Interaction of serotonin reuptake inhibitors with tamoxifen

In reply to Dr Jenkinson: Our(1) and previous(2-5) recommendations to
avoid co-prescribing of fluoxetine and tamoxifen are not based on a
hypothesis alone, as indicated by Dr. Jenkinson, but on the growing amount
of evidence suggesting a central role of cytochrome P450 2D6 (CYP2D6)
activity for tamoxifen efficacy. A marked reduction in the plasma
concentrations of endoxifen during co-treatment with the strong CYP2D6
inhibitors paroxetine or fluoxetine has been demonstrated.(6,7) A recent
study on genetically determined variation in CYP2D6 activity also
indicated the importance of an unimpaired CYP2D6 metabolism for tamoxifen
efficacy.(8) The increased risk of death from breast cancer during co-
treatment with paroxetine reported by Kelly et al.(9) is in line with
these findings. If a drug needs bioactivation via CYP2D6, it is reasonable
to avoid co-treatment with all strong inhibitors of this enzyme until
their safe concurrent use has been demonstrated. In the study of Kelly et
al.(9) and in the case control study cited by Dr. Jenkinson,(10) the
confidence intervals of the risk estimates for fluoxetine were wide and
thus did not exclude a clinically relevant increase in risk. In the light
of these data, a "presumption of innocence" with respect to fluoxetine
seems inappropriate and may cause inacceptable harm. Instead, convincing
evidence for the safe concurrent use of fluoxetine and tamoxifen is needed
before current recommendations(1-5) need revision.

References

(1) Andersohn F, Willich SN. Interaction of serotonin reuptake
inhibitors with tamoxifen. BMJ 2010; 340:c783.

(2) Consortium on Breast Cancer Pharmacogenomics. Drug-Interactions
With Tamoxifen - A Guide for Breast Cancer Patients and Physicians.
http://medicine.iupui.edu/clinpharm/COBRA/Tamoxifen and 2D6v7.pdf.

(3) Desmarais JE, Looper KJ. Interactions between tamoxifen and
antidepressants via cytochrome P450 2D6. J Clin Psychiatry 2009;
70(12):1688-1697.

(4) Henry NL, Stearns V, Flockhart DA, Hayes DF, Riba M. Drug
interactions and pharmacogenomics in the treatment of breast cancer and
depression. Am J Psychiatry 2008; 165(10):1251-1255.

(5) National Institute for Health and Clinical Excellence. Early and
locally advanced breast cancer: diagnosis and treatment (Clinical
guideline 80). London: NICE; 2009.

(6) Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A et al.
Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen
metabolism: implication for optimization of breast cancer treatment. Clin
Pharmacol Ther 2006; 80(1):61-74.

(7) Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P
et al. Active tamoxifen metabolite plasma concentrations after
coadministration of tamoxifen and the selective serotonin reuptake
inhibitor paroxetine. J Natl Cancer Inst 2003; 95(23):1758-1764.

(8) Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M,
Winter S et al. Association between CYP2D6 polymorphisms and outcomes
among women with early stage breast cancer treated with tamoxifen. JAMA
2009; 302(13):1429-1436.

(9) Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin
PC et al. Selective Serotonin Reuptake Inhibitors and Breast Cancer
Mortality in Women Receiving Tamoxifen: A Population-Based Cohort Study.
BMJ 2010.

(10) Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL. No
increase in breast cancer recurrence with concurrent use of tamoxifen and
some CYP2D6-inhibiting medications. Cancer Epidemiol Biomarkers Prev 2009;
18(9):2562-2564.

Competing interests:
FA declared no competing interests. SNW served as a consultant for Sanofi-aventis.