LETROZOLE

LETROZOLE- letrozole tablet, film coated
Arab Pharmaceutical Manufacturing Co. PSC Ltd

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 hormonereceptor 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 inpostmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Letrozole Tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with Letrozole Tablets for a median of 60 months [s e e C lini c al Studi e s ( 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 hormonereceptor 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 [s e e C lini c al Studi e s ( 14.4, 14.5) ] .

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose of Letrozole Tablets are 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 letrazole, 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 [ s e e C lini c al Studi e s ( 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 are 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 [s e e C lini c al Studi e s ( 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. [ s e e C lini c al Studi e s ( 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 blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Letrozole Tablet in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [s e e W ar n ings and Pr ec autions ( 5.3) ] . The recommended dose of Letrozole Tablets for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Letrozole Tablets 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 e e C lini c al Pharma c ology ( 12.3) ].

3 DOSAGE FORMS AND STRENGTHS

2.5 mg tablets: yellow, round film-coated tablets embossed with “WW” at one side and “74” on the other side of 6mm diameter.

4 CONTRAINDICATIONS

Letrozole Tablets 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 is contraindicated in women while taking this drug, the patient should be apprised of the potential hazard to a fetus. [s e e U s e in Sp ec ific Populations ( 8.1) ]

5 WARNINGS AND PRECAUTIONS

5.1 Bone Effects

Use of Letrozole Tablets 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) [S e e A d ve rse r e a c tions ( 6.1) ]. Updated results from the BMD sub-study in the extended adjuvant setting demonstrate 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 [s e e Ad ve rse R e a c tions ( 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 [S e e A d ve rse R e a c tions ( 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 e e Ad v e rse R e a c tions ( 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 e e Ad ve r s e R e a c tions ( 6.1) ] .