Femara (letrozole) - 4 indications

Scroll down for information on each indication:

advanced breast cancer in post-menopausal women; approved July 1997

first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; approved January 2001

extended adjuvant treatment of early breast cancer in postmenopausal women who have received five years of adjuvant tamoxifen therapy; approved October 2004

adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer; approved December 2005 

General Information

Femara (letrozole) is an aromatase inhibitor. 

Femara is specifically indicated for the following:

• the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer
• the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy
• first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer.
• for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Femara is supplied as tablets for oral administration. The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals. In the adjuvant and extended adjuvant setting, the optimal duration of treatment with Femara is unknown. In patients with advanced disease, treatment with Femara should continue until tumor progression is evident.

Mechanism of Action

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult non-tumor and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

Side Effects

Adverse effects associated with the use of Femara may include, but are not limited to, the following:

• hot flashes
• arthralgia
• flushing
• asthenia
• edema
• headache
• dizziness
• hypercholesterolemia
• sweating increased
• bone pain
• musculoskeletal

Indication 1 - advanced breast cancer in post-menopausal women

approved July 1997

Clinical Trial Results

Femara was evaluated in a randomized, double-blind, multinational phase III trial that compared Femara 2.5 mg to tamoxifen 20 mg in 907 postmenopausal women with locally advanced (stage IIIB) disease, metastatic breast cancer, or recurrences not amenable to treatment with surgery or radiotherapy. Results of the trial demonstrated that Femara delayed progression of advanced breast cancer for 9.4 months compared to 6.0 months for tamoxifen. Significant differences were also observed between Femara and tamoxifen in terms of objective response rate (30% vs. 20%), clinical benefit (49% vs. 38%) and time to treatment failure (9.1 months vs. 5.7 months). Femara and tamoxifen were equally well tolerated.

Indication 2 - first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer

approved January 2001

Clinical Trial Results

A randomized, double-blind, multinational trial (P025) compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Femara was superior to tamoxifen in TTP (9.4 months versus 6.0 months) and rate of objective tumor response (32% versus 21%). 

Indication 3 - extended adjuvant treatment of early breast cancer in postmenopausal women who have received five years of adjuvant tamoxifen therapy

approved October 2004

Clinical Trial Results

A double-blind, randomized, placebo-controlled trial of Femara was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen. The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara. In this updated analysis Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo. However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11%. There was no significant difference in distant DFS or overall survival.

Indication 4 - adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer

approved December 2005 

Clinical Trial Results

In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptorpositive early breast cancer, one of the following treatments was randomized in a double-blind manner: Option 1: A. Tamoxifen for 5 years B. Femara for 5 years C. Tamoxifen for 2 years followed by Femara for 3 years D. Femara for 2 years followed by tamoxifen for 3 years Option 2: A. Tamoxifen for 5 years B. Femara for 5 years The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). The primary endpoint of this trial was DFS (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen 2 years followed by] Femara 3 years versus tamoxifen beyond 2 years and Femara 2 years followed by] tamoxifen 3 years versus Femara beyond 2 years. There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.