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Femara: Warning Against Use for Infertility

December 2, 2005

Femara (letrozole), an approved drug used as adjuvant breast cancer therapy for post-menopausal women, can cause miscarriage and birth defects when used off-label as a fertility drug, Canadian authorities have warned.

Health Canada published the warning on 17 November, and it was reported by MedPage Today on 29 November 2005.

The warning was prompted by a Canadian study showing that babies of mothers took Femara and then pregnant had a nearly tripled risk of fetal abnormalities, compared with mothers who did not take Femara.

In Canada, use of Femara to induce ovulation has nearly replaced use of Clomid (clomiphene citrate), because Femara has until now seemed so safe, according to Marinko Biljan, MD, director of the Montreal Fertility Center. Dr Femara, who drew the Canadian government's attention to Femara's risk, said that the perceived safety of Femara as increasing off-label in the US and Europe.

Responses in Canada and the US

Together, Health Canada and Novartis Pharmaceuticals Canada, who manufacture Femara, warned doctors in a letter that Femara should be used only for its primary indication, as adjuvant treatment for breast cancer in post-menopausal women.

"Femara (letrozole) is contraindicated in women with premenopausal endocrine status, in pregnancy, and/or lactation due to the potential for maternal and fetal toxicity and fetal malformations," said the letter, which was posted on Health Canada's website.

Femara is being used off-label, the letter continued (according to MedPage Today), despite clear warnings in the Femara product monograph about possible toxicity to the mother and fetus.

In the US, a US Food and Drug Administration (FDA) spokesman said the FDA is considering whether a similar warning is necessary.

At the US offices of Novartis, a spokesman said that Novartis will be sending a letter to doctors and other health-care providers to remind them that Femara is not approved for use as a fertility drug, and reiterating the dangers. "The letter will be sent by the end of the week to fertility specialists," said Novartis'a Kim Fox.

The concern in Canada over Femara's off-label use arose from a recent study whose results were presented this fall: Researchers analyzed 150 births that occurred after treatment with Femara.

"We found seven serious malformations in 150 cases, which is about 4.7%," said Dr Biljan, which included:

  • Three bone malformations (one each of laryngomalacia, craniosynostosis and fusion of the sacrum);
  • Two cases of cardiac stenosis;
  • Two gastrointestinal malformations: a hepatocellular carcinoma and a cystic lymphangioma of the stomach.

In a comparison of the 150 Femara-related births with a database of 36,050 normal deliveries, the incidence of abnormalities in the control group was 1.8%, versus 4.7% in the babies whose mothers had received Femara-a statistically significant increased risk.

Dr Biljan noted that he previously had supported using Femara as a fertility drug because it seemed to have few side effects. "I thought it was a very good medication," he said, "until we collected this data."

However, after Dr Biljan and colleagues examined the data, he said, he communicated the result to Health Canada and to Novartis, which consequently resulted in the current warning.

How Femara Works

Femara increases the likelihood of ovulation and is therefore being given to women who have difficulty getting pregnant because they do not ovulate normally.

When used in the early follicular phase, Femara blocks the synthesis of estrogen, which then causes normal or enhanced follicular recruitment. Femara is rapidly cleared from the body and considered to be less likely than other medications to adversely affect the cervical mucus and endometrium.

Approved Indications

The approved indications for Femara in the US are:

  • Extended adjuvant treatment of early breast cancer in postmenopausal women who have received five years of adjuvant therapy with Nolvadex (tamoxifen).
  • First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer.
  • Treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

Health Canada Endorsed Important Safety Information on Femara* (letrozole), Health Canada, 17 November 2005.
The Outcome of 150 Babies Following the Treatment With Letrozole or Letrozole and Gonadotropins. Biljan MM et al, Fertility and Sterility, volume 84(Suppl 1), page S95, 2005.

Posted: December 2005