WARNINGS
Pregnancy
Femara® (letrozole tablets) may cause fetal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.
Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hindlegs.
There are no studies in pregnant women. Femara is indicated for postmenopausal women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.
The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.
PRECAUTIONS
Since fatigue and dizziness have been observed with the use of Femara® (letrozole tablets) and somnolence was uncommonly reported, caution is advised when driving or using machinery.
Laboratory Tests
No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.
Increases in SGOT, SGPT, and gamma GT ≥5 times the upper limit of normal (ULN) and of bilirubin ≥1.5 times the ULN were most often associated with metastatic disease in the liver. About 3% of study participants receiving Femara had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to study drug therapy. In the megestrol acetate comparative study about 8% of patients treated with megestrol acetate had abnormalities in liver chemistries that were not associated with documented liver metastases; in the aminoglutethimide study about 10% of aminoglutethimide-treated patients had abnormalities in liver chemistries not associated with hepatic metastases.
In the adjuvant setting, an increase in total cholesterol (generally non-fasting) in patients who had baseline values of total serum cholesterol within the normal range, and then subsequently had an increase in total serum cholesterol of 1.5 ULN was 173/3203 (5.4%) on letrozole vs 40/3224 (1.2%) on tamoxifen. Lipid lowering medications were used by 18% of patients on letrozole and 12% on tamoxifen.
Bone Effects
In the extended adjuvant setting, preliminary results (median duration of follow-up was 20 months) from the bone sub-study (Calcium 500 mg and Vitamin D 400 IU per day mandatory; bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to baseline in hip BMD in Femara patients was 3% vs 0.4% for placebo ( P=0.048). The mean decrease from baseline BMD results for the lumbar spine at 2 years was Femara 4.6% decrease and placebo 2.2% (P=0.069). Consideration should be given to monitoring BMD.
Drug Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of Femara with these drugs does not result in clinically-significant drug interactions. (See CLINICAL PHARMACOLOGY.)
Co-administration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. There is no clinical experience to date on the use of Femara in combination with other anticancer agents.
Hepatic Insufficiency
Subjects with cirrhosis and severe hepatic dysfunction (see CLINICAL PHARMACOLOGY, Special Populations) who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been determined. (See DOSAGE AND ADMINISTRATION.)
Drug/Laboratory Test-Interactions
None observed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 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.
Femara 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).
Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively).
Pregnancy
Pregnancy Category D (See WARNINGS.)
Nursing Mothers
It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when letrozole is administered to a nursing woman (see WARNINGS and PRECAUTIONS).
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were ≥70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70.
For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse events were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.
|
