Letrozole Warning Called 'Knee-Jerk' Reaction

American and Canadian fertility experts have expressed surprise and disappointment about new warnings concerning the aromatase inhibitor letrozole and its off-label use in fertility treatment.

“This is a knee-jerk reaction without a proper review of the data,” said Dr. Kutluk Oktay, referring to the Swiss company Novartis Pharmaceuticals' letter to health care professionals in Canada and the United States warning that the drug may be associated with congenital anomalies. Letters are also planned for all other countries where the drug is available, said a company spokesperson.

Novartis markets letrozole under the name Femara for the treatment of breast cancer. But worldwide the drug is used off label for ovulation induction, and has replaced clomiphene citrate in many intrauterine insemination programs because of its superior pregnancy success rates and ability to decrease gonadotropin requirements. Additionally, it is one of the only safe options for breast cancer patients wishing to undergo in vitro fertilization with ovarian stimulation to freeze embryos prior to their cancer therapy.

Although Femara's label has always stated a contraindication in premenopausal women because of “the potential for maternal and fetal toxicity,” Novartis' renewed concerns about the drug's use in fertility treatment arose after a small, unpublished Canadian study was presented at the recent conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society, said company spokesperson Kim Fox.

Dr. Marinko M. Biljan, medical director of the Montreal Fertility Clinic, reported that among his patients, letrozole, used at the 5-mg dose for ovulation induction, was associated with an increased rate of serious fetal anomalies.

“We stopped using it at our center in September and we hope others will stop using it, at least at this dose,” Dr. Biljan said in an interview.

An analysis of 150 babies born at his clinic after letrozole therapy (5 mg daily on days 3–7) found a 4.7% rate of major anomalies compared with a 1.8% rate in a control group of more than 36,000 babies born at a local “low-risk” hospital. As a result of this study, Novartis subsequently reviewed its safety database and found 13 reports of obstetric exposures to letrozole, of which 4 had adverse obstetric outcomes, said Fox.

Health Canada said three of the four adverse obstetric outcomes occurred in women who were exposed to letrozole as a result of infertility treatment, and the fourth exposure was a result of breast cancer treatment in the first and second trimesters of pregnancy. Two of the three infertility patients had spontaneous abortions, while the third gave birth to a baby who was diagnosed at 1 year with bilateral adrenal neuroblastoma, said Christopher Williams, a spokesman for Health Canada. The breast cancer patient who was exposed to letrozole during pregnancy gave birth to a female baby with a genital abnormality.

Novartis has not studied Femara as an infertility therapy and so cannot comment on this, said Fox. But “because there were some adverse events reported it is important that we remind physicians about the appropriate use and warnings about Femara, regarding not only pregnancy and lactation, but also premenopausal status,” she said.

Although the Food and Drug Administration is reviewing the matter, Health Canada has endorsed the Novartis warning. But several fertility experts with extensive experience using letrozole say the matter has been blown way out of proportion.

“There is a growing body of literature supporting the use of aromatase inhibitors in infertility therapy and the peer-reviewed literature is expected to support its continued use,” said Roger Pierson, Ph.D., professor of obstetrics, gynecology, and reproductive sciences at the University of Saskatchewan, Saskatoon.

“The study reported by Dr. Biljan et al. has done more harm than good as the conclusions are not supported by appropriate data,” he said. Dr. Robert Casper, one of the pioneers of letrozole in the treatment of infertility, said the Biljan study is seriously flawed because it has an inappropriate control group. “It compares young fertile with older infertile women,” said Dr. Casper, professor of obstetrics and gynecology at the University of Toronto.

“An infertile control group would be more valid and the Canadian IVF database for last year showed an overall anomaly rate of 2.6% in over 1,600 deliveries. Using this number, Dr. Biljan's relative risk numbers would be quite a bit lower,” he said. In addition, most of the major anomalies detected in the study's control group would have been referred to specialists prenatally and thus would not have shown up as adverse outcomes in the final analysis, he said.

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

American and Canadian fertility experts have expressed surprise and disappointment about new warnings concerning the aromatase inhibitor letrozole and its off-label use in fertility treatment.

“This is a knee-jerk reaction without a proper review of the data,” said Dr. Kutluk Oktay, referring to the Swiss company Novartis Pharmaceuticals' letter to health care professionals in Canada and the United States warning that the drug may be associated with congenital anomalies. Letters are also planned for all other countries where the drug is available, said a company spokesperson.

Novartis markets letrozole under the name Femara for the treatment of breast cancer. But worldwide the drug is used off label for ovulation induction, and has replaced clomiphene citrate in many intrauterine insemination programs because of its superior pregnancy success rates and ability to decrease gonadotropin requirements. Additionally, it is one of the only safe options for breast cancer patients wishing to undergo in vitro fertilization with ovarian stimulation to freeze embryos prior to their cancer therapy.

Although Femara's label has always stated a contraindication in premenopausal women because of “the potential for maternal and fetal toxicity,” Novartis' renewed concerns about the drug's use in fertility treatment arose after a small, unpublished Canadian study was presented at the recent conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society, said company spokesperson Kim Fox.

Dr. Marinko M. Biljan, medical director of the Montreal Fertility Clinic, reported that among his patients, letrozole, used at the 5-mg dose for ovulation induction, was associated with an increased rate of serious fetal anomalies.

“We stopped using it at our center in September and we hope others will stop using it, at least at this dose,” Dr. Biljan said in an interview.

An analysis of 150 babies born at his clinic after letrozole therapy (5 mg daily on days 3–7) found a 4.7% rate of major anomalies compared with a 1.8% rate in a control group of more than 36,000 babies born at a local “low-risk” hospital. As a result of this study, Novartis subsequently reviewed its safety database and found 13 reports of obstetric exposures to letrozole, of which 4 had adverse obstetric outcomes, said Fox.

Health Canada said three of the four adverse obstetric outcomes occurred in women who were exposed to letrozole as a result of infertility treatment, and the fourth exposure was a result of breast cancer treatment in the first and second trimesters of pregnancy. Two of the three infertility patients had spontaneous abortions, while the third gave birth to a baby who was diagnosed at 1 year with bilateral adrenal neuroblastoma, said Christopher Williams, a spokesman for Health Canada. The breast cancer patient who was exposed to letrozole during pregnancy gave birth to a female baby with a genital abnormality.

Novartis has not studied Femara as an infertility therapy and so cannot comment on this, said Fox. But “because there were some adverse events reported it is important that we remind physicians about the appropriate use and warnings about Femara, regarding not only pregnancy and lactation, but also premenopausal status,” she said.

Although the Food and Drug Administration is reviewing the matter, Health Canada has endorsed the Novartis warning. But several fertility experts with extensive experience using letrozole say the matter has been blown way out of proportion.

“There is a growing body of literature supporting the use of aromatase inhibitors in infertility therapy and the peer-reviewed literature is expected to support its continued use,” said Roger Pierson, Ph.D., professor of obstetrics, gynecology, and reproductive sciences at the University of Saskatchewan, Saskatoon.

“The study reported by Dr. Biljan et al. has done more harm than good as the conclusions are not supported by appropriate data,” he said. Dr. Robert Casper, one of the pioneers of letrozole in the treatment of infertility, said the Biljan study is seriously flawed because it has an inappropriate control group. “It compares young fertile with older infertile women,” said Dr. Casper, professor of obstetrics and gynecology at the University of Toronto.

“An infertile control group would be more valid and the Canadian IVF database for last year showed an overall anomaly rate of 2.6% in over 1,600 deliveries. Using this number, Dr. Biljan's relative risk numbers would be quite a bit lower,” he said. In addition, most of the major anomalies detected in the study's control group would have been referred to specialists prenatally and thus would not have shown up as adverse outcomes in the final analysis, he said.

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

American and Canadian fertility experts have expressed surprise and disappointment about new warnings concerning the aromatase inhibitor letrozole and its off-label use in fertility treatment.

“This is a knee-jerk reaction without a proper review of the data,” said Dr. Kutluk Oktay, referring to the Swiss company Novartis Pharmaceuticals' letter to health care professionals in Canada and the United States warning that the drug may be associated with congenital anomalies. Letters are also planned for all other countries where the drug is available, said a company spokesperson.

Novartis markets letrozole under the name Femara for the treatment of breast cancer. But worldwide the drug is used off label for ovulation induction, and has replaced clomiphene citrate in many intrauterine insemination programs because of its superior pregnancy success rates and ability to decrease gonadotropin requirements. Additionally, it is one of the only safe options for breast cancer patients wishing to undergo in vitro fertilization with ovarian stimulation to freeze embryos prior to their cancer therapy.

Although Femara's label has always stated a contraindication in premenopausal women because of “the potential for maternal and fetal toxicity,” Novartis' renewed concerns about the drug's use in fertility treatment arose after a small, unpublished Canadian study was presented at the recent conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society, said company spokesperson Kim Fox.

Dr. Marinko M. Biljan, medical director of the Montreal Fertility Clinic, reported that among his patients, letrozole, used at the 5-mg dose for ovulation induction, was associated with an increased rate of serious fetal anomalies.

“We stopped using it at our center in September and we hope others will stop using it, at least at this dose,” Dr. Biljan said in an interview.

An analysis of 150 babies born at his clinic after letrozole therapy (5 mg daily on days 3–7) found a 4.7% rate of major anomalies compared with a 1.8% rate in a control group of more than 36,000 babies born at a local “low-risk” hospital. As a result of this study, Novartis subsequently reviewed its safety database and found 13 reports of obstetric exposures to letrozole, of which 4 had adverse obstetric outcomes, said Fox.

Health Canada said three of the four adverse obstetric outcomes occurred in women who were exposed to letrozole as a result of infertility treatment, and the fourth exposure was a result of breast cancer treatment in the first and second trimesters of pregnancy. Two of the three infertility patients had spontaneous abortions, while the third gave birth to a baby who was diagnosed at 1 year with bilateral adrenal neuroblastoma, said Christopher Williams, a spokesman for Health Canada. The breast cancer patient who was exposed to letrozole during pregnancy gave birth to a female baby with a genital abnormality.

Novartis has not studied Femara as an infertility therapy and so cannot comment on this, said Fox. But “because there were some adverse events reported it is important that we remind physicians about the appropriate use and warnings about Femara, regarding not only pregnancy and lactation, but also premenopausal status,” she said.

Although the Food and Drug Administration is reviewing the matter, Health Canada has endorsed the Novartis warning. But several fertility experts with extensive experience using letrozole say the matter has been blown way out of proportion.

“There is a growing body of literature supporting the use of aromatase inhibitors in infertility therapy and the peer-reviewed literature is expected to support its continued use,” said Roger Pierson, Ph.D., professor of obstetrics, gynecology, and reproductive sciences at the University of Saskatchewan, Saskatoon.

“The study reported by Dr. Biljan et al. has done more harm than good as the conclusions are not supported by appropriate data,” he said. Dr. Robert Casper, one of the pioneers of letrozole in the treatment of infertility, said the Biljan study is seriously flawed because it has an inappropriate control group. “It compares young fertile with older infertile women,” said Dr. Casper, professor of obstetrics and gynecology at the University of Toronto.

“An infertile control group would be more valid and the Canadian IVF database for last year showed an overall anomaly rate of 2.6% in over 1,600 deliveries. Using this number, Dr. Biljan's relative risk numbers would be quite a bit lower,” he said. In addition, most of the major anomalies detected in the study's control group would have been referred to specialists prenatally and thus would not have shown up as adverse outcomes in the final analysis, he said.

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