Letrozole pills 2,5mg №30

Active substance

Letrozole

Composition

1 pill contains:

Active ingredients: letrozole 2.5 mg.

Excipients: lactose monohydrate 50 mg, carboxymethyl starch sodium 2.5 mg, colloidal silicon dioxide 500 mcg, microcrystalline cellulose 28 mg, crospovidone 4 mg, corn starch pregelatinized 11.5 mg, Magnesium stearate 1 mg.

The composition of the film shell: opadry Y 1-7000 (hypromellose, titanium dioxide, macrogol (polyethylene glycol)) 3.73 mg, iron dye yellow oxide 270 mcg.

In the blister of 10 tablets. In carton pack 3 blisters.

Mechanism of action

Pharmacodynamics

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

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

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 ACTH does not reveal any violations of the synthesis of aldosterone or cortisol. Additional administration of glucocorticoids and mineralocorticoids is not required.

The blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen.

While receiving Letrozole, there were no changes in the concentrations of LH and FSH in the blood plasma, changes in thyroid function, changes in the lipid profile, an increase in the incidence of myocardial infarction and stroke. During treatment with letrozole, the incidence of osteoporosis increases to a small extent (6.9% compared with 5.5% against placebo). However, the incidence of bone fractures in patients receiving Letrozole is not different from that in healthy people of the same age.

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

Extended adjuvant therapy with letrozole reduces the risk of recurrence by 42%. A significant survival benefit without signs of disease in the letrozole group was noted regardless of the involvement of lymph nodes. Treatment with letrozole reduces mortality in patients with lymph node involvement by 40%.

Pharmacokinetics

Suction

After oral administration, letrozole is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability averages 99.9%.Food intake slightly reduces the rate of absorption. Average t_max is 1 hour when taking letrozole on an empty stomach and 2 hours when taken with food; mean C_max in blood 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 absorption of letrozole (as measured by AUC value) does not change.

Small changes in the rate of absorption are regarded as having no clinical significance, therefore Letrozole can be taken regardless of the meal.

Pharmacokinetics is nonlinear.

Distribution

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 plasma. Seeming v_d in equilibrium state is about 1.87 ± 0.47 l / kg. Css is achieved within 2-6 weeks of daily administration of the drug in a daily dose of 2.5 mg. Cumulation with prolonged use is not marked.

Metabolism

Letrozole is largely metabolized with the participation of CYP3A4 and CYP2A6 isoenzymes with the formation of a pharmacologically inactive carbinol compound.

Removal

Excreted mainly by the kidneys in the form of metabolites, to a lesser extent - through the intestines. Final t_1/2 is 48 hours

Pharmacokinetics in special clinical situations

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

In renal failure, the pharmacokinetic parameters do not change.

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

Indications

• The early stages of breast cancer expressing estrogen receptors, in postmenopausal women, as an adjuvant therapy;
• early stages of breast cancer in postmenopausal women after the 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 artificially induced) who received prior anti-estrogen therapy.

Use during pregnancy and lactation

Contraindicated use during pregnancy and lactation (breastfeeding).

Contraindications

• Endocrine status characteristic of the reproductive period;
• pregnancy;
• lactation period (breastfeeding);
• children's age (efficacy and safety for children has not been established);
• hypersensitivity to the drug.

With caution: the drug should be used in case of lactase deficiency, lactase intolerance, glucose-galactose malabsorption. There is no data on the use of letrozole in patients with CC <30 ml / min (before prescribing the drug, such patients should carefully weigh the ratio 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 the suppression of estrogen synthesis.

Determination of the frequency of adverse reactions:

• very often (> 10%);
• often (1-10%);
• sometimes (0.1-1%);
• rarely (0.01–0.1%);
• very rarely (<0.01%), including individual messages.

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

On the part of the nervous system: often - headache, dizziness, depression; sometimes - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, episodes of cerebral circulation.

From the hemopoietic system: sometimes - leukopenia.

Cardiovascular: sometimes - a feeling of heartbeat, tachycardia, thrombophlebitis of the superficial and deep veins, increased blood pressure, coronary heart disease (angina, myocardial infarction, heart failure), thromboembolism; rarely - pulmonary embolism, arterial thrombosis, stroke.

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

Dermatological reactions: often - alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rash); sometimes - itching, dry skin, urticaria; very rarely - angioedema, Anaphylactic reactions .

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

On the part of the senses: sometimes - cataract, irritation of the eyes, blurred vision, impaired taste.

On the part of the urinary system: sometimes - frequent urination, urinary tract infections.

Reproductive system: sometimes - vaginal bleeding, vaginal discharge, vaginal dryness, pain in the mammary glands.

On the part of the metabolism: often - an increase in body weight, hypercholesterolemia, anorexia, increased appetite; sometimes - weight loss, thirst.

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

Interaction

With simultaneous use of letrozole with cimetidine and Warfarin, there is no clinically significant interaction.

Clinical experience on the use of Letrozole in combination with other anticancer agents is currently not available.

According to the results of in vitro studies, letrozole inhibits the activity of CYP2A6 and CYP2C19 isoenzymes (the latter is moderate). When deciding on the significance of this data for the clinic, it is necessary to take into account that the CYP2A6 isoenzyme does not play a significant role in the metabolism of drugs. 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 suppress the metabolism of diazepam (the substrate of the 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 the combined use of Letrozole and drugs that are metabolized mainly with the participation of these isoenzymes and have a narrow therapeutic index.

How to take, the course of administration and dosage

The drug is taken orally, regardless of the meal.

The recommended dose of Letrozole is 2.5 mg 1 time per day, daily, for a long time (for 5 years or until relapse).

As extended adjuvant therapy, treatment should continue for 4 years (not longer than 5 years).

If there is evidence of disease progression, the administration of the drug Letrozole should be discontinued.

In patients with late-stage disease or a metastatic tumor, the treatment with Letrozole should be continued until tumor progression is expressed.

In elderly patients, dose adjustment of the drug Letrozole is not required.

In case of impaired liver or kidney function (CC> 10 ml / min), dose adjustment is not required. However, for severely impaired liver function (Child-Pugh class C), patients need constant medical supervision.

Overdose

There are separate reports of cases of overdose of Letrozole.

Treatment: Symptomatic and supportive therapy is indicated. No specific treatment for overdose is known. Letrozole is excreted from the plasma through hemodialysis.

Special instructions

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

During therapy with Letrozole, taking into account the possibility of pregnancy, women in the perimenopausal and early postmenopausal period should use reliable methods of contraception until a stable postmenopausal hormonal status is established.

Influence on the ability to drive vehicles and other mechanisms that require high concentration of attention

Some side effects of the drug, such as general weakness and dizziness, can affect the ability to perform potentially hazardous activities that require increased concentration and psychomotor speed. Therefore, patients should be careful when driving and working with mechanisms.

Release form

pills

Storage conditions

Keep out of reach of children, dry, dark place at temperatures not above 25 ° C.