Venlafaxine Lowers Endoxifen Levels, Reduces Tamoxifen Effectiveness

Caroline Helwick

March 2013, Highlights - Clinical Research


The antidepressant venlafaxine (Effexor) is often prescribed to patients with breast cancer who are taking tamoxifen (Nolvadex) to help reduce the side effect of hot flashes. But according to research presented at the meeting, venlafaxine may reduce the effectiveness of tamoxifen.

The findings came from a multicenter prospective pharmacologic study that looked at paired blood samples from 30 women who were taking tamoxifen for at least 4 weeks and were initiated treatment with venlafaxine for the treatment of hot flashes. Blood samples were taken before starting venlafaxine and 8 to 16 weeks afterward.

Genotyping was done for alleles associated with no, reduced, and ultrarapid metabolism. The goal was to determine whether venlafaxine altered the pharmacokinetics of tamoxifen and to determine the distribution of the cytochrome (CY) P2D6 metabolizers in this population.

CYP2D6 is the rate-limiting enzyme that is responsible for the metabolic activation of tamoxifen to endoxifen. Among women taking tamoxifen, those who are extensive metabolizers of CYP2D6 have higher endoxifen concentrations, have more vasomotor symptoms, and are more likely to discontinue tamoxifen compared with those who are poor metabolizers.

“The data regarding CYP2D6 genotype and cancer recurrence has been mixed,” said lead investigator Matthew P. Goetz, MD, an oncologist with the Mayo Clinic in Rochester, MN. “Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended for tamoxifen-induced hot flashes.”

The women with tamoxifen-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 extensive and ultrarapid metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Across all genetic subgroups, levels were depressed by a median of approximately 1.6 ng/mL over time (P = .04). Limited evidence suggests that at least 6 ng/mL is needed. In the study, 3 women with low CYP2D6 activity had levels drop below that.

Dr Goetz acknowledged that the amount of endoxifen that is needed for benefit is still unknown, and that the effect of venlafaxine on breast cancer outcomes remains unknown.

“The bottom line,” he said, “is that there is a decrease. It’s small, but it’s statistically significant. The question really is, ‘Are there subgroups of patients in which this is important?’”

Dr Goetz concluded that although the optimal concentration of endoxifen is currently unknown, “given previous data linking low endoxifen concen­trations with recurrence, ven­la­faxine should be used with caution in tamoxifen-treated patients.”

Hiltrud Brauch, DPhil, PhD, Deputy Head and Coordinator of the Oncology Program at the Dr Margarete Fischer-Bosch-Institute of Clinical Pharma­cology in Stuttgart, Germany, led a 2009 study showing that variations in CYP2D6 have an effect on disease-free and event-free survival in patients taking tamoxifen.

“Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers,” Dr Brauch said. “The long and the short of it is that this matters to women.”