Data back letrozole's safety for ovulation induction.
The findings contradict a report presented at last year's conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society suggesting that the aromatase inhibitor could cause serious fetal anomalies when used off-label for ovulation induction.
Novartis, which markets the drug as Femara for the treatment of breast cancer, issued global warnings to health care professionals about the potential for embryo and fetus toxicity.
"The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data," wrote Dr. Togas Tulandi and Dr. Robert F. Casper, professors of obstetrics and gynecology at McGill University in Montreal and the University of Toronto, respectively. Both physicians pioneered the use of the drug for ovulation induction.
The Canadian team examined the rates of congenital malformations among 911 newborns of women who conceived using either clomiphene citrate (n = 397) or letrozole (n = 514) and compared them with known malformation rates in the general population (Fertil. Steril. 2006;doi:10.1016/j.fertnstert.2006.03.014).
There were no significant differences among the malformation rates in the letrozole group (2.4%), the clomiphene citrate group (4.8%), and the general population (2%-3%). Congenital cardiac anomalies appeared to be less common in the letrozole-treated group (0.2%) than in the clomiphene group (1.8%).
Dr. Marinko M. Biljan of the Montreal Fertility Center previously found a significantly higher rate of major fetal anomalies among 150 babies conceived with letrozole (4.7%), than among babies of 36,000 control patients (1.8%) (ASRM 2005 abstract #0-231).
Dr. Tulandi and his colleagues wrote, "We believe there were several methodologic problems with the ASRM abstract as presented that led to an erroneous conclusion."
It was "an apples-and-oranges comparison, because there are always fewer birth defects in children conceived spontaneously," he said. Also, there is no biologic plausibility for the drug causing birth defects, coauthor Dr. Casper said in an interview. "With the short half-life of letrozole, it should be completely cleared before implantation."
In response, Dr. Biljan reiterated his opinion that letrozole is teratogenic for ovulation induction. "I personally received numerous messages from Femara-treated individuals expressing their personal accounts of similar malformations," he said in an interview.
The Novartis warning has been endorsed by Health Canada, but the U.S. Food and Drug Administration has not yet followed suit. Yet even with the new data, few fertility doctors will feel comfortable using the drug, Dr. Tulandi said. "We still can't use it. Physicians use a lot of off-label drugs. But when someone specifically advises you against it, it becomes a legal issue."
Dr. Tulandi remains hopeful that physicians might successfully appeal to Novartis. "I hope the company reads our paper and reconsiders their stand on this," he said in an interview.
Novartis spokesperson Kim Fox said that the company stands by its warning. "Femara is classified as Pregnancy Category D and is not indicated for the induction of ovulation," according to a statement posted on the company's Web site for health care professionals (www.oncologymedicalservices.com).
Dr. Casper has a licensing agreement with Ares-Serono for the use of aromatase inhibitors for ovulation induction; the company markets clomiphene. Dr. Tulandi reported no financial conflicts of interest.
BY KATE JOHNSON
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|Publication:||Internal Medicine News|
|Date:||Jun 15, 2006|
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