Loretta, 2,5mg 30 pcs.

Pharmacodynamics

Letrozole has anti-estrogenic effect, selectively inhibits aromatase (enzyme of estrogen synthesis) by a highly specific competitive binding to the subunit of this enzyme – cytochrome P450 hem. It blocks estrogen synthesis in both peripheral and tumor tissues.

In postmenopausal women, estrogens are formed mainly with the participation of aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol.

Daily administration of letrozole at a daily dose of 0.1-5 mg leads to a decrease in plasma concentrations of estradiol, estrone and estrone sulfate by 75-95% of baseline. Suppression of estrogen synthesis is maintained throughout the treatment period.

When letrozole is used in the dose range from 0.1 to 5 mg no disturbance of steroid hormone synthesis in the adrenal glands is observed, the test with ACTH does not reveal disturbances of aldosterone or cortisol synthesis. No additional prescription of glucocorticoids and mineralocorticoids is required.

Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen. No changes in plasma concentrations of luteinizing and follicle stimulating hormones, changes in thyroid function, changes in lipid profile, and increased incidence of myocardial infarctions and strokes were observed during letrozole administration.

The incidence of osteoporosis slightly increased with letrozole treatment (6.9% compared to 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 for early breast cancer reduces the risk of recurrence, increases 5-year symptom-free survival, and reduces the risk of developing secondary tumors.

Long-term adjuvant therapy with letrozole reduces the risk of recurrence by 42%.

A significant survival advantage in the letrozole group was observed regardless of lymph node involvement. Treatment with letrozole reduced mortality in patients with lymph node involvement by 40%.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal tract of the GI tract with an average bioavailability of 99.9%. Food intake slightly reduces the absorption rate. Mean Tmax time is 1 hour when letrozole is taken on an empty stomach and 2 hours when taken with food; mean Cmax is (129±20.3) nmol/l when taken on an empty stomach and (98.7±18.6) nmol/l when taken with food, but letrozole absorption degree (when estimated by AUC value) is not changed.

Significant changes in absorption rate are considered to be of no clinical significance, so letrozole can be taken regardless of food intake. The binding of letrozole with blood plasma proteins is approximately 60% (predominantly with albumin – 55%). Letrozole concentration in erythrocytes is about 80% of that in blood plasma. The apparent volume of distribution in equilibrium is about (1.87±0.47) l/kg. The equilibrium concentration is reached within 2-6 weeks of a daily dose of 2.5 mg.

Pharmacokinetics is non-linear. No cumulation has been noted with long-term use. Letrozole is largely metabolized by the CYP3A4 and CYP2A6 isoenzymes of cytochrome P450 to form a pharmacologically inactive carbinol compound.

Extracted mainly by the kidneys as metabolites, to a lesser extent – through the intestine. Final T1/2 is 48 hours. Pharmacokinetic parameters of letrozole do not depend on the age of the patient. In renal failure pharmacokinetic parameters do not change. In moderately expressed hepatic impairment (Child-Pugh B) mean values of AUC, although higher by 37%, but remain within the range of values observed in patients without hepatic impairment.

In patients with cirrhosis and severe liver dysfunction (Child-Pugh C) AUC is increased by 95% and T1/2 by 187%. However, taking into account good tolerability of high doses of the drug (5-10 mg/day), there is no need to change the dose of letrozole in these cases.

Indications

Early stages of breast cancer, the cells of which have hormone receptors, in postmenopausal women as adjuvant therapy.

Early stages of breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen as 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 artificially induced) who have received previous antiestrogens therapy.

Pharmacological effect

Pharmacodynamics

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

In postmenopausal women, estrogens are formed mainly with the participation of the enzyme aromatase, which converts androgens 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 the blood plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the entire treatment period.

When using letrozole in a dose range from 0.1 to 5 mg, disturbances in the synthesis of steroid hormones in the adrenal glands are not observed, and the ACTH test does not reveal disturbances in the synthesis of aldosterone or cortisol. Additional administration of glucocorticoids and mineralocorticoids is not required.

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

During treatment with letrozole, the incidence of osteoporosis 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 in healthy people of the same age.

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

Extended adjuvant therapy with letrozole reduces the risk of relapse by 42%.

A significant advantage in disease-free survival in the letrozole group was observed regardless of lymph node involvement. Treatment with letrozole reduces mortality in patients with lymph node involvement by 40%.

Pharmacokinetics

Letrozole is quickly and completely absorbed from the gastrointestinal tract, the average bioavailability is 99.9%. Eating slightly reduces the rate of absorption. The average Tmax time is 1 hour when taking letrozole on an empty stomach and 2 hours when taking it with food; the average Cmax value 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 (as assessed by AUC value) does not change.

Minor changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be taken with or without food. The binding of letrozole to 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 steady state is about (1.87 ± 0.47) l/kg. Steady-state concentrations are achieved within 2-6 weeks of daily administration of a daily dose of 2.5 mg.

Pharmacokinetics is nonlinear. No accumulation was observed with long-term use. Letrozole is extensively metabolized by cytochrome P450 isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound.

It is excreted primarily by the kidneys in the form of metabolites, and to a lesser extent through the intestines. The final 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 moderately severe liver dysfunction (Child-Pugh B), the average AUC values, although higher by 37%, remain within the range of values ​​observed in individuals without liver dysfunction.

In patients with cirrhosis of the liver 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.

Special instructions

Patients with severely impaired liver function should be under constant supervision.

During letrozole therapy, given the potential for pregnancy, perimenopausal and early postmenopausal women should use reliable methods of contraception until stable postmenopausal hormonal levels are established.

Influence on the ability to drive a car and operate machinery. Some side effects of the drug, such as general weakness and dizziness, may affect the ability to perform potentially hazardous activities that require concentration and quick reactions. In this regard, care should be taken when operating vehicles and machinery.

Active ingredient

Letrozole

Composition

Film-coated tablets 2.5 mg.

10 tablets in blisters made of polyamide/aluminum foil/PVC//aluminum foil.

3 or 9 blisters are packed together with instructions for use in a cardboard box.

Contraindications

Hypersensitivity to letrolose or any other component of the drug; endocrine status characteristic of the reproductive period;

pregnancy; breastfeeding period;

children’s age (efficacy and safety for children have not been established).

With caution: there is no data on the use of letrozole in patients with creatinine clearance less than 10 ml/min. Before prescribing letrozole, such patients should carefully weigh the balance between the potential risk and the expected effect of treatment.

Side Effects

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

The incidence of adverse reactions is estimated as follows: occurring very often – ˃10%, often – 1-10%, sometimes – 0.1-1%, rarely – 0.01-0.1%, very rarely – ˂0.01%, including individual reports.

From the digestive system: often – nausea, vomiting, dyspepsia, constipation, diarrhea; sometimes – abdominal pain, stomatitis, dry mouth, increased activity of liver enzymes; very rarely – hepatitis.

From the nervous system: often – headache, dizziness, depression; sometimes – anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, impaired taste perception, episodes of cerebrovascular accident.

From the hematopoietic organs: sometimes – leukopenia.

From the cardiovascular system: sometimes – palpitations, tachycardia, thrombophlebitis of the superficial and deep veins, increased blood pressure, coronary heart disease (angina pectoris, myocardial infarction, heart failure), thromboembolism; rarely – pulmonary embolism, arterial thrombosis, stroke.

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

From the skin and skin appendages: often – alopecia, increased sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rash); sometimes – itching, dry skin, urticaria; very rarely – angioedema, anaphylactic reactions, Lyell’s syndrome (toxic epidermal necrolysis), Steven-Johnson syndrome (erythema multiforme).

From the musculoskeletal system: very often – arthralgia; often – myalgia, bone pain, osteoporosis, bone fractures; sometimes – arthritis.

From the senses: sometimes – cataracts, eye irritation, blurred vision, disturbance of taste.

From the urinary system: sometimes – frequent urination, urinary tract infections.

From 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.

Interaction

When letrozole is coadministered with cimetidine and warfarin, no clinically significant interactions are observed.

There is currently no clinical experience with the use of letrozole in combination with other antitumor agents.

According to the results of an in vitro study, letrozole suppresses the activity of cytochrome P450 isoenzymes – CYP2A6 and CYP2C19 (the latter – moderately). When deciding on the clinical significance of these data, it is necessary to take into account that the CYP2A6 isoenzyme does not play a significant role in the metabolism of drugs.

In vitro experiments have shown that letrozole at concentrations 100 times higher than equilibrium plasma values ​​does not significantly inhibit the metabolism of diazepam (a substrate for CYP2C19). Therefore, clinically significant interactions with the CYP2C19 isoenzyme are unlikely. However, caution should be exercised when concomitantly using letrozole and drugs that are metabolized primarily with the participation of the above-mentioned isoenzymes and have a narrow therapeutic index.

Overdose

Symptoms: There are isolated reports of cases of overdose of letrozole.

Treatment: symptomatic and supportive therapy. There are no specific treatments for overdose known.

Letrozole is eliminated from plasma by hemodialysis.

Manufacturer

Sinton Spain S.L., Spain