An epidemiological study suggests that paroxetine significantly reduces the effects of tamoxifen by inhibiting its conversion to an active metabolite; other strong inhibitors of cytochrome P450 (CYP) 2D6, including some other SSRI, may have similar effects.
Tamoxifen is highly effective in the treatment of breast cancer, however it is now known that it acts as a prodrug and its effects are due to conversion to active metabolites: the most important of these is endoxifen. The conversion relies mainly on CYP2D6, thus drugs that inhibit this enzyme could potentially reduce the efficacy of tamoxifen (which is also reduced in the 7% of so of the population who lack the functional enzyme). The most widely used drugs that inhibit CYP2D6 are some of the SSRI antidepressives: this population-based retrospective cohort study aimed to determine whether use of any SSRI concurrently with tamoxifen affected its efficacy.
The study population was identified using healthcare databases from Ontario, Canada, and comprised female residents who were aged over 65 and who started tamoxifen therapy for the first time between January 1993 and December 2005 inclusive. Follow-up was up to December 2007 or death. Those who were prescribed a single SSRI antidepressive or venlafaxine during tamoxifen treatment were identified, and their outcomes were evaluated according to time on SSRI therapy. Primary outcome was breast cancer mortality; all-cause mortality was a secondary outcome.
Over the study period, there were 24,430 women who started taking tamoxifen; 7,489 (30.6%) were prescribed an antidepressive drug and 2,430 of these were available for analysis after exclusions (received no SSRI or multiple SSRI, had poor tamoxifen adherence, or unknown cause of death). Most started tamoxifen within a year of breast cancer diagnosis, at a median age of 74 years, and median duration of use was 4.0 years. Paroxetine was the SSRI most commonly prescribed, followed by sertraline, citalopram, venlafaxine, fluoxetine, and fluvoxamine.
By the end of the follow-up period, 1,024 (44.2%) had died, with breast cancer recorded as the primary cause of death in 374 (15.4%). Those taking paroxetine concurrently with tamoxifen had an increased risk of death: after adjustment for confounding factors, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen that overlapped with use of paroxetine were associated with relative increases of 24%, 54%, and 91% in the risk of death from breast cancer, respectively. There was no significant increase in risk of death due to breast cancer associated with use of any other SSRI.
Secondary analysis including death from any cause also showed an increased risk of death associated with increasing duration of concurrent tamoxifen and paroxetine use, which persisted when those women whose cause of death was unknown were included. In both these analyses, no significant increase in risk was seen in association with use of other SSRI.
The authors conclude that concurrent use of paroxetine and tamoxifen is associated with an increased risk of death, directly related to duration of overlapping use. They suggest that this is consistent with the hypothesis that paroxetine can reduce or abolish the metabolic activation of tamoxifen via inhibition of CYP2D6. They note that paroxetine, unlike some other compounds, is an irreversible CYP2D6 inhibitor. The study has some limitations, but the authors suggest that these were unlikely to negate the results. They also note the lack of observed effect with fluoxetine, a known strong inhibitor of CYP2D6: they comment that this may have been due to the small numbers on this drug, and emphasise that it should not be taken to conclude safety with fluoxetine.
An accompanying editorial discusses the study: the authors conclude that it would support avoidance of paroxetine and fluoxetine in women taking tamoxifen, and suggest that prescribing information needs to be amended accordingly. Patients should be started on or switched to an antidepressive with a low potential to inhibit CYP2D6, although they emphasise that abrupt discontinuation is not justified. They comment that further study is needed to reproduce the findings and clarify the interaction.