Letrozole

General characteristics. Structure:

Active ingredient: 2,5 mg of letrozole.

Excipients: magnesium stearate, FD&C Yellow No. 6 dye, лудипрессо (lactose, povidone, кросповидон).

Antineoplastic drug.

Pharmacological properties:

Pharmacodynamics. Letrozole is antineoplastic drug from group of nonsteroid inhibitors of aromatase (inhibitor of synthesis of estrogen). The disseminated cancer of mammary glands in the postmenopauzny period can be estrogenzavisimy. At this age androgens (first of all, androstendion and testosterone) are the main source of estrogen. When growth of tumoral fabric depends on presence of estrogen, elimination of the stimulating influences mediated by them is premises for suppression of growth of a tumor.

At women in a postmenopause estrogen is formed preferential with the participation of aromatase enzyme which turns the androgens which are synthesized in adrenal glands into estrone and oestradiol. Therefore by means of specific inhibition of enzyme of aromatase it is possible to reach suppression of biosynthesis of estrogen in peripheral fabrics and in tumoral fabric. Letrozole is the high-selection (considerably surpasses фадрозол, анастрозол, etc.) nonsteroid inhibitor of this enzyme. Drug inhibits aromatase by competitive linkng with prosthetic subunit of this enzyme – iron P450 cytochrome gem that as a result reduces biosynthesis of estrogen in all fabrics.

Healthy women in a postmenopause have a single dose of letrozole, a component of 0.1, 0.5 and 2.5 mg, reduces the level of estrone and oestradiol in blood serum (in comparison with initial level) by 75%, 78% and 78%, respectively. The maximum decrease is reached in 2-3 days. At women with a common form of a breast cancer in a postmenopause daily use of letrozole in a dose from 0.1 to 5 mg leads to decrease in levels of oestradiol, estrone and estrone of sulfate in a blood plasma for 75-95% of initial level. When using drug in a dose of 0.5 mg and more in many cases of concentration of estrone and estrone of sulfate turn out below a threshold of sensitivity of the used method of definition of hormones that points to more expressed suppression of synthesis of estrogen.

Suppression of estrogen was supported throughout treatment at all patients. Disturbance of synthesis of steroid hormones in adrenal glands is not revealed. At women in a postmenopause treatment by letrozole in a daily dose of 0.1-5 mg did not reveal clinically significant changes of concentration in a blood plasma of cortisol, Aldosteronum, 11-deoksikortizol, 17 hydroxyprogesterone, AKTG, and also activities of a renin. Test of stimulation with AKTG in 6 and 12 weeks of treatment by letrozole in a daily dose 0.1; 0.25; 0.5; 1; 2.5 and 5 mg did not reveal a little noticeable reduction of synthesis of Aldosteronum or cortisol. Thus, there is no need for addition of glucocorticoids and mineralokortikoid.

After single use of letrozole in doses of 0.1, 0.5 and 2.5 mg at healthy women in a postmenopause changes of concentration of androgens (androstendion and testosterone) in a blood plasma are not revealed. Also changes of level of androstendion in a blood plasma at the patients in a postmenopause receiving letrozole in a daily dose from 0.1 to 5 mg are noted. All this indicates that blockade of biosynthesis of estrogen does not lead to accumulation of androgens, being predecessors of estrogen. At the patients receiving letrozole changes of concentration of luteinizing and follicle-stimulating hormones in a blood plasma, and also changes of function of a thyroid gland which was estimated on the level of thyritropic hormone, T4 and T3 were not noted.

Pharmacokinetics. Absorption. Letrozole is quickly and completely soaked up from digestive tract, bioavailability makes 99,9%. Food slightly reduces absorption speed, however extent of absorption of drug does not change. Letrozole can be accepted irrespective of meal.

Distribution. Letrozole about 60% (it is preferential with albumine) contacts proteins of a blood plasma. Concentration of drug in erythrocytes makes about 80% of its level in a blood plasma. After daily use of 2,5 mg equilibrium concentration of letrozole is reached ranging from 2 up to 6 weeks, at the same time it is about 7 times higher, than after a single dose of the same dose. Letrozole is quickly and widely distributed in fabrics.

Metabolism. Letrozole substantially is exposed to metabolism with formation pharmacological of inactive karbinolovy connection. Transformation of letrozole into its metabolite is carried out under the influence of isoenzymes 3A4 and 2A6 of P450 cytochrome. At persons with moderately expressed dysfunction baking average sizes of the area under a curve "concentration time" (AUC) were 37% higher, than at healthy faces, but remained within that range of values which were observed at persons without abnormal liver functions.

Removal. Plasma elimination half-life of blood makes about 2 days. It is removed by kidneys and with a stake.

Any influence of renal failures (calculated values of clearance of creatinine made 20–50 ml/min.) or a liver on concentration of letrozole in plasma was not noted.

The pharmacokinetics of letrozole does not depend on age.

Indications to use:

As drug of the first line of therapy of a breast cancer at women in a postmenopause.

Treatment of common forms of a breast cancer at the women in a postmenopause (natural or caused artificially) receiving the previous therapy by anti-estrogen.

Route of administration and doses:

At the disseminated forms of cancer of mammary glands at women in a postmenopause (adults and advanced age) the recommended dose of letrozole makes 2.5 mg once a day, daily. Treatment by drug is continued before emergence of signs of progressing of a disease.

Drug dose adjustment is not required from patients of advanced age.

 With diseases of a liver or kidneys (at clearance of creatinine it is more or equal 10 ml/min.) dose adjustment of drug is not required from patients.

At children drug is not used.

Features of use:

There are no data on use of letrozole for patients with clearance of creatinine

At children drug is not used.

Influence on ability to driving of motor transport and to control of mechanisms. It is improbable that use of letrozole will break ability of patients to drive the car or to manage mechanisms. However, as at treatment drug observed the general weakness and dizzinesses, it is necessary to warn patients that their physical and/or mental abilities which are required for driving of the car or control of mechanisms can be broken.

Side effects:

Side effects of letrozole generally poorly or are moderately expressed. The undesirable phenomena of considerable degree of manifestation demanding the treatment termination were registered only in rare instances. Many undesirable effects can be caused by both a basic disease, and natural pharmacological effects of deficit of estrogen (for example, inflows, thinning of hair).

At use of drug the following side effects are possible:

Infections: sometimes – infections of uric ways.

From a tumor: sometimes – morbidity in the field of a tumor.

From blood: sometimes – a leukopenia.

Metabolic disturbances: often – anorexia, increase in appetite, sometimes – a hypercholesterolemia, hypostases.

From mentality: sometimes – a depression, uneasiness.

From TsNS: often – a headache, dizziness; sometimes – drowsiness, sleeplessness, a memory impairment, dizesteziya, taste disturbances, it is rare – cerebrovascular disturbances.

From eyes: sometimes – a cataract, irritation of eyes, indistinct sight.

From cardiovascular system: sometimes – tachycardia, tachycardia, thrombophlebitis; seldom – hypertensia, an embolism of a pulmonary artery, arterial thrombosis, a heart attack.

From respiratory system: seldom – an asthma.

From bodies of a GIT: often – nausea, vomiting, dyspepsia, lock/diarrhea, sometimes – abdominal pains, stomatitis, dryness in a mouth, increase in hepatic transaminases.

Dermatological reactions: often – a hair loss, the increased sweating, skin rashes, sometimes – an itch, a xeroderma, a small tortoiseshell.

From a musculoskeletal system: often – mialgiya, ostealgias, artralgiya, arthritis.

From an urinary system: sometimes – a frequent urination.

From reproductive system: sometimes – vaginal bleedings, a leukorrhea, dryness of a vagina, a mammary gland pain.

From an organism in general; very often – inflows; often – fatigue, peripheral hypostases, increase in body weight; sometimes – fervescence, dryness of mucous membranes, thirst, decrease in body weight.

Interaction with other medicines:

At co-administration of letrozole with Cimetidinum and warfarin of clinically significant interactions it is not observed. significant interactions of letrozole with other often used drugs were also not noted.

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

letrozole suppresses in vitro activity of isoenzymes of P450 cytochrome – 2A6 and 2C19 (and the last – it is moderate). The isoenzyme of CYP2A6 does not play an essential role in metabolism of medicines. In experiments of in vitro it was shown that the letrozole applied 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 interactions with an isoenzyme of CYP2C19 are 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-named isoenzymes and having the small range of therapeutic concentration.

Contraindications:

Letrozole is contraindicated:

- to women with the endocrine status, characteristic of the premenopauzny period;

- at pregnancy and a lactation;

- at hypersensitivity to drug components.

Overdose:

There are no data on overdose of letrozole. There are no specific antidotes. In case of overdose treatment has to be symptomatic and supporting.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 2,5 mg. On 10 or 20 tablets in blisters. On 1, 2 or 3 blisters in a cardboard box. On 5, 15, 25, 50, 100, 500 tablets in packages. On 5, 15, 25, 50, 100 tablets in bottles.