-fold higher breast cancer recurrence rate in patients receiving a CYP2D6 inhibitor concomitantly with tamoxifen than those receiving tamoxifen alone . However, one small case control study found that pharmacokinetic alterations in tamoxifen metabolism did not significantly increase tumor recurrence in breast cancer patients .

Severity

Moderate

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Coadministration of tamoxifen and paroxetine, an inhibitor of CYP2D6, has resulted in decreased plasma concentrations of 4-hydroxy-N-desmethyl tamoxifen, an active metabolite of tamoxifen. As terbinafine is classified as a moderate CYP2D6 inhibitor , monitoring for decreased tamoxifen efficacy with coadministration may be necessary.

Mechanism Of Interaction

Inhibition of CYP2D6-mediated tamoxifen metabolism

Literature Reports

A) The use of CYP2D6 inhibitors should be avoided in breast cancer patients receiving tamoxifen due to the risk of substantially reduced plasma concentrations of the antiestrogenic tamoxifen metabolite, endoxifen. In a prospective randomized trial, 256 postmenopausal breast cancer patients receiving tamoxifen were genotyped and grouped according to CYP2D6 metabolism and medication history. Adjusted analysis showed that decreased metabolizers (n=65) had significantly worse relapse-free survival (hazard ratio 1.74; 95% confidence interval (CI), 1.1 to 2.74; p=0.017), disease-free survival (hazard ratio 1.6; 95% CI, 1.06 to 2.43; p=0.027), and shorter time to recurrence (hazard ratio 1.91; 95% CI, 1.05 to 3.45; p=0.034) compared with extensive metabolizers (n=115). The greatest risk of breast cancer relapse was found in the poor metabolizer group (hazard ratio 3.12; 95% CI, 1.37 to 7.55; p=0.007) . Decreased metabolizers had either one or two CYP2D6*4 alleles or was receiving a CYP2D6 inhibitor together with tamoxifen (regardless of genotype), and extensive metabolizers did not have a *4 allele and were not receiving a CYP2D6 inhibitor .

B) A retrospective analysis of breast cancer patients revealed a 1.9-fold higher 2-year recurrence rate of breast cancer in patients receiving concomitant therapy with tamoxifen and a CYP2D6 inhibitor compared with those receiving tamoxifen therapy alone. Based on medical and pharmacy claims data, 1928 patients who were new to tamoxifen therapy in a 30-month period and who had follow-up data for at least 24 months were included in the analysis. Among these patients, 353 (median age, 53 years) received tamoxifen concurrently with a CYP2D6 inhibitor and 945 (median age, 52 years) received tamoxifen alone. Disease recurrence was identified by diagnosis and insurance billing codes for mastectomy, lumpectomy, lymph node dissection, or radiation therapy, occurring at least 6 months after initiation of tamoxifen therapy. The 2-year breast cancer recurrence rate was 13.9% in women receiving concomitant tamoxifen and CYP2D6 inhibitor therapy compared with 7.5% in women receiving tamoxifen alone (95% CI, 1.33 to 2.76, p=0.001; hazard ratio, 1.92). Intervention procedures in the tamoxifen/CYP2D6 inhibitor group to treat breast cancer included mastectomy (54%), lumpectomy (36%), and radiation therapy (47%); corresponding intervention rates in the tamoxifen only group were 52%, 38%, and 46%, respectively .

C) A case control study (n=28) designed to evaluate the effect of CYP isoform inhibitors on therapeutic outcome in women taking tamoxifen for estrogen receptor-positive breast cancer found no significant impact on breast cancer recurrence from chronic exposure (3 months or greater) to CYP2D6, 2C9, or 3A4 inhibitors or substrates. Cases (recurrences of breast cancer) and controls (patients without recurrent breast cancer) were matched by cancer stage, year of diagnosis, and CYP inhibitor or substrate exposure. Selective serotonin reuptake inhibitors, including paroxetine, are inhibitors of CYP2D6, 2C9, and 3A isoforms responsible for the metabolism of tamoxifen to the potent antiestrogen 4-hydroxy metabolite . As selective serotonin and norepinephrine reuptake inhibitors are also inhibitors of CYP2D6, similar results could be expected.

D) 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 statistically significantly lower in those with a CYP2D6 homozygous variant genotype (20 nM; 95% CI, 11.1 to 28.9) or a heterozygous genotype (43.1 nM; 95% CI, 33.3 to 52.9) than those with a homozygous wild-type genotype (78 nM; 95% CI, 65.9 to 90.1; both p=0.003). 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, 95% CI of difference, -86.1 to -19.5; p=0.0025). 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 .

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.

Terbinafine Overview

• Terbinafine granules are used to treat fungal infections of the scalp. Terbinafine tablets are used to treat fungal infections of the toenails and fingernails. Terbinafine is in a class of medications called antifungals. It works by stopping the growth of fungi.

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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.