Dr. Casper has reviewed his experience with more than 200 letrozole births and found no major congenital anomalies—which is “much below the expected rate” even in the general population, he said. Nevertheless, his clinic has stopped using letrozole as a result of the Novartis warning.
“Unfortunately this is going to negatively impact physicians and patients,” said Dr. Oktay, of Cornell University, New York. Dr. Biljan believes the discrepancy between his results and those of others could be explained by his use of a higher than normal dose of letrozole (the more common dose is 2.5 mg daily on days 3–7).
Regardless of dose, both Dr. Oktay and Dr. Casper said that the short half-life of letrozole makes it biologically implausible that the drug could cause anomalies, since it is discontinued before conception occurs.
However, according to the FDA, “although the terminal elimination half-life is said to be 2 days, steady state is not reached for 2–6 weeks—and steady-state levels are maintained over extended periods.”
Dr. Oktay said one would expect fetal exposure to letrozole to result in abnormal sexual development. Indeed, Novartis's one record of second trimester exposure did result in a child with genital abnormalities. But the cases resulting from preconceptual exposure (two spontaneous abortions and one bilateral neuroblastoma) are not obviously drug related, and in some cases could be explained by factors related to infertility, he suggested. Similarly, in Dr. Biljan's study, none of the adverse outcomes were related to abnormal sexual development.
The short half-life of letrozole makes it biologically implausible that the drug could cause anomalies. DR. OKTAY