BE CAREFUL WITH CONCOMINANT USE OF ANTIDEPRESSANTS AND TAMOXIFEN

February 9, 2010 — Paroxetine and fluoxetine should not be prescribed for depression or hot flashes in women who have had breast cancer and are now taking tamoxifen to prevent a recurrence. Citalopram or venlafaxine should be considered instead.

This message comes from a new study showing that paroxetine, by interfering with the metabolism of tamoxifen, reduces or abolishes its protective effect against breast cancer recurrence, and that women taking both drugs have an increased risk for death from breast cancer. Paroxetine is a strong inhibitor of the CYP2D6 enzyme that converts tamoxifen to its active metabolite, reducing the amount of active drug that is released.

"We found that women with breast cancer who received paroxetine in combination with tamoxifen were at increased risk of death from breast cancer and death from any cause," say the researchers, led by Catherine Kelly, MD, medical oncology fellow at the Sunnybrook Health Sciences Center in Toronto, Ontario. The increase in risk was directly related to the extent of coprescribing, they note.

"These results highlight a drug interaction that is extremely common, widely underappreciated, potentially life-threatening, yet uniformly avoidable," they add.

The study, published online February 8 in the British Medical Journal, provides the "first evidence of a clinical effect of long-term CYP2D2 inhibition during tamoxifen treatment," according to an accompanying editorial.

There have been suggestions of this, but the data were inconclusive. Two studies presented at last year's annual meeting of the American Society of Clinical Oncology reported contradictory results; nevertheless, the message to clinicians was to avoid coprescribing the selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluoxetine in patients taking tamoxifen.

This is also the message in the BMJ editorial, authored by Frank Andersohn, MD, and Stefan Willich, MD, from the Institute for Social Medicine, Epidemiology and Health Economics at Charité University Medical Center, in Berlin, Germany.

In light of these findings, clinicians treating depression or hot flashes in women who are taking tamoxifen should avoid prescribing strong CYP2D6-inhibiting SSRIs, such as paroxetine and fluoxetine, and consider instead drugs with low potential to inhibit CYP2D6, such as citalopram or venlafaxine, they write.

In patients on tamoxifen who are already taking paroxetine or fluoxetine, a switch to another antidepressant with no or low inhibition of CYP2D6 should be considered, they add. But there is no justification for "abrupt discontinuation" of paroxetine or fluoxetine, they report. "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)," they note.

The study showed an effect on the risk for breast cancer death only with paroxetine, not with fluoxetine, although it, too, is a strong inhibitor of CYP2D6. The authors speculate that this is due to the low number of women taking fluoxetine in this study. The editorialists note that the further study is needed but, in the meantime, "for safety reasons, the coprescription of fluoxetine and tamoxifen in women with breast cancer should be avoided until additional evidence becomes available."

Study Shows Increase in Deaths From Breast Cancer

The study reported by the Canadian researchers was retrospective and population based, and initially analyzed data from 24,430 women over a 13-year period (1993 to 2005). These women were 66 years or older, living in Ontario, and were taking tamoxifen after a diagnosis of breast cancer. Of these women, 7489 (30.6%) received at least 1 antidepressant during the time they were taking tamoxifen. Because some women were excluded from the study — for reasons such as poor adherence to tamoxifen and death from unknown causes — there were 2430 women in the primary analysis.

Most of these women started taking tamoxifen within a year of their breast cancer diagnosis, and the median duration of tamoxifen treatment was 4 years.

The most commonly prescribed antidepressant was paroxetine (in 25.9% of women), followed by sertraline (22.3%), citalopram (19.2%), venlafaxine (15%), fluoxetine (10.4%), and fluvoxamine (7.2%). Older cyclic antidepressants were prescribed in 18.3% of women.

By the end of follow-up (mean, 2.38 years), a total of 1074 women (44.2%) had died; breast cancer was recorded as the cause of death in 374 women (15.4%).

"In the primary analysis, we found an increased risk of death from breast cancer among women who received paroxetine, an irreversible CYP2D6 inhibitor, in combination with tamoxifen," the authors write.

By contrast, no such risk was seen with the other antidepressants, they note.

"The choice of antidepressant can significantly affect survival in women receiving tamoxifen for breast cancer," Dr. Kelly and colleagues note.

We estimate that the use of paroxetine in 41% of those receiving tamoxifen treatment (the median overlap in our sample) would result in 1 additional breast cancer death within 5 years of the discontinuation of tamoxifen for every 19.7 patients so treated," they explain.

"The risk with more extensive overlap would be greater," they add.

Absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with an increase of 25%, 54%, and 91%, respectively, in the risk for death from breast cancer, the researchers report. Each comparison was statistically significant (P < .05).

"The increased risk was directly related to the extent of coprescribing and is consistent with the hypothesis that irreversible CYP2D6 inhibition by paroxetine can reduce or abolish the survival advantage conferred by long-term tamoxifen therapy in patients with breast cancer," the researchers write.

"Our findings are consistent with an emerging body of literature indicating the critical role of CYP2D6 in metabolic activation and clinical effectiveness of tamoxifen," they add. Among the papers cited are several by Mathew Goetz, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, who have been vocal about how testing for CYP2D6 can identify women who are poor metabolizers of tamoxifen and who are therefore likely to respond less well to the drug. However, a recent editorial in the Journal of Clinical Oncology suggested that the data to date are not clear enough for routine use of such testing; it did agree, however, that the use of drugs that are known to inhibit CYP2D6 are be avoided in women taking tamoxifen.

The editorialists and all of the authors except for 1 have disclosed no relevant financial relationships. Kathleen Pritchard, MD, from Sunnybrook Health Sciences Center, reports acting as a consultant and receiving research funding from several pharmaceutical companies, as detailed in the paper.

BMJ. Published online February 9, 2010.