Letrozole, 2,5mg 30 pcs.

Pharmacodynamics

Antitumor drug, inhibitor of estrogen synthesis. Letrozole has anti-estrogenic effect, selectively inhibits aromatase (enzyme of estrogen synthesis) by a highly specific competitive binding to a subunit of this enzyme – cytochrome P450 heme. 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 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 using Letrozole in the dose range from 0.1 to 5 mg there is no disturbance of steroid hormone synthesis in adrenal glands, ACTH test does not reveal disturbance 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.

Letrozole does not cause changes in plasma concentrations of LH and FSH, changes in thyroid function, changes in lipid profile, increased incidence of myocardial infarction and stroke. Against the background of Letrozole treatment the incidence of osteoporosis slightly increased (6.9% compared to 5.5% against 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 survival without signs of disease for 5 years, and reduces the risk of secondary tumors.

Letrozole extended adjuvant therapy reduces the risk of recurrence by 42%. A significant benefit in terms of symptom-free survival was observed in the letrozole group regardless of lymph node involvement. Treatment with Letrozole reduces mortality in patients with lymph node involvement by 40%.

Pharmacokinetics

Intake

Letrozole is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Bioavailability on average is 99.9%. Food intake slightly reduces the absorption rate. Mean T_max is 1 h when letrozole is taken on an empty stomach and 2 h when taken with food; mean C_max in plasma 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 letrozole absorption (when assessed by AUC value) does not change.

Significant changes in the absorption rate are considered to be of no clinical significance, so Letrozole can be taken regardless of food intake.

Pharmacokinetics are nonlinear.

Distribution

The binding of letrozole to plasma proteins is approximately 60% (predominantly to albumin, 55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. The apparent V_d in equilibrium is about 1.87±0.47 l/kg. Css is achieved over 2-6 weeks of daily use at a daily dose of 2.5 mg. No cumulation was noted with long-term use.

Metabolism

Letrozole is largely metabolized with the isoenzymes CYP3A4 and CYP2A6 to form a pharmacologically inactive carbinol compound.

Extracted mainly by the kidneys as metabolites, to a lesser extent – through the intestine. The final T_1/2 is 48 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of letrozole are independent of patient age.

In renal insufficiency pharmacokinetic parameters do not change.

In moderately severe hepatic impairment (Child-Pugh class B) mean AUC values, although 37% higher, remain within the range of values observed in persons without hepatic impairment. In patients with cirrhosis and severe liver dysfunction (class C according to Child-Pugh scale) AUC is increased by 95%, T_1/2 – by 187%. However, given the good tolerability of the drug in high doses (5-10 mg/day), there is no need to change the dose of Letrozole in these cases.

Indications

Active ingredient

Composition

1 tablet contains:

Active substances:

letrozole 2.5 mg.

Associates:

Lactose monohydrate 50 mg,

sodium carboxymethyl starch 2.5 mg,

silica colloidal dioxide 500 µg,

Microcrystalline cellulose 28 mg,

Crospovidone 4 mg,

Pregelatinized corn starch 11.5 mg,

Magnesium stearate 1 mg.

Composition of the film coating:

Opadray Y 1-7000 (hypromellose, titanium dioxide, macrogol (polyethylene glycol) 3.73 mg, iron oxide yellow dye 270 µg.

There are 10 tablets in the blister. There are 3 blisters in the carton pack.

How to take, the dosage

The drug is taken orally, regardless of meals.

The recommended dose of Letrozole is 2.5 mg once daily, long term (for 5 years or until relapse).

For extended adjuvant therapy, treatment should be continued for 4 years (no longer than 5 years).

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

In patients with advanced stage disease or metastatic tumor, treatment with Letrozole should be continued as long as the tumor progression is evident.

In elderly patients, there is no need to adjust the dose of Letrozole.

In patients with hepatic or renal impairment (CK >10 ml/min) no dose adjustment is required. However, patients with severe hepatic impairment (class C on the Child-Pugh scale) require continuous medical monitoring.

Interaction

In concomitant use of Letrozole with cimetidine and warfarin no clinically significant interaction is 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 studies letrozole inhibits the activity of CYP2A6 and CYP2C19 isoenzymes (the latter moderately). When deciding about 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 experimental studies in vitro it was shown that letrozole in concentrations 100 times higher than Css in plasma does not have the ability to significantly inhibit the metabolism of diazepam (substrate of CYP2C19 isoenzyme). Thus, a clinically significant interaction due to the effect on the activity of CYP2C19 isoenzyme is unlikely.

However, caution should be exercised in co-administration of Letrozole and drugs that are metabolized primarily with the participation of the mentioned isoenzymes and have a narrow therapeutic index.

Special Instructions

Patients with severe liver dysfunction should be under constant monitoring.

At the time of therapy with Letrozole, considering the possibility of pregnancy, women in perimenopausal and early postmenopausal periods should use reliable methods of contraception until a stable postmenopausal hormonal status is established.

Impact on ability to drive vehicles and other mechanisms requiring increased concentration

Some side effects of the drug, such as general weakness and dizziness, may affect the ability to perform potentially dangerous activities requiring increased concentration and rapid psychomotor reactions. Therefore, patients should use caution when driving vehicles and operating machinery.

Contraindications

With caution: the drug should be used in lactase deficiency, lactase intolerance, glucose-galactose malabsorption. There are no data on the use of Letrozole in patients with CKD < 30 ml/min (before prescribing the drug to these patients the ratio between the potential risk and the expected treatment effect should be carefully weighed).

Side effects

In general, adverse reactions were mild to moderate and mostly related to suppression of estrogen synthesis.

Determining the frequency of adverse reactions:

Gastrointestinal system: frequently – nausea, vomiting, dyspepsia, constipation, diarrhea; sometimes – abdominal pain, stomatitis, dry mouth, increased liver enzyme activity.

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

Hematopoietic system disorders: sometimes – leukopenia.

The cardiovascular system: sometimes – palpitations, tachycardia, thrombophlebitis of superficial and deep veins, increased BP, CHD (angina, myocardial infarction, heart failure), thromboembolism; rarely – pulmonary embolism, arterial thrombosis, stroke.

Respiratory system disorders: sometimes – dyspnea, cough.

Dermatological reactions: frequently – alopecia, increased sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rash); sometimes – skin itching, dry skin, urticaria; very rarely – angioedema, anaphylactic reactions.

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

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

The urinary system: sometimes – frequent urination, urinary tract infections.

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

Mechanisms: often – weight gain, hypercholesterolemia, anorexia, increased appetite; sometimes – weight loss, thirst.

Others: very often – hot flashes (hot flashes); often – fatigue, asthenia, malaise, peripheral edema; sometimes – hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor foci.

Overdose

There have been isolated reports of cases of Letrozole overdose.

Treatment: Symptomatic and supportive therapy is indicated. No specific methods of treatment of overdose are known. Letrozole is excreted from the plasma by hemodialysis.

Pregnancy use

The use is contraindicated in pregnancy and during lactation (breastfeeding).

Similarities