Letrozole - instructions for use, dose, side effects, contraindications

Antitumor agent. It is a non-steroidal aromatase inhibitor, an enzyme that involves the synthesis of estrogens in postmenopausal women.Aromatase promotes the conversion of androgens synthesized in the adrenal glands (primarily androstenedione and testosterone), to estrone and estradiol. The inhibition of aromatase activity is realized by competitive binding to the subunit of this enzyme - heme cytochrome P450, which leads to a decrease in the biosynthesis of estrogens in all tissues, including in tissues of estrogen-dependent tumors.

The absence of gestagenic, androgenic and estrogenic activity does not affect the secretion of endogenous glucocorticoids and thyroid hormones.

Pharmacokinetics:

Absorption is fast and complete (regardless of food intake) and is about 99%. Daily admission by patients in postmenopausal women at a dose of 0.1-5 mg per day leads to a decrease in the concentration of estradiol, estrone and estrone sulfate in plasma by 75-95%, which persists throughout treatment. With prolonged treatment, no cumulation was noted. Pharmacokinetics for long-term admission is nonlinear. Stationary concentration of substance in blood plasma is 1.5-2 times higher than that after a single dose. The elimination half-life is 48 hours. Elimination mainly by the kidneys (about 90%, 6% in the form of unchanged substance, 75% in the form of conjugates with glucuronic acid, 9% in the form of two indefinite metabolites) and intestine.In renal and hepatic insufficiency, the pharmacokinetic parameters do not change. Removed during hemodialysis.

Indications:

The spread of breast cancer, especially in postmenopausal women, including those with resistance to antiestrogen therapy.

ICD-10

II.C50.C50 Malignant neoplasm of breast

Contraindications:

Hypersensitivity, pregnancy, breast-feeding, premenopause, children's age.

Carefully:

Severe hepatic and renal insufficiency (creatinine clearance less than 10 ml / min).

Pregnancy and lactation:

Contraindicated in pregnancy and lactation.

During letrozole therapy, taking into account the potential for pregnancy, women in perimenopausal and early postmenopausal period should use reliable methods of contraception to establish a stable, post-menopausal hormone levels.

If pregnancy occurs during treatment the patient should be informed of the potential risk to the fetus and the possibility of a miscarriage. In the experiments in vivo the drug showed embryo- and fetotoxicity, teratogenic effects.

There is no information on the penetration into breast milk. In view of the potential risk of undesirable effects on the child during treatment with letrozole, breastfeeding is recommended to be discontinued.

FDA recommendation category D.

Dosing and Administration:

Inside, regardless of food intake.

The recommended dose of the drug is 2.5 mg once a day, daily, long. As an extended adjuvant therapy treatment can last 5 years (no longer). If signs of disease progression appear, the drug should be discontinued.

In elderly patients, dosage correction of letrozole is not required.

For hepatic or renal (creatinine clearance ≥ 10 ml / min), no dose adjustment is required. Nevertheless, with severe hepatic insufficiency (severity - C on the Child-Pugh scale), patients should be under constant supervision.

Side effects:

From the digestive tract: nausea, anorexia, constipation, diarrhea, vomiting, pain or discomfort in the abdomen.

From the respiratory system: dyspnea, exudate pleurisy, cough.

From the cardiovascular system: Arterial hypertension, myocardial infarction, myocardial ischemia,thromboembolism of the pulmonary artery, thromboembolism.

Dermatological: alopecia.

Hypersensitivity: skin rashes, itching.

On the part of the reproductive system: uterine bleeding.

Overdose:

The cases of taking large doses of letrozole (up to 62.5 mg) are described, but side effects and overdose are not registered.

There is no specific antidote.

Treatment is symptomatic: gastric lavage, control of vital body functions.

Interaction:

Tamoxifen - a decrease in the concentration of letrozole in the blood by 38% without affecting its effectiveness.

Special instructions:

The treatment should be managed by specialists who have experience in carrying out endocrine therapy for malignant tumors. Before treatment, women should undergo a thorough gynecological examination (pregnancy should be excluded).

Monitoring the activity of transaminases, γ-glutamyl transpeptidase and bilirubin concentration in the blood (periodically during treatment, the increase may be a sign of metastasis to the liver).

If the liver function is not expressed or is moderate, a dose correction of letrozole is not required.

If renal function impairment with creatinine clearance less than 10 ml / min dose correction letrozola is not required.

Instructions

Letrozole (Letrozolum)