Femara

FEMARA — letrozole tablet, film coated
Physicians Total Care, Inc.

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 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 Adjuvan t Treatment of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. 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 was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed 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 ≥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

Femara may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Femara is contraindicated in women who are or may become pregnant. If Femara is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [see Use in Specific Populations (8.1)]

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 substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (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) [See Adverse reactions (6.1) ]. Updated results from the BMD sub-study 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 (6.2)].

In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [See Adver se R eactions (6.1) ]. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [ s ee Adverse Reactions (6. 3 ) ] .

5. 2 Cholesterol

Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC 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 ≥1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., <=1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen [ s ee Adverse R eactions (6.1)].

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. 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.

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