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

Letrozole has an antiestrogenic effect, selectively inhibits aromatase (an enzyme for the synthesis of estrogens) by highly competitive binding to the subunit of this enzyme, the heme cytochrome P450.

It blocks the synthesis of estrogens in both peripheral and tumor tissues.

In postmenopausal women, estrogens are formed predominantly with the participation of the aromatase enzyme, which turns the androgen synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol. Daily intake of letrozole in a daily dose of 0.1 - 5 mg leads to a decrease in the concentration of estradiol, estrone and estrone sulfate in blood plasma by 75-95% of the original content.Suppression of the synthesis of estrogens is maintained throughout the treatment period.

With the use of letrozole in the dose range from 0.1 to 5 mg, there is no violation of the synthesis of steroid hormones in the adrenal glands, the test with adrenocorticotropic hormone (ACTH) does not reveal violations of the synthesis of aldosterone or cortisol. Additional appointment of glucocorticoids and mineralocorticoids is not required.

The blockade of the biosynthesis of estrogens does not lead to the accumulation of androgens, which are precursors of estrogens. With the use of letrozole, there are no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma, changes in thyroid function, changes in the lipid profile, an increase in the frequency of myocardial infarctions and strokes.

Against the backdrop of treatment with letrozole, the incidence of osteoporosis is slightly increased (6.9% compared with 5.5% with placebo). However, the frequency of bone fractures in patients does not differ from that of healthy people of the same age.

Adjuvant therapy with letrozole early stages of breast cancer reduces the risk of relapse, increases the disease-free survival for 5 years, reduces the risk of developing secondary tumors.

With prolonged adjuvant therapy letrozol reduces the risk of relapse by 42%.

Pharmacokinetics:

Suction

Letrozole is quickly and completely absorbed from the gastrointestinal tract (GIT), the average bioavailability is 99.9%. Food intake slightly reduces the absorption rate. The mean time to reach the maximum concentration of letrozole in the blood (Tmah) is 1 hour when taking letrozole on an empty stomach and 2 hours - when taking with food; the mean value of the maximum concentration (Cma) is 129 ± 20.3 nmol / L for fasting and 98.7 ± 18.6 nmol / L for food intake, however, the extent of letrozole absorption (when estimated by the area under the concentration-time curve (AUC) ) does not change.

Small changes in the rate of absorption are regarded as having no clinical significance, so letrozole can be taken regardless of food intake.

Distribution

The connection between letrozole and plasma proteins is approximately 60% (mainly with albumin - 55%). The concentration of letrozole in erythrocytes is about 80% of that in blood plasma. The apparent volume of distribution in the equilibrium state is about 1.87 ± 0.47 l / kg.The equilibrium concentration is achieved during 2-6 weeks of daily intake of a daily dose of 2.5 mg.

Pharmacokinetics is nonlinear. Cumulation with long-term use is not noted.

Metabolism

Letrozole is significantly exposed to metabolism under the action of CYP3A4 and CYP2A6 isozymes of cytochrome P450 to form a pharmacologically inactive carbinol compound.

Excretion

Letrozole is excreted mainly by kidneys in the form of metabolites, to a lesser extent - through the intestines. The final half-life (T1 / 2) is 48 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of letrozole do not depend on the age of the patient.

With renal failure, the pharmacokinetic parameters of letrozole do not change.

With moderate hepatic insufficiency (degree "B" on the Child-Pugh scale), the mean AUC values, although 37% higher, remain within the range of values that are observed in individuals without liver function disorders. In patients with cirrhosis of the liver and severe impairment of its function (degree of severity "C" on the Child-Pugh scale), AUC increases by 95% and T1 / 2 by 187%. However, given the good tolerability of high doses of the drug (5-10 mg / day), in these cases there is no need to change the dose of letrozole.

Indications:

- Early stages of invasive breast cancer, whose cells have hormone receptors in postmenopausal women, as adjuvant therapy.

- Early stages of invasive breast cancer in postmenopausal women after completion standard adjuvant therapy with tamoxifen for 5 years as extended adjuvant therapy.

- Common hormone-dependent forms of breast cancer in postmenopausal women (first-line therapy).

- Common hormone-dependent forms of breast cancer in the development of recurrence or progression of the disease in postmenopausal women (natural or induced artificially) who received previous therapy with antiestrogens.

Contraindications:

- Hypersensitivity to letrozole or any other component of the drug.

- Endocrine status characteristic of the reproductive period.

- Pregnancy, the period of breastfeeding.

- Age to 18 years.

Carefully:

Severe hepatic insufficiency (degree of severity "C" on the Child-Pugh scale), renal failure (creatinine clearance less than 10 ml / min).

Simultaneous use of letrozole with drugs that have a low therapeutic index.

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption (since lactose is contained in the dosage form).

Pregnancy and lactation:

The drug is contraindicated for use during pregnancy and during breastfeeding.

Dosing and Administration:

Inside, regardless of food intake.

The recommended dose of the drug Estrolet® is 2.5 mg (1 tablet) once a day, daily, long.

As an extended adjuvant therapy treatment should last for 5 years (no longer than 5 years).

When there are signs of progression of the disease, taking the drug Estrolet® should be discontinued.

In elderly patients, dose adjustment Estrolet® not required. Patients with impaired hepatic and / or renal function

With hepatic or renal (creatinine clearance> 10 ml / min), no dose adjustment is required. However, in severe hepatic insufficiency (degree of severity "C" on the Child-Pugh scale), patients should be under constant supervision.

Side effects:

Adverse reactions, as a rule, are weakly or moderately expressed and, mainly, are associated with suppression of the synthesis of estrogens.

The incidence of adverse reactions is classified according to the recommendations of the 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%; rarely - more than 0.01 and less than 0.1%; very rarely - less than 0.01%, including individual reports.

Disturbances from the digestive system: often - nausea, vomiting, indigestion, constipation, diarrhea; infrequently - abdominal pain, stomatitis, dry mouth, increased activity of "liver" enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)); very rarely - hepatitis.

Impaired nervous system: often - headache, dizziness, depression; infrequently - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, eating disorders, episodes of cerebral circulation disorders, carpal tunnel syndrome.

Violations from the blood and lymphatic system: infrequently, leukopenia.

Disorders from the cardiovascular system: infrequently - sensation palpitations, tachycardia, increased blood pressure (BP), coronary heart disease (angina, myocardial infarction, heart failure), thrombophlebitis of the superficial and deep veins, thromboembolism; rarely - embolism of the pulmonary artery, thrombosis of the arteries, stroke.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, cough.

Disturbances from the skin and subcutaneous tissues: often - alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rashes); infrequently - itchy skin, dry skin, urticaria; very rarely - angioedema, anaphylactic reactions, Lyell's syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (erythema multiforme).

Disturbances from the musculoskeletal and connective tissue: very often - arthralgia; often - pain in the bones, myalgia, osteoporosis, fractures of bones; infrequently - arthritis; frequency is not known - a snapping finger syndrome.

Disorders from the side of the organ of vision: infrequently - cataract, eye irritation, "clouding" the view.

Disorders from the kidneys and urinary tract: infrequent urination, urinary tract infections.

Violations of the genitals and breast: infrequently - vaginal bleeding, vaginal discharge, vaginal dryness, pain in the mammary glands.

Other: very often - paroxysmal sensations of heat ("hot flashes"), often - increased fatigue, asthenia, malaise, peripheral edema, weight gain, hypercholesterolemia, increased appetite, anorexia; infrequently - weight loss, thirst, hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor foci.

Overdose:There are separate reports of cases of dozethozin overdose. There are no specific treatments for overdose. Symptomatic and supportive therapy is indicated. Letrozole is removed from the plasma by hemodialysis.

Interaction:

With the simultaneous use of letrozole with cimetidine and warfarin, clinically significant interactions are not observed.

Clinical experience in the application of letrozole in combination with other antitumour agents is currently not available.

According to the research results in vitro, letrozole suppresses activity of cytochrome P450 isoenzymes - CYP2A6 and CYP2C19 (the latter is moderately). When deciding the importance of these data for the clinic, it is necessary to take into account that the isoenzyme CYP2A6 does not play a significant role in the metabolism of drugs. In experiments in vitro it was shown that letrozole in concentrations 100 times higher than the equilibrium values in plasma, does not have the ability to significantly suppress the metabolism of diazepam (a substrate for CYP2C19). Thus, clinically significant interactions with the isoenzyme CYP2C19 unlikely. Caution should be exercised in the combined use of letrozole and drugs metabolized predominantly with the aforementioned isoenzymes and having a narrow therapeutic index.

Special instructions:

Patients with severe hepatic insufficiency (severity "C" on the Child-Pugh scale) should be under constant supervision. It is recommended to determine the concentration of cholesterol in the blood.

During drug therapy Estrolet®, given the potential for pregnancy, women in the perimenopausal and early postmenopausal period should usereliable methods of contraception until the establishment of a stable postmenopausal hormone level.

During the therapy with letrozole, monitoring of bone density is recommended.

Effect on the ability to drive transp. cf. and fur:

Some of the side effects of the drug, such as general weakness and dizziness, can affect the ability to carry out potentially dangerous activities requiring attention concentration and quick reactions (including driving and machine management).

When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets, film-coated, 2.5 mg.

Packaging:

In the production of the drug at OOO "Nativa", Russia:

Form of issue

Tablets, film-coated, 2.5 mg.

For 10 tablets in a planar cell pack of polymer film and aluminum foil.

For 1, 3, 6, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard box.

For 10, 30, 60, 90 or 100 tablets in polymer bottles, sealed with plastic caps.

One bottle together with the instruction for use is placed in a cardboard box.

Or, at manufacture of a preparation on Open Society "Farmstadart-UfaVITA", Russia:

Form of issue

Tablets, film-coated, 2.5 mg.

For 10 tablets in a planar cell pack of polymer film and aluminum foil.

For 1, 3, 6, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002339

Date of registration:10.01.2014

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

PHARMSTANDART-UFIM VITAMIN FACTORY, OJSC Russia

NATIVA, LLC Russia

Information update date: & nbsp15.10.2015

Illustrated instructions

Instructions

Estrolet® (Estrolet®)