NEW YORK (Reuters Health) – Use of paroxetine during tamoxifen therapy reduces the breast cancer survival benefit by 25% or more depending on the amount of time the drugs are used together, according to a report in the February 9th Online First issue of BMJ.

Prior research has shown that by blocking cytochrome P450 2D6, paroxetine can reduce the metabolism of tamoxifen to its active form. However, “there have been no previous studies examining mortality, and most of what is published involves surrogate outcomes or small sample sizes,” study co-author Dr. David N. Juurlink, from Sunnybrook Health Sciences Center, Toronto, told Reuters Health by email.

According to the report, there is no evidence that paroxetine has any direct effect on the clinical course of breast cancer. Rather, it simply makes tamoxifen less effective than it otherwise would be. Thus, a paroxetine user on tamoxifen is still likely to fare better than one not taking tamoxifen, although this was not the focus of the current study.

Use of other selective serotonin reuptake inhibitors (SSRIs) did not affect breast cancer mortality in tamoxifen users. Exactly why this was the case for fluoxetine, which is also a strong inhibitor of cytochrome P450 2D6, is unclear and will require further study.

The take-home message is that if an SSRI is needed in a woman who will be using tamoxifen, there are better choices than paroxetine, such as venlafaxine and citalopram, Dr. Juurlink said. He emphasized, however, that tamoxifen users already taking paroxetine “should absolutely not stop paroxetine suddenly based on these results.”

The findings stem from a cohort study of 2430 women living in Ontario, Canada, who were 66 years of age or older and were treated with tamoxifen between 1993 and 2005. The median age in the year before tamoxifen was started was 74 years. At some point during tamoxifen therapy, each woman was also treated with a single SSRI, including paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram, or venlafaxine (a serotonin-norepinephrine reuptake inhibitor).

During a mean follow-up period of 2.38 years, 374 women (15.4%) died from breast cancer.

On multivariate analysis, the duration of overlap between tamoxifen and paroxetine use was directly related to the risk of death from breast cancer. As the proportion of time with overlap increased from 25% to 50% and 75%, the relative risk of death from breast cancer climbed from 24% to 54% and 91%, respectively (p < 0.05 for each).

The authors calculate that if paroxetine were used during 41% of the course of tamoxifen therapy — the median overlap period in the study — then one extra breast cancer death would occur within 5 years of stopping tamoxifen for every 19.7 patients treated.

Furthermore, using paroxetine for 100% of the time on tamoxifen would result in one extra death for every 6.9 treated patients, compared to a setting in which the two drugs overlapped for only 1% of the time.

As noted, overlap with other SSRIs and tamoxifen did not seem to influence breast cancer mortality.

Dr. Frank Andersohn, co-author of an accompanying editorial, told Reuters Health by email that the findings are consistent with the known drug interactions between tamoxifen and paroxetine. However, “it remains unclear how to interpret the rather unexpected finding of no increased risk for fluoxetine. For safety reasons, it seems safer also to avoid fluoxetine in combination with tamoxifen.”

“It seems important to further study the impact of concurrent treatment with fluoxetine. If the finding of an increased risk with paroxetine, but not with fluoxetine, is replicated in additional studies, one should further try to identify the reasons for this heterogeneity,” according to Dr. Andersohn, a senior research associate with Charite University Medical Centre, Berlin.

Reference:
BMJ 2010.