Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. Extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. First-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Nonsteroidal aromatase inhibitor
Mechanism of Action: Letrozole is a potent and highly specific nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Letrozole exerts its antitumor effect by depriving estrogen-dependent breast cancer cells of their growth stimulus. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which coverts adrenal androgens primarily androstenedione and testosterone-to oestrone (E1) and oestradiol (E2). The suppression of estrogen biosynthesis in the peripheral tissues and the malignant tissues can be achieved by specifically inhibiting the aromatase enzyme.
In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5mg letrozole suppress serum oestrone and oestradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours. In post-menopausal patients, with advanced breast cancer, daily doses of 0.1 to 5mg suppress plasma concentration of oestradiol, oestrone, and oestrone sulphate by 78-95% from baseline in all patients treated. Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5mg indicating that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Impairment of adrenal steroidogenesis has not been observed.
Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability 99.9%). Food slightly decreases the rate of absorption, but the extent of absorption remains unchanged. The minor effect of the absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken after, with or before food. Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole but is relatively slow when compared to hepatic blood flow. The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite in vitro but their individual contributions to letrozole metabolism in vivo have not been established. The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5mg of letrozole, steady-state levels are reached within 2 to 6 weeks.
The recommended dose is one 2.5 mg tablet administered once a day, regardless to meals. In patients with advanced disease, treatment with Letrozole Tablet should be continued until tumor progression is evident. Treatment should be discontinued at tumor relapse. No dose adjustment is required for elderly patients. Patients treated with Letrozole Tablet do not require glucocorticoid or mineralocorticoid replacement therapy.
Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of letrozole with these drugs does not result in clinically significant drug reactions, even through cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro.
Letrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Letrozole is contraindicated in women who are or may become pregnant. If this drug 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. Since fatigue and dizziness have been observed with the use of Letrozole and somnolence was uncommonly reported, caution is advised when driving or using machinery.
Letrozole is generally well tolerated. The observed adverse reactions are mild or moderate in nature including hot flashes, night sweats, weight increase, nausea, vaginal bleeding & irritation, endometrial proliferation disorders etc.
Pregnancy Category D. 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.
There is no clinical experience of overdosage. There is no specific antidote to letrozole. Since letrozole is not highly protein-bound, dialysis may be helpful. Emesis may be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs is appropriate.
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
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