Letroza

General characteristics. Structure:

Active ingredient: 2,5 letrozole in 1 tablet.

Excipients: cellulose microcrystallic, sodium of a kroskarmelloz, magnesium stearate.

Structure of a film cover: инстакоат (gipromelloza, macrogoal, talc, titanium dioxide).

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug. Letrozole has anti-oestrogenic effect, selectively inhibits aromatase (enzyme of synthesis of estrogen) by highly specific competitive linkng with subunit of this enzyme - gemy P450 cytochrome. Blocks synthesis of estrogen both in peripheral, and in tumoral fabrics. At women in the postmenopauzny period estrogen is formed preferential with the participation of aromatase enzyme which turns the androgens which are synthesized in adrenal glands (first of all, androstendion and testosterone) into estrone and oestradiol.

Daily reception of letrozole in a daily dose of 0.1-5 mg leads to decrease in concentration of oestradiol, estrone and estrone of sulfate in a blood plasma for 75-95% of initial contents. Suppression of synthesis of estrogen is supported throughout the entire period of treatment.

At use of letrozole in the range of doses from 0.1 to 5 mg of disturbance of synthesis of steroid hormones in adrenal glands it is not observed, the test with AKTG does not reveal disturbances of synthesis of Aldosteronum or cortisol. Additional purpose of glucocorticoids and mineralokortikoid is not required.

Blockade of biosynthesis of estrogen does not lead to accumulation of androgens, being predecessors of estrogen. Against the background of reception of letrozole of changes of maintenance of LG and FSG in a blood plasma, changes of function of a thyroid gland, changes of a lipidic profile, increase in frequency of myocardial infarctions and strokes were not noted.

Against the background of treatment by letrozole osteoporosis frequency poorly increases (6.9% in comparison with 5% for placebo). However the frequency of fractures of bones at the patients receiving letrozole does not differ from that at healthy people of the same age.

Adjuvant therapy by letrozole of early stages of a breast cancer reduces risk of a recurrence, increases survival without symptoms of a disease within 5 years, reduces risk of development of secondary tumors.

The prolonged adjuvant therapy by letrozole reduces risk of a recurrence by 42%. Reliable advantage on survival without symptoms of a disease in group of letrozole was noted regardless of an involvement of lymph nodes. Treatment by letrozole reduces mortality of patients with involvement of lymph nodes by 40%.

Pharmacokinetics. Absorption. Letrozole is quickly and completely soaked up from the digestive tract (DT), average bioavailability makes 99,9%. Meal slightly reduces absorption speed. Average value of time of achievement of the maximum concentration of letrozole in blood (TCmax) makes 1 hour at letrozole reception on an empty stomach and 2 hours - at reception with food; average value of the maximum concentration (Cmax) makes 129±20,3 nmol/l at reception on an empty stomach and 98,7±18,6 nmol/l - at reception with food, however extent of absorption of letrozole (at assessment on the area under a curve "concentration time" (AUC)) does not change.

Little changes in the speed of absorption are regarded as not having clinical value therefore letrozole can be accepted irrespective of meal.

Distribution. Communication of letrozole with proteins of a blood plasma makes about 60% (preferential with albumine - 55%). Concentration of letrozole in erythrocytes makes about 80% of that in a blood plasma. The seeming distribution volume in an equilibrium state makes about 1,87±0,47 l/kg. Equilibrium concentration is reached within 2-6 weeks of daily reception of a daily dose of 2,5 mg. The pharmacokinetics is not linear. Cumulation at prolonged use is noted.

Letrozole substantially is exposed to metabolism under the influence of isoenzymes of CYP3A4 and CYP2A6 of P450 cytochrome with formation pharmacological of inactive karbinolovy connection.

Removal. It is removed preferential by kidneys in the form of metabolites, to a lesser extent - through intestines. The final elimination half-life (T1/2) makes 48 h.

Pharmacokinetics in special clinical cases. Pharmacokinetic parameters of letrozole do not depend on age of the patient.

At a renal failure pharmacokinetic parameters do not change.

At moderately expressed abnormal liver function (Child-Pugh B) the average sizes AUC though are 37% higher, but remain within that range of values which are noted at persons without abnormal liver functions. At patients with cirrhosis and heavy disturbances of its function (Child-Pugh C) of AUC also T1/2 for 187% increases by 95%. However, considering good tolerance of high doses of drug (5-10 mg/days) in these cases of need to change a dose of letrozole is not present.

Indications to use:

• Early stages of a breast cancer which cells have receptors to hormones, at women in a postmenopause, as adjuvant therapy.

• Early stages of a breast cancer at women in a postmenopause after completion of standard adjuvant therapy by Tamoxifenum as the prolonged adjuvant therapy.

• Common hormonedependent forms of a breast cancer at women in a postmenopause (therapy of the first line).

• Common forms of a breast cancer at the women in a postmenopause (natural or induced) receiving the previous therapy by anti-estrogen.

Route of administration and doses:

Appoint 2.5 mg of 1 times a day.

Features of use:

The decision on purpose of letrozole patients with clearance of creatinine <should accept 10 ml/min. only after careful assessment of a ratio between potential risk and the expected effect.

Patients with heavy abnormal liver functions (on the Child-Pugh system a class C) have to be under constant observation.

Side effects:

The most often observed undesirable phenomena: inflows, nausea, feeling of fatigue arthralgia.

Other often observed undesirable phenomena: anorexia, the increased appetite, peripheral hypostases, a headache, dizziness, vomiting, dyspepsia, a lock, diarrhea, an alopecia, the increased perspiration, rash, a mialgiya, ostealgias, arthritises, osteoporosis, fractures of bones, a hypercholesterolemia, increase in body weight, a depression.

Other rare, but potentially heavy undesirable phenomena: leukopenia, cataract, disturbances of cerebral circulation, thrombophlebitis, embolism of a pulmonary artery, arterial thrombosis, coronary heart disease.

Interaction with other medicines:

At co-administration of letrozole with Cimetidinum and warfarin of clinically significant interaction it is not observed.

Clinical experiment on use of letrozole in a combination with other antineoplastic means is not available now.

According to results of the researches in vitro letrozole suppresses activity of isoenzymes of CYP2A6 and CYP2C19 (the last - moderately). At the solution of a question of value of these data for clinic it is necessary to consider that the isoenzyme of CYP2A6 does not play an essential role in metabolism of medicines. In experiments of in vitro it was shown that letrozole in the concentration, by 100 times exceeding equilibrium values in plasma has no ability significantly to suppress diazepam metabolism (substrate for CYP2C19). Thus, clinically significant interaction with an isoenzyme of CYP2C19 is improbable. Nevertheless, it is necessary to be careful at the combined use of letrozole and drugs which are metabolized preferential with the participation of the above-stated isoenzymes and having a narrow therapeutic index.

Contraindications:

Hypersensitivity to letrozole or other components of drug. Endocrine status characteristic of the reproductive period. Pregnancy, feeding period breast. Age up to 18 years.

Overdose:

There are separate messages on letrozole overdose cases.

Treatment: any specific methods of treatment of overdose are not known. The symptomatic and maintenance therapy is shown. Letrozole is removed from plasma by means of a hemodialysis.

Storage conditions:

List B. Drug should be stored in unavailable to children, the dry place at a temperature not above 30 °C. A period of validity - 4 years.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, 2.5 mg on 30 pieces in packaging.