Interaction of serotonin reuptake inhibitors with tamoxifenBMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c783 (Published 09 February 2010) Cite this as: BMJ 2010;340:c783
- Frank Andersohn, senior research associate,
- Stefan N Willich, professor and director
- 1Institute for Social Medicine, Epidemiology, and Health Economics, Charité University Medical Centre, 10098 Berlin, Germany
Tamoxifen has an established role in the treatment of hormone receptor positive invasive breast cancer.1 Evidence has emerged in recent years that the main pharmacological effects of tamoxifen are not mediated by the parent drug itself but by an active metabolite called endoxifen (4-hydroxy-N-desmethyltamoxifen).2 The bioactivation of tamoxifen to endoxifen is mainly catalysed by the cytochrome P450 isoenzyme 2D6 (CYP2D6).2 Certain drugs inhibit the activity of CYP2D6, and this results in decreased plasma concentrations of endoxifen.2 3
In the linked observational study (doi:10.1136/bmj.c693), Kelly and colleagues show that the risk of breast cancer related death is higher in women taking tamoxifen plus the selective serotonin reuptake inhibitor (SSRI) paroxetine. The authors suggest that this is explained by inhibition of CYP2D6.4
SSRIs are prescribed for women with breast cancer who are taking tamoxifen for two main reasons. Firstly, to treat depression or anxiety, and, secondly, to reduce hot flushes, which are a common side effect of tamoxifen. Some SSRIs such as paroxetine are strong inhibitors of CYP2D6. It is reasonable to suggest that concomitant use of these drugs attenuates the clinical effectiveness of tamoxifen, but observational data supporting this hypothesis were lacking until now.
Kelly and colleagues used data from a healthcare record database in Ontario, Canada, to evaluate the clinical consequences for women with breast cancer who were treated with both tamoxifen and an SSRI. They selected a cohort of women who were at least 66 years old, who were newly treated with tamoxifen for breast cancer between 1993 and 2005, and who received a single SSRI during tamoxifen treatment. They found that the risk of death from breast cancer increased with the length of concomitant treatment with paroxetine, but not with other SSRIs. For example, if women used paroxetine for 41% of the time that they took tamoxifen, one additional death from breast cancer occurred within five years of stopping tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) women treated.
This finding is in accordance with what might be expected because of the strong CYP2D6 inhibiting properties of paroxetine, and it provides the first evidence of a clinical effect of long term CYP2D6 inhibition during tamoxifen treatment. Previous observational studies that looked for an increased risk of the recurrence of breast cancer after the concomitant use of CYP2D6 inhibitors and tamoxifen failed to identify increased risks, but they were limited by low statistical power,5 6 7 or they focused on a weaker CYP2D6 inhibitor.8
How should clinicians treat depression or hot flushes in women who take tamoxifen in the light of these findings? The straightforward answer is to avoid prescribing strong CYP2D6 inhibiting SSRIs (such as paroxetine or fluoxetine) for women with breast cancer who are prescribed tamoxifen, and to consider instead drugs with low potential to inhibit CYP2D6 (such as citalopram or venlafaxine).9 A switch to an antidepressant with low or no CYP2D6 inhibitory activity should be considered in patients who are already treated with tamoxifen and paroxetin or fluoxetine. In the rare case that the patient cannot tolerate other SSRIs or did not respond to them in the past, switching tamoxifen to an aromatase inhibitor might be an option in postmenopausal women.9 Importantly, however, Kelly and colleagues’ study does not justify abrupt discontinuation of the antidepressants fluoxetine or paroxetine. The potential longer term benefits of discontinuing their use do not yet clearly outweigh the potential adverse effects of immediate withdrawal of effective SSRI treatment (such as recurrence of severe depression).10
The clinical effects of CYP2D6 related drug interactions with tamoxifen need further study. Two yet unpublished cohort studies on the risk of breast cancer recurrence that were presented at the 2009 meeting of the American Society of Clinical Oncology (ASCO) showed conflicting results. One study from the Netherlands reported no increased risk of recurrence with concomitant CYP2D6 inhibitor use,11 whereas an American study found that the risk of breast cancer recurrence roughly doubled in two years if CYP2D6 inhibitors were used together with tamoxifen.12 The reasons for the different findings should be evaluated after full publication.
In Kelly and colleagues’ study, concurrent use of the strong CYP2D6 inhibitor fluoxetine was not associated with increased risk of death from breast cancer.4 The authors speculate that this might result from the low number of women exposed to fluoxetine in their cohort, which suggests that the effects of concomitant use of fluoxetine and tamoxifen need to be studied further. Their findings also need to be reproduced in other populations because residual confounding from other drugs, disease severity, or comorbidity cannot be reliably excluded. For safety reasons, coprescription of fluoxetine and tamoxifen in women with breast cancer should be avoided until additional evidence becomes available.
At present, information contained in different summaries of product characteristics of tamoxifen and paroxetine is not consistent. According to the electronic Medicines Compendium, three manufacturers in the United Kingdom are currently marketing products that contain tamoxifen. Two of them list the possibility of reduced tamoxifen efficacy caused by concurrent use of CYP2D6 inhibitors, whereas one does not. In Germany, 13 companies make tamoxifen, and nine of them report a potential interaction via CYP2D6, whereas four do not. Similarly, the summary of product characteristics for most products that contain paroxetine in the UK and Germany do not yet mention explicitly an interaction with tamoxifen, even though a pharmacokinetic study showed the interaction in 2003.3 Promotion of the paroxetine-tamoxifen drug interaction among doctors and pharmacists and harmonisation of the summary of product characteristics are needed.
Cite this as: BMJ 2010;340:c783
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: (1) No financial support for the submitted work from anyone other than their employer; (2) SNW did consultancy for Sanofi-Aventis but FA declares no financial relationships with commercial entities that might have an interest in the submitted work; (3) FN and SNW have no spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; and (4) they have no non-financial interests that may be relevant to the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.