Femara

FEMARA- letrozole tablet, film coated
Novartis Pharmaceuticals Corporation

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Early Breast Cancer

Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

1.2 Extended Adjuvant Treatment of Early Breast Cancer

Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival (DFS) in patients treated with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)].

1.3 First and Second-Line Treatment of Advanced Breast Cancer

Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals.

2.2 Use in Adjuvant Treatment of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the post approval adjuvant study, median treatment duration was 5 years. Treatment should be discontinued at relapse [ see Clinical Studies (14.1) ] .

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for Femara was 60 months. Seventy-one percent (71%) of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)].

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

In patients with advanced disease, treatment with Femara should continue until tumor progression is evident [see Clinical Studies (14.4, 14.5)].

2.5 Use in Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5. 3 ) ] . The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

2.6 Use in Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min [ s ee Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side).

4 CONTRAINDICATIONS

  • Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)].
  • Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects

Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [ s ee Adverse Reactions (6)]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6)].

In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [ s ee Adver se R eactions (6)]. In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [ s ee Adverse Reactions (6) ] .

5.2 Cholesterol

Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than =1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [ s ee Adverse R eactions (6)].

5.3 Hepatic Impairment

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function [see Clinical Pharmacology ( 12.3 ) ]. 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 (2. 5 ) ] .

5.4 Fatigue and Dizziness

Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised when driving or using machinery until it is known how the patient reacts to Femara use.

5.5 Laboratory Test Abnormalities

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.

5.6 Embryo-Fetal Toxicity

Based on post-marketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with Femara and for at least 3 weeks after the last dose [see Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)].

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