Novartis has issued a Dear Healthcare Professional Letter to alert our healthcare professionals about its concern on the off-label use of letrozole (Femara®, Novartis) in treating infertility, even though the package insert has warned about potential embryo- and fetotoxicity with or without teratogenicity, including contraindications for use in women with premenopausal endocrine status as well as pregnancy and lactation.

Letrozole, an aromatase inhibitor, is used in postmenopausal women with breast
cancer. It is licensed for:

• Extended adjuvant treatment of early breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy.
  
  
• First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer.
  
  
• Treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status, who have previously been treated with anti-oestrogens.
  
  
  

Adverse reports in babies following maternal exposure to letrozole has been observed in a retrospective study and the company's adverse drug reactions database.

A retrospective analysis¹ of the outcome of 150 babies following the treatment with letrozole alone or letrozole and gonadotropins at the Montreal Fertility Centre showed that the incidence of locomotor malformations (p=0.0005 95% CI=2.64-27.0) and cardiac anomalies (p=0.0006 95% CI=3.30-58.1) was higher than in the control groups.

The company safety database contains 13 case reports of women exposed to Femara® during pregnancy. Of the 13 reports, 4 reported adverse outcomes for the foetus (2 miscarriages and 2 birth defects), 3 of which involved the off-label use for infertility. Of the remaining 9 cases, 4 women had normal foetal ultrasounds and delivery while the outcomes of the remaining 5 cases were unknown.

To date, HSA has not received any ADR reports associated with maternal exposure of the drug. Novartis, in its letter recommends the use of letrozole within the labeled indications.

1.  Fertility and Sterility 2005;84(S1):S95