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

auxiliary substances: lactose monohydrate - 50.00 mg, sodium carboxymethyl starch - 2.50 mg, silicon colloidal dioxide - 0.50 mg, microcrystalline cellulose - 28.00 mg, crospovidone - 4.00 mg, corn pregelatinized corn starch - 11.50 mg, magnesium stearate 1.0 mg;

film sheath: "Fallen Y 1-7000 "[hypromellose, titanium dioxide, macro-gol (polyethylene glycol)] - 3.73 mg, iron-oxide oxide yellow-0.27 mg.

Description:

Round biconvex tablets, covered with a film coating of yellow color. On the cross section, the core of the tablet is white or white with a yellowish tinge.

Pharmacotherapeutic group:Antitumor agent, estrogen synthesis inhibitor

ATX: & nbsp

L.02.B.G.04 Letrozole

L.02.B.G Enzyme Inhibitors

Pharmacodynamics:

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 gland (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. Against the background of the use of letrozole, there were no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma, changes in the thyroid function, changes in the lipid profile, an increase in the frequency of myocardial infarction and strokes.

Against the background of treatment with letrozole, the incidence of osteoporosis is slightly increased (6.9% compared with 5.5% on placebo). However, the incidence of bone fractures in patients receiving letrozole, 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%. A significant advantage over the disease-free survival in the letrozole group was noted regardless of the involvement of the lymph nodes. Treatment with letrozole reduces the mortality of patients with lymph node involvement by 40%.

Pharmacokinetics:

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 (TS_m_Oh) is 1 hour when taking letrozole on an empty stomach and 2 hours - when taking with food; the mean value of the maximum concentration (C_m_Oh) is 129 ± 20.3 nmol / l when taken on an empty stomach and 98.7 ± 18.6 nmol / l - when taken with food, but the degree of absorption of letrozole (when estimating the area under the curve "concentration-time" (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.

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.

Letrozole is largely metabolized by isozymes CYP3A4 and CYP2A6 cytochrome P450 to form a pharmacologically inactive carbinol compound.

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

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

In renal failure pharmacokinetic parameters do not change.

With a moderate violation of liver function (class B on the Child-Pugh scale), the average values AUC although higher by 37%, but remain within the range of values that are observed in individuals without violations of liver function. In patients with cirrhosis of the liver and severe impairment of its function (class 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 breast cancer expressing estrogen receptors in postmenopausal women, as adjuvant therapy.

■ Early stages of breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen as an extended adjuvant therapy.

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

■ Common forms of breast cancer in postmenopausal women (natural or induced artificially) who received previous therapy with antiestrogens.

Contraindications:

■ Hypersensitivity to letrozole or any other component preparation.

■ Endocrine status characteristic of the reproductive period.

■ Pregnancy, the period of breastfeeding.

■ Child age (effectiveness and safety for children not established)

Carefully:

Deficiency of lactase, lactase intolerance, glucose-galactose malabsorption.

There is no data on the use of letrozole in patients with creatinine clearance less than 30 ml / min. Before prescribing letrozole, such patients should carefully weigh the relationship between the potential risk and the expected effecttreatment.

Dosing and Administration:

Inside, regardless of food intake.

Adults: recommended dose of the drug Letrozole is 2.5 mg once daily, daily, prolonged (for 5 years or until relapse).

As an extended adjuvant therapy treatment should last for 4 years (no longer than 5 years).

If signs of disease progression appear, the use of Letrozole should be discontinued.

In patients with a disease in the last stage or a metastatic tumor, treatment with letrozole should be continued until the tumor progresses.)

In elderly patients, dose adjustment Letrozole not required.

Patients with impaired hepatic and / or renal function: with violations of the liver or kidneys (creatinine clearance> 10 ml / min), dose adjustment is not required. However, for severe violations of the liver (class C on the Child-Pugh scale), patients should be under constant supervision.

Side effects:

As a rule, adverse reactions were mild or moderate and mainly related to suppression of the synthesis of estrogens.

The incidence of adverse reactions is estimated as follows: arising "very often" -> 10%, "often" - 1-10%, "sometimes" - 0.1-1%, "rarely" - 0.01-1.1% , "very rarely" - <0.01%, including individual messages.

On the part of the digestive system: often - nausea, vomiting, indigestion, constipation, diarrhea; sometimes - abdominal pain, stomatitis, dry mouth, increased activity of "liver" enzymes.

From the nervous system: often - headache, dizziness, depression; sometimes - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypesthesia, eating disorders, episodes of cerebral circulation disorders.

From the hematopoiesis: sometimes - a leukopenia.

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

From the respiratory system: sometimes - shortness of breath, cough.

From the skin and skin appendages: often - alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rashes); sometimes - itchy skin, dry skin, urticaria; very rarely - angioedema, anaphylactic reactions.

From the musculoskeletal system: very often - arthralgia; often - miology, bone pain, osteoporosis, fractures of bones, and sometimes - arthritis.

From the sense organs: sometimes - cataract, eye irritation, "blurring" of vision, a violation of taste sensations.

From the side of the urinary system: sometimes - frequent urination, urinary tract infections.

On the part of the reproductive system: sometimes - 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, anorexia, increased appetite; sometimes - weight loss, thirst, hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor foci.

Overdose:

There are separate reports of cases of dozethozin overdose. No specific methods of treatment of overdose are known. 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 equilibrium concentrations in plasma, does not have the ability to significantly inhibit the metabolism of diazepam (substrate isoenzyme CYP2C19). Thus, clinically significant interactions with the isoenzyme CYP2C19 unlikely.Nevertheless, 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 impairment of liver function should be under constant supervision.

During therapy with letrozole, considering the possibility of pregnancy, women in the perimenopausal and early postmenopausal period should use reliable contraceptive methods before establishing a stable postmenopausal hormonal status.

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 perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. In this regard, care should be taken when driving vehicles and working with machinery.

Form release / dosage:

Tablets, film-coated, 2.5 mg.

Packaging:

10 tablets per contour cell packaging made of polyvinylchloride film and aluminum foil.

3 contour mesh packages together with instructions for use are placed in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:5 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000179