About Femara/Letrozole Safety for Ovulation Induction

I'm just starting to research the safety of Femara/Letrozole but I'll continue to update this post as I find out more. This summary from the ASRM 2005 Conference was interesting:


Biljan (Montreal, Canada) and colleagues[7] reported the results of a study of the births of 150 babies following treatment with the aromatase inhibitor letrozole. In this study, 5 mg of letrozole was given in all cycles analyzed. Perinatal outcome information over 36,000 deliveries from the same hospital was used to provide the control population. Maternal age and the proportion of multifetal deliveries (110 singleton and 20 twins) were higher in the letrozole group. Malformations were detected in 4.7% of the newborns in the letrozole group and in only 1.8% of the newborns in the control population. When the type of malformation was considered, locomotor, bone and cardiac malformations were more common following letrozole treatment.

The findings of this study are surprising, as until now no adverse perinatal effects had been reported with aromatase inhibitors. They were considered to be safe because they are used in only the early follicular phase and their half-life is short. Some points about this report need to be raised, however. The rate of malformations in the control group is lower than that usually observed. Several factors influence the rate of malformations, such as maternal age, the order of the pregnancy, gestational age at delivery, medication use during pregnancy, and maternal medical complications. One must make an effort to control for these factors during the analysis. Maternal age was higher in the study group and there were more multiple gestations. It is also known that the incidence of congenital malformations is higher following infertility treatment, so it would be better to compare the letrozole group to groups undergoing other types of infertility treatment. Still, the findings of this study should lead to more careful use of aromatase inhibitors for infertility management. Further studies need to evaluate the association between aromatase inhibitors (various doses) and congenital malformations.

More about the Highlights of the ASRM 2005 Conference

The half-life of Letrozole is about 2 days. This means that it takes about 2 days for the concentration of the drug to drop in one-half in the serum. In general, a drug will be completely eliminated in 5 half-lives. In the case of Letrozole, this is about 10 days. The pharmacokinetic studies which determined the half-life of the drug may not have been done in women of reproductive age as the drug was to be used in post-menopausal women. Thus it may be metabolized differently in younger women. In fact, two unknown metabolites are mentioned in the PDR which may have untoward biological activity. Most studies used Letrozole until about day 7 of the cycle. Thus, it is possible that the drug could still be in the system at the time of conception around day 14 or so if we assume it takes 5 half-lives to be completely excreted and potential metabolites exist that could have biological activity. Also, the half-life of a drug may be increased by increasing the dose of the drug. Some use Letrozole at 5.0 mg or 7.5 mg doses, potentially increasing the half-life of the drug. The dose in breast cancer patients is 2.5 mg per day. There is more to drug disposition than simply the half-life. The clearance of the drug is slow and the volume of distribution is approximately 2 L/kg, indicating that it is widely distributed in the body (2). This raises the possibility that the drug or its metabolites could be distributed to the ovary or uterus, organs vital for reproduction. Letrozole is mainly bound to albumin as a carrier protein in the blood. The PDR warns of fetal toxicity in rodent studies at doses of 0.003 mg/kg (about 1/100th the human dose) where increased intrauterine mortality, increased fetal resorption, increased post-implantation loss, decreased numbers of live fetuses, fetal anomalies fetal anomalies including shortening of the renal papilla and ureter dilation and incomplete ossification of the frontal skull and metatarsal. In rabbits, Letrozole was embryotoxic at doses of 1/100,000th and fetotoxic at doses 1/10,000th of the maximal recommended human dose. Thus, standard experimental models showed that Letrozole is toxic to the fetus. The PDR considers Letrozole to be a Category D drug in pregnancy (Positive evidence of fetal risk). Anytime a drug is Category D, the benefits must clearly outweigh the risks. Data on the health on the babies would certainly help to determine this. While the patients are not technically pregnant at the time they are taking the drug, can we be absolutely certain that it or one of its metabolites is no longer in the body especially given the low doses that are toxic in experimental animals?
From: Femara (Letrozole) as a Fertility Treatment: Potential Risks

AIs may be a viable option to replace CC in the
future as the new primary treatment for ovulation induction and in combination with FSH for assisted reproduction procedures. However, larger randomized controlled studies are required to determine the best treatment regimen. If such large studies confirm effectiveness and safety, the use of AIs for ovulation induction would be the first improvement in oral ovulation induction in decades.
Aromatase Inhibitors for ovulation induction
Casper and Mitwally, Sunday, August 21, 2005