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Femara

Brand Name:	Femara	Trade Name:	letrozole
FDA Approved For:	Femara (letrozole tablets) is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.	Pediatric Use:	The safety and effectiveness in pediatric patients have not been established.
Carcinogen:	A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about one to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.	Mutagen:	Letrozole was not mutagenic in in vitro tests (Ames and E. coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).
Manufacturer and/or Distributor:	Novartis

Adverse Reactions:

Femara (letrozole tablets) was generally well tolerated in two controlled clinical trials. Study discontinuations in the megestrol acetate comparison study for adverse events other than progression of tumor occurred in 5/188 (2.7%) of patients on Femara 0.5 mg, in 4/174 (2.3%) of the patients on Femara 2.5 mg, and in 15/190 (7.9%) of patients on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (2 of 362 patients or 0.6% vs. 9 of 190 patients or 4.7%). There was also less vaginal bleeding (1 of 362 patients or 0.3% vs. 6 of 190 patients or 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) of patients on 0.5 mg Femara, 7/185 (3.8%) of patients on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide. Comparisons of the incidence of adverse events revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse events observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. Adverse events, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in the following table: (See Table) 1. Includes peripheral edema, leg edema, dependent edema, edema 2. Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 3. Includes rash, erythematous rash, maculopapular rash, psoriaform rash, vesicular rash Other less frequent (< 5%) adverse experiences considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo. )

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