Letrozole tablets 2.5mg, No. 30

• Early stages of invasive breast cancer, whose cells have receptors for hormones, in postmenopausal women, as an adjuvant therapy.

• Early stages of invasive breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen for 5 years as an extended adjuvant therapy.

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

• Widespread breast cancer with the development of a relapse 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.

The recommended dose is 2.5 mg 1 time / day daily, for a long time.

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

If signs of disease progression appear, letrozole should be discontinued. In the neoadjuvant (preoperative) regimen, letrozole treatment should be continued for 4-8 months to achieve optimal tumor shrinkage. If an adequate tumor response to treatment is not achieved, letrozole should be discontinued, it is necessary to decide on surgical or other types of treatment.

Film-coated tablets

active substance: letrozole

Hypersensitivity to letrozole; endocrine status characteristic of the premenopausal period; pregnancy, lactation (breastfeeding); children under 18 years of age (efficacy and safety for children has not been established). With caution: severe hepatic impairment (class C on the Child-Pugh scale), severe renal impairment (creatinine clearance <10 ml / min), rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, simultaneous use with potent inhibitors of CYP3A4 and CYP2A6 isoenzymes. Simultaneous use with drugs with a narrow therapeutic index, the excretion of which depends mainly on the isoenzyme CYP2C19.

pharmachologic effect

Antineoplastic agent. It is a non-steroidal inhibitor of aromatase, an enzyme with the participation of which estrogen is synthesized in postmenopausal women. Aromatase promotes the conversion of androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol. The inhibition of aromatase activity is realized by competitive binding with the subunit of this enzyme - cytochrome P450 heme, which leads to a decrease in estrogen biosynthesis in all tissues, incl. in the tissues of estrogen-dependent tumors.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal tract, the average bioavailability is approximately 99.9%. Food intake slightly reduces the rate of absorption. The average time to reach Cmax of letrozole in the blood is approximately 1 hour when taking letrozole on an empty stomach and 2 hours when taken with food; the average Cmax is about 129 ± 20.3 nmol / L when taken on an empty stomach and about 98.7 ± 18.6 nmol / L when taken with food, but the degree of absorption of letrozole (as measured by AUC) does not change. The binding of letrozole to blood 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 Vd at equilibrium is approximately 1.87 ± 0.47 l / kg.Equilibrium concentration is achieved within 2-6 weeks of daily intake of a daily dose of 2.5 mg. Pharmacokinetics is nonlinear. Cumulation with prolonged use was not noted. Letrozole is largely metabolized by the 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 intestines. T1 / 2 is approximately 48 hours.

Side effect

Possibly: headache, nausea, peripheral edema, general weakness, hot flashes, thinning hair, skin rash, vomiting, dyspepsia, weight gain, musculoskeletal pain, anorexia, vaginal bleeding, leucorrhea, constipation, dizziness, increased appetite, increased sweating ... Rarely: shortness of breath, thrombophlebitis, spotting from the vagina. From the hematopoietic system: infrequently - leukopenia. From the immune system: the frequency is unknown - anaphylactic reactions. From the side of metabolism: very often - hypercholesterolemia; often - anorexia, increased appetite. From the side of the psyche: often - depression; infrequently - anxiety (including nervousness), irritability. From the nervous system: often - headache, dizziness; infrequently - drowsiness, insomnia, memory impairment, impaired sensitivity (including paresthesia,hypesthesia), taste disturbances, episodes of cerebrovascular accident, carpal tunnel syndrome. From the side of the organ of vision: infrequently - cataracts, eye irritation, blurred vision. From the side of the cardiovascular system: very often - hot flashes ('hot flashes'); often - increased blood pressure; infrequently - palpitations, tachycardia, coronary artery disease (including newly diagnosed or worsening of the course of existing angina pectoris, angina pectoris requiring surgery, myocardial infarction, myocardial ischemia), thrombophlebitis (including thrombophlebitis of superficial and deep veins); rarely - pulmonary embolism, arterial thrombosis, stroke, ischemic attack. From the respiratory system: infrequently - dyspnea, cough. From the digestive system: often - nausea, vomiting, dyspepsia, constipation, diarrhea, abdominal pain;infrequently - stomatitis, dry mouth. From the liver and biliary tract: infrequently - increased activity of liver enzymes; very rarely - hepatitis. On the part of the skin and subcutaneous tissues: very often - increased sweating; often - alopecia, dry skin, rash (including erythematous, maculopapular, psoriasiform and vesicular); infrequently - itching, urticaria; frequency unknown - angioedema, Lyell's syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (malignant polymorphic exudative erythema). From the musculoskeletal system: very often - argralgia; often - myalgia, bone pain, osteoporosis, bone fractures; infrequently - arthritis; frequency unknown - snapping finger syndrome. From the urinary system: infrequently - frequent urination, urinary tract infections.From the genitals and mammary glands: often - vaginal bleeding; infrequently - vaginal discharge, vaginal dryness, 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, weight gain; infrequently - benign, malignant and unspecified neoplasms (including cysts and polyps), pain in the area of ??the tumor, weight loss.often - peripheral edema; infrequently generalized edema, dry mucous membranes, thirst, fever, weight gain; infrequently - benign, malignant and unspecified neoplasms (including cysts and polyps), pain in the area of ??the tumor, weight loss.often - peripheral edema; infrequently generalized edema, dry mucous membranes, thirst, fever, weight gain; infrequently - benign, malignant and unspecified neoplasms (including cysts and polyps), pain in the area of ??the tumor, weight loss.

Application during pregnancy and lactation

The use of letrozole during pregnancy and during breastfeeding is contraindicated. Letrozole should not be used in pregnant women unless the expected benefit to the mother clearly outweighs the potential risk to the fetus. Letrozole should not be used in women who are breastfeeding unless the expected benefit clearly outweighs the risk. Women of reproductive age should use effective contraception at all times during treatment.

Application for violations of liver function

It should be used with caution in patients with severe hepatic impairment (class C on the Child-Pugh scale).

Application for impaired renal function

It should be used with caution in patients with severe renal impairment (creatinine clearance <10 ml / min). The relationship between the expected therapeutic effect and the possible risk of treatment should be carefully weighed.

Application in children

Contraindicated for use in children and adolescents under the age of 18 years.

Use in elderly patients

It is possible to use letrozole in patients over 65 years of age according to indications, in recommended doses.

special instructions

Patients with severely impaired liver function should be monitored continuously. There is no data on the use of letrozole in patients with creatinine clearance less than 10 ml / min. Before starting the use of the drug 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 starting treatment. An increase in serum FSH levels leads to stimulation of follicular growth and can cause ovulation, and therefore, during therapy with letrozole,there is the potential for pregnancy in perimenopausal and early postmenopausal women. In such cases, reliable methods of contraception should be used until a stable postmenopausal hormonal level is 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, and therefore it is recommended to carefully monitor the state of the bone tissue during the entire period of use of letrozole. It is recommended to avoid the simultaneous use of letrozole with tamoxifen, other anti-estrogenic and estrogen-containing drugs, since these drugs can weaken the pharmacological effect of letrozole. Letrozole is not indicated for the treatment of breast cancer.not containing receptors for steroid hormones (estrogen or progesterone).

Influence on the ability to drive vehicles and use mechanisms

Some side effects of the drug, such as general weakness, drowsiness and dizziness, can affect the ability to perform potentially hazardous activities that require increased concentration and psychomotor speed. In this regard, care should be taken when driving vehicles and when working with mechanisms. When the described undesirable phenomena appear, you should refrain from performing these activities.

Drug interactions

Letrozole is metabolized mainly in the liver with the participation of isoenzymes CYP3A4 and CYP2A6 of cytochrome P450. The systemic elimination of letrozole can be influenced by drugs acting on these isozymes. The metabolism of letrozole demonstrates a low affinity for 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 the metabolism of letrozole. Inhibitors of isoenzymes CYP3A4 and CYP2A6 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 isoenzyme CYP2A6 - methoxalen) may increase the exposure to letrozole. Care must be taken with the simultaneous use of letrozole and potent inhibitors of CYP3A4 and CYP2A6 isoenzymes. Inducers of the isoenzyme CYP3A4 and CYP2A6 are able to increase the metabolism of letrozole, thereby reducing its serum concentration. The simultaneous use of inducers of these isoenzymes (for the CYP3A4 isoenzyme, these are, for example, phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort) can lead to a decrease in letrozole exposure; for isoenzyme CYP2A6 - inducers are not known. 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 the blood serum by an average of 38%.There are no clinical data on the effect on the efficacy and safety of letrozole after the administration of tamoxifen. In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P450 and slightly the CYP2C19 isoenzyme. Care must be taken with the simultaneous use of letrozole and drugs with a narrow therapeutic index, the excretion of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel). With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P450 and slightly inhibits the CYP2C19 isoenzyme. Care must be taken with the simultaneous use of letrozole and drugs with a narrow therapeutic index, the excretion of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel). With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P450 and slightly inhibits the CYP2C19 isoenzyme. Care must be taken with the simultaneous use of letrozole and drugs with a narrow therapeutic index, the excretion of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel). With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.Care must be taken with the simultaneous use of letrozole and drugs with a narrow therapeutic index, the excretion of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel). With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.Care must be taken with the simultaneous use of letrozole and drugs with a narrow therapeutic index, the excretion of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel). With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.With the simultaneous use of letrozole with cimstidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy in patients taking letrozole), clinically significant interactions are not observed.