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 stage breast cancer whose cells have hormone receptors, in postmenopausal women as adjuvant therapy.

The early stages of breast cancer in postmenopausal women after completion of standard adjuvant tamoxifen therapy as extended adjuvant therapy.

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

The common forms of breast cancer in postmenopausal women (natural or artificially induced) who received prior anti-estrogen therapy.

Active ingredient

Composition

Tablets, film-coated 2.5 mg.

Ten tablets each in blister packs of polyamide/aluminum foil/PVC/aluminum foil.

3 or 9 blisters are packed together with instructions for use in a carton pack.

How to take, the dosage

Ingestion, regardless of meals.

In adults, the recommended dose of LORETA is 2.5 mg once daily, long-term.

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

LORETA should be discontinued if there are signs of disease progression.

In elderly patients no dose adjustment of LORETA is required.

Patients with impaired hepatic and/or renal function: In patients with hepatic or renal impairment (creatinine clearance >10 ml/min) no adjustment of the drug dose is required.

Patients with severe hepatic impairment (Child-Pugh C scale), however, should be kept under constant observation.

Interaction

In concomitant administration of letrozole 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 anticancer agents.

According to the results of in vitro study letrozole inhibits the activity of cytochrome Р450 isoenzymes – CYP2A6 and CYP2C19 (the latter moderately). When deciding on the significance of these data for the clinic, it should be taken into account that CYP2A6 isoenzyme does not play a significant role in drug metabolism.

In in vitro experiments it was shown that letrozole in concentrations 100 times greater than the equilibrium values in plasma does not have the ability to significantly inhibit the metabolism of diazepam (a substrate for CYP2C19). Thus, clinically significant interactions with CYP2C19 isoenzyme are unlikely. Nevertheless, caution should be exercised when co-administering letrozole and drugs that are metabolized mainly with participation of the above mentioned isoenzymes and have a narrow therapeutic index.

Special Instructions

Patients with severe liver dysfunction should be kept under constant surveillance.

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

Impact on driving and operating ability. Some side effects of the drug, such as general weakness and dizziness, may affect the ability to perform potentially dangerous activities requiring concentration and quick reactions. In this regard, caution should be exercised when driving vehicles and operating machinery.

Contraindications

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

pregnancy; lactation period;

childhood (efficacy and safety in children has not been established).

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

Side effects

As a rule, adverse reactions were mild to moderate and mostly related to suppression of estrogen synthesis.

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

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

Nervous system disorders: frequently – headache, dizziness, depression; sometimes – anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, taste perception disorders, episodes of cerebral circulation disorders.

Hematopoietic disorders: sometimes – leukopenia.

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

Respiratory system disorders: sometimes – dyspnea, cough.

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

Muscular system disorders: very common – arthralgia; common – myalgia, bone pain, osteoporosis, bone fractures; sometimes – arthritis.

Senses: sometimes – cataracts, eye irritation, blurred vision, impaired sense of taste.

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

Reproductive system disorders: sometimes – vaginal bleeding, vaginal discharge, vaginal dryness, pain in the breasts.

Others: very often – hot flashes (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

Symptoms: there have been isolated reports of cases of letrozole overdose.

Treatment: symptomatic and supportive therapy. No specific methods of treatment of overdose are known.

Letrozole is excreted from the plasma by hemodialysis.

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