Эстролет®

General characteristics. Structure:

Active ingredient: 2,5 mg of letrozole in 1 tablet.

Excipients: алюмометасиликат magnesium, croscarmellose sodium, silicon dioxide colloid, magnesium stearate, лудипресс (in terms of components: lactoses monohydrate, povidone, кросповидон).

The cover is film: Opadry II yellow 85F32733 (polyvinyl alcohol — from 35 to 49%, talc — from 9,8 to 25%, a macrogoal 3350 — from 7,35 to 35,2%, titanium dioxide and ferrous oxide yellow — from 15,15 to 30%).

Pharmacological properties:

Pharmacodynamics. 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 post-menopausal 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 adrenocorticotropic hormone (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 changes of concentration of luteinizing and follicle-stimulating hormones in a blood plasma, changes of function of a thyroid gland, changes of a lipidic profile, increase in frequency of myocardial infarctions and strokes are not noted.

Against the background of treatment by letrozole osteoporosis frequency (6,9% in comparison with 5,5% poorly increases  at placebo use). However the frequency of fractures of bones at patients 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%.

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 (Tmax) 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 near 1,87±0,47л/кг. 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.

Metabolism: 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: Letrozole 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 hours.

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

At a renal failure pharmacokinetic parameters of letrozole do not change.

At a liver failure of average degree (severity "In" on a scale of Chayld-Pyyu) the average sizes AUC though are 37% higher, but remain within the range of values which are noted at persons without abnormal liver functions. At patients with cirrhosis and heavy disturbances of its function (severity "With" on a scale of Chayld-Pyyu) AUC increases by 95% and T1/2 for 187%. However, considering good tolerance of high doses of drug (5-10 mg/days), in these cases there is no need to change a dose letrozole is not present.

Indications to use:

• Early stages of a breast cancer which cells have receptors to hormones, at women in the post-menopausal period, as adjuvant therapy.
• Early stages of a breast cancer at women in the post-menopausal period after completion of standard adjuvant therapy by Tamoxifenum within 5 years.
• Common hormonedependent forms of a breast cancer at women in the post-menopausal period (therapy of the first line).
• Common hormonedependent forms of a breast cancer at development of a recurrence or progressing of a disease in the women in the post-menopausal period (natural or caused artificially) receiving the previous therapy by anti-estrogen.

Route of administration and doses:

Inside, irrespective of meal. The recommended dose of the drug Estrolet® makes 2,5 mg (1 tablet) once a day is, daily, long.

As the prolonged adjuvant therapy treatment has to continue within 5 years (not longer than 5 years).

At emergence of signs of progressing of a disease administration of drug of Estrolet® should be stopped.

Dose adjustment of the drug Estrolet® is not required from patients of advanced age.

Patients with an abnormal liver function and/or kidneys. At hepatic or renal (clearance of creatinine of ≥10 ml/min.) insufficiency of dose adjustment of drug is not required. Nevertheless, at a heavy liver failure (severity "With" on a scale of Chayld-Pyyu) patients have to be under constant observation.

Features of use:

Use at pregnancy and during breastfeeding. Drug is contraindicated to use at pregnancy and during breastfeeding.

Patients with a heavy liver failure (severity "With" on a scale of Chayld-Pyyu) have to be under constant observation. Definition of concentration of cholesterol in blood is recommended.

During therapy by the drug Estrolet®, considering pregnancy approach potentiality, women in the perimenopauzalny and early post-menopausal period should use reliable methods of contraception before establishment of stable post-menopausal hormonal level.

In the course of therapy letrozole recommended monitoring of density of a bone tissue.

Influence on ability to manage vehicles and to work with mechanisms. Some side effects of drug, such as general weakness and dizziness, can influence ability of performance of potentially dangerous types of activity demanding concentration of attention and bystry reactions (including driving of the car and control of mechanisms).

At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Side reactions, as a rule, poorly or are moderately expressed and, generally connected with suppression of synthesis of estrogen. Frequency of development of side reactions is classified according to recommendations of World Health Organization: very often – more than 10%; often - more than 1 and less than 10%; infrequently - more than 0,1 and less than 1%; seldom - more than 0,01 and less than 0,1%; very seldom - less than 0,01%, including separate messages.

Disturbances from system of digestion: often - nausea, vomiting, dyspepsia, a lock, diarrhea; infrequently - abdominal pains, stomatitis, dryness in a mouth, increase in activity of "hepatic" enzymes (alaninaminotranspherase (ALT), aspartate aminotransferase (nuclear heating plant)); very seldom - hepatitis.

Disturbances from a nervous system: often - a headache, dizziness, a depression; infrequently - alarm, nervousness, irritability, drowsiness, sleeplessness, a memory impairment, a dizesteziya, paresthesia, a hypesthesia, disturbances of flavoring perception, episodes of disturbance of cerebral circulation, a syndrome of a carpal tunnel.

Disturbances from blood and lymphatic system: infrequently – a leukopenia.

Disturbances from cardiovascular system: infrequently - a heart consciousness, tachycardia, increase in the arterial pressure (AP), coronary heart disease (stenocardia, a myocardial infarction, heart failure), thrombophlebitis of superficial and deep veins, a thromboembolism; seldom - an embolism of a pulmonary artery, fibrinferments of arteries, a stroke.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: infrequently - short wind, cough.

Disturbances from skin and hypodermic fabrics: often - an alopecia, the increased perspiration, skin rash (including erythematic, makulopapulezny, vesicular rash, psoriazopodobny rashes); infrequently - a skin itch, a xeroderma, a small tortoiseshell; very seldom - a Quincke's disease, anaphylactic reactions, a Lyell's disease (a toxic epidermal necrolysis), Stephens-Johnson's syndrome (a multiformny erythema).

Disturbances from skeletal and muscular and connecting fabric: very often – an arthralgia; often - ostealgias, a mialgiya, osteoporosis, fractures of bones; infrequently – arthritis; frequency is not known – a syndrome of the clicking finger.

Disturbances from an organ of sight: infrequently - a cataract, irritation of eyes, sight "misting".

Disturbances from kidneys and urinary tract: infrequently - the speeded-up urination, infections of urinary tract. Disturbances from generative organs and a mammary gland: infrequently - vaginal bleedings, allocations from a vagina, dryness of a vagina, mammary gland pain.

Others: very often - pristupoobrazny feelings of heat ("inflows"), it is frequent -
increased fatigue, adynamy, indisposition, peripheral hypostases, increase in body weight, hyper cholesteremia, increase in appetite, anorexia; infrequently - decrease in body weight, thirst, a hyperthermia (pyrexia), dryness of mucous membranes, generalized hypostases, pains in the tumoral centers.

Interaction with other medicines:

At simultaneous use of letrozole with Cimetidinum and warfarin of clinically significant interactions 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 P450 cytochrome - 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 interactions with an isoenzyme of CYP2C19 are improbable.

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 a narrow therapeutic index.

Contraindications:

- A moderate and heavy liver failure (severity "With" on a scale of Chayld-Pyyu), a renal failure (clearance of creatinine less than 10 ml/min.).
- Simultaneous use of letrozole with the drugs possessing a low therapeutic index.
- Deficit of lactase, a lactose intolerance, glyukozo-galaktazny malabsorption (as the dosage form contains lactose).

With care:
- A moderate and heavy liver failure (severity "With" on a scale of Chayld-Pyyu), a renal failure (clearance of creatinine less than 10 ml/min.).
- Simultaneous use of letrozole with the drugs possessing a low therapeutic index.
- Deficit of lactase, a lactose intolerance, glyukozo-galaktazny malabsorption (as the dosage form contains lactose).

Overdose:

There are separate messages on letrozole overdose cases. Any specific methods of treatment of overdose are unknown. The symptomatic and maintenance therapy is shown. Letrozole is removed from plasma by means of a hemodialysis.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 2,5 mg. On 10 tablets in a blister strip packaging from a film of polymeric and aluminum foil. On 1, 3, 6, 9 or 10 blister strip packagings together with the application instruction place in a cardboard pack. On 10, 30, 60, 90 or 100 tablets in bottles polymeric, corked by plastic covers. On a bottle paste the self-adhesive label. On 1 bottle together with the application instruction place in a cardboard pack.