Expiration date: 01/2026

Dosage form

Round, biconvex tablets coated with a dark yellow film with a brownish tinge of color, with a chamfer and an engraving "H" on one side of the tablet and "5" on the other. In the cross section, the core is white.

Composition

One tablet contains:

Active ingredient: letrozole - 2.5 mg.

Excipients: lactose monohydrate (Pharmatose 200M) - 85.0 mg, croscarmellose sodium (AC-Di-sol) - 5.0 mg, povidone (Plasdone K-29/32) - 4.0 mg, colloidal silicon dioxide (Aerosil 200) - 2.0 mg, magnesium stearate - 1.5 mg.

The composition of the tablet shell: opadray yellow (03B82401) - 2.0 mg:

hypromellose 6 cP - 60.0%, titanium dioxide - 16.0%, iron oxide yellow - 11.0 %,

macrogol 400 - 8.0%, talc - 5.0%.

Pharmacotherapeutic group

antitumor agent - estrogen synthesis inhibitor

Pharmacodynamics

Letrozole has an antiestrogenic effect, selectively inhibits aromatase (an enzyme for the synthesis of estrogens) by highly specific competitive binding to the subunit of this enzyme, heme P450. It blocks the synthesis of estrogens in both peripheral and tumor tissues.

In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily, adrostenedione 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 initial content. Suppression of estrogen synthesis is maintained throughout the entire treatment period.

When using 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 adenocorticotropic hormone (ACTH) does not reveal violations of the synthesis of aldosterone or cortisol. Additional administration of glucocorticosteroids and mineral corticosteroids is not required.

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

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

Adjuvant therapy with letrozole in the early stages of breast cancer reduces the risk of recurrence, increases survival without signs of the disease for 5 years, and reduces the risk of developing secondary tumors.

Prolonged adjuvant therapy with letrozole reduces the risk of recurrence by 42%. A significant advantage in survival without signs of disease in the letrozole group was noted regardless of the involvement of lymph nodes.

Letrozole treatment reduces mortality in patients with lymph node involvement by 40%. Prolonged adjuvant therapy with letrozole after the end of 5 years of tamoxifen therapy led to a significant reduction in the risk of progression and development of contralateral breast cancer compared with placebo.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (GI tract), the average bioavailability is 99.9%. Eating slightly reduces the rate of absorption. The average time to reach the maximum concentration of letrozole in the blood (Tmax) is 1 hour when taking letrozole on an empty stomach and 2 hours when taken with food; the average maximum concentration (Cmax) is 129 ± 20.3 nmol/l when taken on an empty stomach and 98.7 ±18.6 nmol/l when taken with food, however, the degree of absorption of letrozole (when estimated by the area under the concentration-time curve (AUC)) it does not change.

Small changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be taken regardless of food intake. The relationship of letrozole with 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 at equilibrium is about 1.87±0.47 l/kg. The equilibrium concentration is reached within 2-6 weeks of daily intake of a daily dose of 2.5 mg.

Pharmacokinetics is nonlinear. There was no accumulation with prolonged use. Letrozole is largely metabolized by the action of cytochrome P450 isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound. It is excreted mainly by the 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 insufficiency, the pharmacokinetic parameters do not change.

In cases of moderate liver dysfunction (Child Pugh B), the average AUC values, although 37% higher, remain within the range of values observed in persons without impaired liver function. In patients with cirrhosis and severe impairment of its function (Child Pugh C), 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

The drug is indicated for therapy:

• 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 of 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 forms of breast cancer with the development of recurrence or progression of the disease in postmenopausal women (natural or artificially induced) who received previous antiestrogen therapy.
• Hormone-dependent HER-2 negative breast cancer in postmenopausal women as neoadjuvant therapy with contraindications to chemotherapy and no need for emergency surgery.

Contraindications

• Hypersensitivity to letrozole or any other component of the drug.
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
• Endocrine status characteristic of the reproductive period.
• Pregnancy, lactation period
• Under the age of 18.

With caution

Caution should be exercised when using letrozole in patients with severe hepatic insufficiency (Child Pugh class C), severe renal insufficiency (creatinine clearance less than 10 ml/min).

Use during pregnancy and breastfeeding

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

Method of administration and dosage

Inside, regardless of the meal.

If a dose is missed, it should be taken as soon as possible, but avoiding duplication (if the time for taking the next dose is almost here). Exceeding the daily dose of > 2.5 mg threatens to increase the systemic effects of the drug.

Adults

The recommended dose of letrozole is 2.5 mg once a day, daily, for a long time.

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

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

In the neoadjuvant (preoperative) mode, treatment with letrozole should be continued for 4-8 months to achieve optimal reduction in tumor size. If an adequate response of the tumor to treatment is not achieved, the use of letrozole should be discontinued, it is necessary to resolve the issue of surgical or other types of treatment.

Patients with impaired liver function

In case of impaired liver function of mild to moderate severity, dose adjustment of letrozole is not required (class A or B on the Child-Pugh scale). There is insufficient data on the use in patients with severe hepatic impairment (class C on the Child-Pugh scale), and therefore the use of the drug in such patients should be carried out under constant supervision of a doctor.

Patients with impaired renal function

In case of impaired renal function (creatinine clearance ?10 ml / min) dose adjustment is not required. Data on the use in patients with creatinine clearance ?10 ml/min is not enough.

Are the patients aged ?65 years old

In elderly patients, dose adjustment of letrozole is not required.

Side effects

As a rule, adverse reactions were mild or moderate and mainly associated with the suppression of estrogen synthesis.

The frequency of adverse reactions is estimated as follows: "very often" - > 10 %, "often" - > 1 - ? 10 %), "infrequently" - ? 0,1 % - ? 1 %, "rarely" - > 0,01 - ? 0,1 %, " very rarely" - ? 0.01%, including individual messages.

Infectious and parasitic diseases: infrequently - urinary tract infections.

Benign and malignant and unspecified neoplasms (including cysts and polyps): infrequently - pain in the tumor area.

Disorders of the blood and lymphatic system: infrequently - leukopenia.

Disorders of the immune system: the frequency is unknown - anaphylactic reactions.

Metabolic and nutritional disorders: very often - hypercholysterinemia; often - anorexia, increased appetite.

Mental disorders: often - depression; infrequently - anxiety (including nervousness), irritability.

Disorders of the nervous system: often - headache, dizziness; infrequently - drowsiness, insomnia, memory impairment, impaired sensitivity (including paresthesia, hypesthesia), impaired taste perception, episodes of cerebral circulatory disorders, carpal tunnel syndrome.

Visual disturbances: infrequently - cataracts, eye irritation, blurred vision.

Cardiac disorders: infrequently - palpitations?, tachycardia, coronary heart disease (including newly diagnosed or worsening of the course of existing angina pectoris, angina pectoris requiring surgery, myocardial infarction, myocardial ischemia).

Vascular disorders: very often - paroxysmal sensations of heat ("hot flashes"); often - increased blood pressure (BP); infrequently - thrombophlebitis (including thrombophlebitis of superficial and deep veins); rarely - pulmonary embolism, arterial thrombosis, stroke.

Disorders of the respiratory system, chest and mediastinal organs: infrequently - dyspnea, cough.

Disorders of the gastrointestinal tract: often - nausea, vomiting, dyspepsia, constipation, diarrhea, abdominal pain; infrequently - stomatitis, dry mouth.

Disorders of the liver and biliary tract: infrequently - increased activity of "liver" enzymes; very rarely - hepatitis.

Disorders of the skin and subcutaneous tissues: very often - excessive sweating; often - alopecia, dry skin, rash (including erythematous, maculopapular, psoriasis and vesicular); infrequently - itching, urticaria; frequency unknown - angioedema, Lyell syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (malignant polymorphic exudative erythema).

Disorders of musculoskeletal and connective tissue: very often - arthralgia; often - myalgia, bone pain?, osteoporosis, bone fractures; infrequently - arthritis; frequency unknown - snapping finger syndrome.

Disorders of the kidneys and urinary tract: infrequently - frequent urination.

Violation of the genital organs and mammary glands: often - vaginal bleeding; infrequently - vaginal discharge, pain in the mammary glands.

General disorders and disorders at the injection site: very often - increased fatigue (including asthenia and discomfort); often - peripheral edema; infrequently - generalized edema, dry mucous membranes, thirst, fever.

Laboratory and instrumental data: often - an increase in body weight; infrequently - a decrease in body weight.

? - adverse reactions detected in the metastatic period.

Individual adverse reactions

Adverse reactions from the heart

With adjuvant therapy with letrozole for 5 years, compared with placebo therapy for 3 years, the following adverse reactions were noted: angina pectoris requiring surgical intervention occurred in 0.8% of cases in 0.6% of cases, respectively; coronary heart disease (including newly diagnosed or worsening of the course of existing angina pectoris) - in 1.4% and in 1.0 % of cases, respectively; myocardial infarction - in 1.0% and 0.7 % of cases, respectively; thromboembolic events - in 0.9% and 0.3 % of cases, respectively; stroke/transient ischemic attack - in 1.5% and 0.8% of cases, respectively.

Adverse reactions from the musculoskeletal system and connective tissue

During adjuvant therapy with letrozole for 5 years, compared with placebo therapy for 3 years, the following adverse reactions were noted: bone fractures - in 10.4% and 5.8% of cases, respectively; osteoporosis - in 12.2% and 6.4% of cases, respectively.

If any of the side effects listed in the instructions worsen, or you notice any other side effects not listed in the instructions, inform your doctor.

Overdose

There are isolated reports of cases of letrozole overdose. Any specific overdose treatment methods are unknown. Symptomatic and supportive therapy is indicated. Letrozole is eliminated from plasma by hemodialysis.

Drug interaction

Letrozole is metabolized mainly in the liver with the participation of cytochrome P450 isoenzymes CYP3A4 and CYP2A6. The systemic elimination of letrozole may be influenced by drugs acting on these isoenzymes.

Letrozole metabolism demonstrates low affinity with the CYP3A4 isoenzyme, since this isoenzyme in normal clinical situations at concentrations 150 times higher than the equilibrium values of letrozole in blood plasma does not have the ability to suppress letrozole metabolism.

Drugs that lead to an increase in the concentration of letrozole in the blood serum

Inhibitors of the CYP3A4 and CYP2A6 isoenzymes are able to reduce the metabolism of letrozole, thereby increasing its concentration in blood serum. Simultaneous use of powerful inhibitors of these isoenzymes (for the CYP3A4 isoenzyme, these are, for example, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; for the CYP2A6 isoenzyme, methoxalen) may lead to increased exposure to letrozole. Caution should be exercised when concomitantly using letrozole and potent CYP3A4 and CYP2A6 inhibitors.

Drugs that lead to a decrease in the concentration of letrozole in the blood serum

Inducers of the CYP3A4 and CYP2A6 isoenzymes are able to increase the metabolism of letrozole, thereby reducing its concentration in blood serum. Simultaneous use of inducers of these isoenzymes (for the CYP3A4 isoenzyme, such as phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort) may lead to a decrease in letrozole exposure; for the CYP2A6 isoenzyme, inducers are unknown.

The simultaneous use of letrozole (at a dose of 2.5 mg) and tamoxifen at a dose of 20 mg / day leads to a decrease in the concentration of letrozole in serum by an average of 38%. There is no clinical data on the effect on the efficacy and safety of the use of letrozole after the appointment of tamoxifen.

Drugs whose concentration in the blood serum depends on the use of letrozole

In vitro, letrozole inhibits the cytochrome P450 CYP2A6 isoenzyme and slightly the CYP2C19 isoenzyme, the clinical significance of this phenomenon has not been established. Caution should be exercised when concomitantly using letrozole and drugs with a narrow therapeutic index, the administration of which depends mainly on the isoenzyme CYP2C19 (for example, phenytoin, clopidogrel). Drugs with a narrow therapeutic index for the CYP2A6 isoenzyme are currently unknown.

When concomitantly prescribing letrozole with cimetidine (a known non-specific inhibitor of the isoenzymes CYP2C19 and CYP3A4) and warfarin (a sensitive substrate of the isoenzyme CYP2C9 with a narrow therapeutic index, which is often prescribed as concomitant therapy to patients taking letrozole), clinically significant interactions are not observed.

Special instructions

Patients with severe hepatic impairment should be under constant supervision.

There is no data on the use of letrozole in patients with creatinine clearance less than 10 ml/min. Before starting the use of letrozole in such patients, the ratio between the potential risk and the expected effect of treatment should be carefully evaluated.

Since letrozole is used only in postmenopausal patients, in case of an unclear status of hormonal regulation of the reproductive system, it is recommended to determine the concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH and/or estradiol before treatment).

An increase in serum FSH levels leads to stimulation of follicle growth and can cause ovulation, and therefore, during therapy with letrozole, there is a potential possibility of pregnancy in women in the perimenopausal and early postmenopausal period. In such cases, reliable methods of contraception should be used until stable postmenopausal hormonal levels are established in this category of patients.

There is evidence of the development of osteoporosis and / or the occurrence of bone fractures during the use of letrozole (see "Adverse reactions from the musculoskeletal system and connective tissue"), and therefore careful monitoring of the condition of bone tissue is recommended throughout the period of use of the drug.

It is recommended to avoid concomitant use of letrozole with tamoxifenone, other antiestrogens and estrogen-containing drugs, since these drugs may weaken the pharmacological effect of letrozole (see "Interaction with other drugs"). The mechanism of this interaction has not been studied.

The drug is not indicated for the treatment of breast cancer that does not contain receptors for steroid hormones (estrogen or progesterone).

Influence on the ability to drive vehicles, mechanisms

Some side effects of the drug, such as general weakness, dizziness and drowsiness, may affect the ability to perform potentially dangerous activities that require concentration and rapid reactions.

In this regard, care should be taken when driving vehicles and mechanisms. If the described adverse events occur, you should refrain from performing these types of activities.

Storage temperature

from 2℃ to 25℃