Letrozole Alvogen

Letrozole Alvogen

letrozole

Manufacturer:

Alvogen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Letrozole.
Description
Each film-coated tablet contains 2.5 mg letrozole.
Action
Pharmacotherapeutic Group: Enzyme inhibitor. Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis).
Pharmacology: Pharmacodynamics: Pharmacodynamic effects: The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg letrozole suppress serum oestrone and oestradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate are below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses.
Oestrogen suppression was maintained throughout treatment in all these patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH levels, T4 levels, and T3 uptake test.
Pharmacokinetics: Absorption/ Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract. Food slightly decreases the rate of absorption. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Steady-state concentration of letrozole are reached after 2-6 weeks and maintain for long periods with no evidence of drug accumulation.
Letrozole is weakly protein bond and has large volume of distribution.
Metabolism and elimination: The major route of elimination of letrozole is metabolism by CYP-450 isoenzymes (CYP 3A4 and CYP 2A6) into an inactive carbunol metabolite.
Age had no effect on the pharmacokinetics of letrozole.
Letrozole's terminal elimination half-life is about 2 days.
Special populations: The pharmacokinetics of letrozole do not change in renal impairment.
In patients with hepatic cirrhosis and severely compromised liver function (Child-Pugh C), the AUC increases by 95% and the T1/2 by 187%. Thus letrozole should be administered with caution and after consideration of the potential risk/benefit to such patients.
Indications/Uses
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 prior standard adjuvant tamoxifen therapy for 5 years.
First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer.
Advanced breast cancer in women with natural or artificially induced postmenopausal status after relapse or disease progression, who have previously been treated with anti-oestrogens.
Dosage/Direction for Use
Recommended Dose: The recommended dose of letrozole is one 2.5 mg tablet administered once a day, without regard to meals.
Mode of Administration: Adult and elderly patients: The recommended dose of letrozole is 2.5 mg once daily. No dose adjustment is required for elderly patients.
In the adjuvant setting, it is recommended to treat for 5 years or until tumour relapse occurs. In patients with advanced or metastatic disease, treatment with letrozole should continue until tumour progression is evident.
Children: Not applicable.
Patients with hepatic and/or renal impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment, although letrozole blood concentrations were modestly increased in the subjects with hepatic impairment due to cirrhosis.
The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduce by 50%.
No dosage adjustment is required for patients with renal insufficiency with creatinine clearance greater than 30 ml/min.
No dosage adjustment is recommended for patients with renal impairment if creatinine clearance is not more than 10 mL/min.
Overdosage
Isolated cases of over dosage have been reported. No specific treatment for over dosage is known; treatment should be symptomatic and supportive.
Contraindications
Hypersensitivity to the active substance or to any of the excipients; premenopausal endocrine status; pregnancy; lactation.
Special Precautions
Hepatic function impairment: Patients with cirrhosis and severe hepatic dysfunction who were dosed with letrozole 2.5 mg experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dosage reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined.
Pregnancy: Category D. Letrozole may cause fetal harm when administered to pregnant women.
There are no studies in pregnant women. Letrozole is indicated for postmenopausal women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.
Nursing Mothers: 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.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in Elderly: The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were ≥70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70.
For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse events were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.
Effect on ability to drive and use machines: Since fatigue and dizziness and somnolence have been reported with the use of letrozole, caution is advise when driving or using machinery.
Use In Pregnancy & Lactation
Use in Pregnancy: Category D. Letrozole may cause fetal harm when administered to pregnant women. There are no studies in pregnant women. Letrozole is indicated for postmenopausal women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy. Letrozole is contraindicated during pregnancy.
Use in Lactation: 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. Letrozole is contraindicated during lactation.
Women of perimenopausal status or child-bearing potential: The physician needs to discuss the necessity of a test before initiating letrozole and of adequate contraception with women who have the potential to become pregnant (i.e. women who are perimenopausal or who recently became postmenopausal) until their postmenopausal status is fully established.
Adverse Reactions
The following adverse drug reactions, listed in the table below were reported from clinical studies and from post marketing experience with letrozole: Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥1/10, common ≥1/100 to <1/10, uncommon ≥1/1,000 to 1/100, rare ≥1/10,000 to 1/1,000, very rare <1/10,000, not know (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image
Drug Interactions
Tamoxifen: Coadministration of Letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. Clinical experience in the second-line breast cancer pivotal trials indicates that the therapeutic effect of Letrozole therapy is not impaired if Letrozole is administered immediately after tamoxifen.
Storage
Store below 30°C.
ATC Classification
L02BG04 - letrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
Presentation/Packing
FC tab (yellow, round, biconvex) 2.5 mg x 30's.
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