Letrozole

LETROZOLE- letrozole tablet, film coated
Lannett Company, Inc.

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment of Early Breast Cancer

Letrozole tablets, USP are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

1.2 Extended Adjuvant Treatment of Early Breast Cancer

Letrozole tablets, USP are 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 letrozole tablets, USP in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets, USP for a median of 60 months [see Clinical Studies (14.2, 14.3)].

1.3 First and Second-Line Treatment of Advanced Breast Cancer

Letrozole tablets, USP are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets, USP are 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 letrozole tablets, USP 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. 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 letrozole tablets, USP 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 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 letrozole tablets, USP 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 letrozole tablets, USP blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets, USP in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of letrozole tablets, USP for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole tablets, USP 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. [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

2.5 mg tablets: dark yellow, film-coated, round, biconvex tablets, debossed with “L” on one side and “12” on the other side.

4 CONTRAINDICATIONS

Letrozole tablets, USP may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole tablets, USP are contraindicated in women who are or may become pregnant. If letrozole tablets, USP are 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 letrozole tablets, USP 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 Adverse Reactions (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 [see 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 [see Adverse Reactions (6.1)].

5.3 Hepatic Impairment

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets, USP experienced approximately twice the exposure to letrozole tablets, USP as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole tablets, USP 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 letrozole tablets, USP, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole tablets, USP use.

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