Use of Certain Antidepressants can increase RISK
An important new study finds that certain popular antidepressants frequently prescribed to women taking the breast cancer drug tamoxifen more than double the risk of a breast cancer recurrence for those using both medications. The research presented by Medco Health Solutions, Inc.(NYSE:MHS) and Indiana University School of Medicine at the 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO) is the largest study to date looking at how these drugs impact breast cancer recurrence rates when taken with tamoxifen.
The antidepressants at issue are three widely used selective serotonin reuptake inhibitors (SSRIs), Prozac® (fluoxetine), Paxil® (paroxetine) and Zoloft® (sertraline), and are among a group of drugs known as CYP2D6 inhibitors. Antidepressants are often prescribed with tamoxifen to treat depression – a common co-morbidity of the disease, as well as hot flashes – a common side-effect of the breast cancer drug.
The three drugs that pose this risk for women on tamoxifen are considered to be moderate to potent CYP2D6 inhibitors. Several other SSRIs examined in the study that are weak CYP2D6 inhibitors did not raise breast cancer recurrence risks for patients using them along with tamoxifen. Those SSRIs included Celexa® (citalopram), Lexapro® (escitalopram) and Luvox® (fluvoxamine).
“We’ve known that these CYP2D6 inhibitor drugs block the activation of tamoxifen chemically, but this is the first time there’s evidence that these drugs are putting women at a much higher risk for recurrent breast cancer,” said Dr. Robert Epstein, Medco’s chief medical officer and one of the study researchers. “It’s also the first time that a comparative analysis has been done looking at various SSRIs and what’s clear is that several of these drugs are extremely risky for women to take with tamoxifen, while others don’t present a problem.”
This study advances prior research which has shown that the active form of tamoxifen, called endoxifen, is found in far lower levels in the blood stream when CYP2D6 inhibitor drugs are present, and it is the first study to show the comparative impact of various antidepressants on breast cancer recurrence.
“While we expected to see some impact on the disease recurrence rate based on already existing evidence, what is remarkable is that the effect is consistent with the pharmacologic potency of these antidepressants as CYP2D6 inhibitors. This lends biological plausibility to the data,” added Dr. David Flockhart, chief of clinical pharmacology at Indiana University School of Medicine and a member of the research team.
The study was a retrospective analysis of almost 1,300 women who were newly prescribed tamoxifen to treat breast cancer between 2003 and 2005 and were monitored for at least two years, with the average being 2.7 years. All study patients had to be at least 70 percent compliant on their medication, while, on average compliance was 90 percent throughout the study period. The median length of time that patients used both Tamoxifen and a CYP2D6 inhibitor concurrently was 255 days.
The analysis first looked at two different cohorts, one with 353 women, about 27 percent of the study sample, who were taking a moderate to potent CYP2D6 inhibitor in conjunction with tamoxifen which included but was not limited to antidepressants, and a group of 945 women on tamoxifen who were not taking any CYP2D6 inhibitor. The patients’ pharmacy and medical records were analyzed to determine the medications used and the incidence of a breast cancer recurrence. Comparisons were made between the cohorts using a CYP2D6 inhibitor and the group on tamoxifen only. The study found that women taking a moderate to strong CYP2D6 inhibitor had a two-year breast cancer recurrence rate of 13.9 percent, 1.9 times higher than the 7.5 percent recurrence rate of those only using tamoxifen.
Given that 60 percent of the women in the study on a CYP2D6 inhibitor were using an SSRI, the researchers examined a subset that included only those patients taking an SSRI and divided it into two cohorts, one that included 213 women on a moderate to potent CYPD2D6 inhibitor SSRI, and one made up of 137 women using a weak CYP2D6 inhibitor SSRI.
Results showed an even greater increase in the risk of a recurrence among those taking a moderate to potent CYP2D6 inhibitor SSRI as compared to the initial analysis. These women had a rate of breast cancer recurrence of 16 percent, 2.2 times higher than women only taking tamoxifen. Patients using SSRIs that are weak CYP2D6 inhibitors had a disease recurrence rate of 8.8 percent and were not at any increased risk for the disease.
“Since the majority of women using a CYP2D6 inhibitor was taking an SSRI, we felt it was incumbent upon us to look specifically at that drug class,” said Epstein. “What we found is that the choice of which SSRI is prescribed could make a huge difference in whether there’s a recurrence of the disease. That’s very important information for breast cancer patients and their physicians.”
Tamoxifen is one of the oldest and most widely used treatments for reducing the risk of breast cancer recurrence among women with estrogen-dependent tumors. The drug works by blocking the estrogen receptors in the breast cells and can reduce the risk of a breast cancer recurrence by up to 50 percent. It’s the only anti-estrogen available for prevention of breast cancer recurrence in pre-menopausal women and is one of several anti-estrogens used to treat post-menopausal breast cancer patients. Approximately 500,000 women take tamoxifen in the U.S., with 80,000 new patients starting on the treatment annually. Nearly 30 percent of women taking tamoxifen also use an antidepressant.
While evidence has been mounting that CYP2D6 inhibitors can reduce the effectiveness of tamoxifen, many physicians treating breast cancer patients are still unaware of the problem or may not know that their patient has been prescribed a strong inhibiting antidepressant by another physician. In an effort to ensure that women get the full benefit of tamoxifen, Medco has been alerting physicians when a patient has been prescribed both tamoxifen and a moderate or potent CYP2D6 inhibitor antidepressant.
For more information about the study, visit www.medcoresearch.com
Presented at American Society for Clinical Oncology, May/June 2009
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