Indications of Letrozol 2.5 mg
Letrozol 2.5 mg is indicated for the first-line treatment of advanced/metastatic breast cancer (hormone receptor positive or receptor status unknown) in post-menopausal women.
Letrozol 2.5 mg is a nonsteroidal aromatase inhibitor. It inhibits the conversion of androgen to estrogen. In contrast to ovariectomy, treatment with Letrozol 2.5 mg does not lead to an increase in serum FSH. Letrozol 2.5 mg selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozol 2.5 mg inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with Letrozol 2.5 mg significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect the adrenal corticosteroid synthesis, ldosterone synthesis, or synthesis of thyroid hormones.
Dosage & Administration of Letrozol 2.5 mg
The recommended dose is one 2.5 mg tablet administered once a day, regardless to meals. In patients with advanced disease, treatment with Letrozol 2.5 mg 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 Letrozol 2.5 mg Tablet do not require glucocorticoid or mineralocorticoid replacement therapy.
Dosage of Letrozol 2.5 mg
The recommended dose of Letrozol 2.5 mg is 2.5 mg once daily. Treatment with Letrozol 2.5 mg should continue as long as tumor response is seen. The drug should be discontinued if tumor stops responding as judged by tumor progression. For elderly patients, no modification of the normal adult dosage regimen is necessary. No dosage adjustment is required for patients with mild to moderate hepatic impairment or renal impairment.
Interaction of Letrozol 2.5 mg
Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of Letrozol 2.5 mg 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 Letrozol 2.5 mg in vitro.
Letrozol 2.5 mg is contraindicated in known or suspected hypersensitivity to Letrozol 2.5 mg, other aromatase inhibitors, or to any of their ingredients. It is contraindicated during pregnancy, lactation and in pre-menopausal women. It is also contraindicated in severe hepatic dysfunction.
Side Effects of Letrozol 2.5 mg
Adverse events associated with Letrozol 2.5 mg are generally mild to moderate and rarely severe enough to require discontinuation. Many can be attributed to either the underlying disease or the normal pharmacological consequence of oestrogen deprivation (hot flushes, hair thinning). The most frequently reported adverse events are musculoskeletal pain, arthralgia, headache, fatigue, nausea, dyspnoea, peripheral oedema, coughing, constipation, vomiting, chest pain, viral infection, diarrhoea, rash, abdominal pain, dyspepsia and anorexia. Dizziness, weight increase and pruritus are less commonly seen.
Pregnancy & Lactation
Pregnancy Category D. It is not known if Letrozol 2.5 mg is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Letrozol 2.5 mg is administered to a nursing woman.
Precautions & Warnings
In breast cancer patients with moderate hepatic dysfunction, no dosage adjustment is necessary, but caution is recommended since Letrozol 2.5 mg elimination depends mainly on intrinsic metabolic clearance. Renal impairment (calculated creatinine clearance: 20 to 50 ml/min) did not affect steady-state plasma Letrozol 2.5 mg concentration at a dose of 2.5 mg or 5 mg. Hence, no dose adjustment is necessary for such renal function impairment. It is anticipated that Letrozol 2.5 mg could be removed from blood by dialysis since it is weakly bound to plasma proteins. The potential risks and benefits to such patients should be considered carefully before prescribing Letrozol 2.5 mg. In some cases, fatigue and dizziness have been observed with the use of Letrozol 2.5 mg. Patients should therefore, be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired.
Overdose Effects of Letrozol 2.5 mg
There is no clinical experience of overdosage. There is no specific antidote to Letrozol 2.5 mg. Since Letrozol 2.5 mg 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.
Use In Special Populations
Renal Impairment: No dosage adjustment is required for patients with renal impairment if creatinine clearance is 10 ml/min.Hepatic Impairment: No dosage adjustment is recommended for patients with mild to moderate hepatic impairment. The dose of Letrozol 2.5 mg in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose for such patients is 2.5 mg administered every other day.Pediatric Use: The safety and effectiveness in pediatric patients have not been established.
Mode Of Action
Mechanism of Action: Letrozol 2.5 mg 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. Letrozol 2.5 mg 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 Letrozol 2.5 mg 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. Letrozol 2.5 mg 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: Letrozol 2.5 mg 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 Letrozol 2.5 mg may be taken after, with or before food. Plasma protein binding of Letrozol 2.5 mg is approximately 60%, mainly to albumin (55%). The concentration of Letrozol 2.5 mg in erythrocytes is about 80% of that in plasma. Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of Letrozol 2.5 mg but is relatively slow when compared to hepatic blood flow. The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting Letrozol 2.5 mg to this metabolite in vitro but their individual contributions to Letrozol 2.5 mg 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 Letrozol 2.5 mg, steady-state levels are reached within 2 to 6 weeks.
Oral administration of Letrozol 2.5 mg in pregnant rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg. Embryotoxicity and foetotoxicity were seen at doses >0.003 mg/kg and there was an increase in the incidence of foetal malformation among the animals treated. However, there are no adequate and well-controlled studies of Letrozol 2.5 mg in pregnant women and its use in these patients is not recommended. It is not known whether Letrozol 2.5 mg is excreted in human milk. Because many drugs are excreted in human milk, Letrozol 2.5 mg should not be administered to a nursing woman.