Letrozole - instructions for use, dose, side effects, contraindications

auxiliary substances (core): lactose monohydrate 20.0 mg; cellulose microcrystalline 61.45 mg; sodium carboxymethyl starch 4.0 mg; silicon dioxide colloid 0.5 mg; magnesium stearate 1.5 mg;

auxiliary substances (shell): hypromellose 0.68 mg; macrogol 0.34 mg; talc 0.34 mg; titanium dioxide 0.34 mg; iron oxide oxide yellow 0.30 mg.

Description:

Round, biconvex tablets, covered with a film coat, from light yellow to dark yellow color. The tablet core is cross-sectional white or almost white in color.

Pharmacotherapeutic group:Antitumor agent - estrogen synthesis inhibitor

ATX: & nbsp

L.02.B.G.04 Letrozole

L.02.B.G Enzyme Inhibitors

Pharmacodynamics:

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

In postmenopausal women, estrogens are formed predominantly with the participation of the aromatase enzyme, which turns the androgen synthesized in the adrenal gland (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 blood plasma by 75-95% of the original content.Suppression of the synthesis of estrogens is maintained throughout the treatment period.

With the use of 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 adrenocorticosteroid hormone does not reveal violations of the synthesis of aldosterone or cortisol. Additional use of glucocorticosteroids and mineralocorticosteroids is not required.

The blockade of the biosynthesis of estrogens does not lead to the accumulation of androgens, which are precursors of estrogens. Against the background of the use of letrozole, there were no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma, changes in the thyroid function, changes in the lipid profile, an increase in the frequency of myocardial infarction and strokes.

Against the background of treatment with letrozole, the frequency of osteoporosis is slightly increased. However, the incidence of bone fractures in patients receiving letrozole, does not differ from that in healthy people of the same age (6.9% compared with 5.5% placebo).

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

With prolonged adjuvant therapy letrozol reduces the risk of relapse by 42%. Extended adjuvant therapy with letrozole after 5 years of therapy with tamoxifen led to a significant reduction in the risk of progression and development of collateral breast cancer compared with placebo. A significant advantage over the disease-free survival in the letrozole group was noted regardless of the involvement of the lymph nodes. Treatment with letrozole reduces the mortality of patients with lymph node involvement by 40%.

Pharmacokinetics:

Letrozole is quickly and completely absorbed from the gastrointestinal tract (GIT), the average bioavailability is approximately 99.9%. Food intake slightly reduces the absorption rate. The mean time to reach the maximum concentration of letrozole in the blood (TS_mOh) is approximately 1 hour when taking letrozole on an empty stomach and 2 hours - when taken with food; the mean value of the maximum concentration (C_mOh) is approximately 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 (when estimating the area under the concentration-time curve (AUC)) does not change.

Small changes in the rate of absorption are regarded as having no clinical significance, so letrozole can be taken regardless of food intake. The connection between letrozole and 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 in the equilibrium state is approximately 1.87 ± 0.47 l / kg. The equilibrium concentration is achieved during 2-6 weeks of daily intake of a daily dose of 2.5 mg.

Pharmacokinetics is nonlinear. Cumulation with long-term use is not noted. Letrozole is significantly exposed to metabolism under the action of CYP3A4 and CYP2A6 isozymes cytochrome P450 to form a pharmacologically inactive carbinol compound.

It is excreted mainly by kidneys in the form of metabolites, to a lesser extent - through the intestine. The final half-life (T_1/2) is about 48 hours.

The pharmacokinetic parameters of letrozole are independent of age of patient.

With renal insufficiency pharmacokinetic parameters do not change.

At an average degree liver dysfunction (class B on the Child-Pugh scale) averages AUC although higher by 37%, but remain within the range of values that are observed in individuals without violations of liver function. In patients with cirrhosis of the liver and severe impairment of its function (class C on the Child-Pugh scale) AUC increases by 95% and T_1/2187%. 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.

Indications:

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

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

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

- Common breast cancer in the development of recurrence or progression of the disease in postmenopausal women (natural or induced artificially) who received previous therapy with antiestrogens.

- The hormone-dependent HER-2 Negative breast cancer in postmenopausal women as neoadjuvant therapy with contraindications to chemotherapy and no need for emergency surgical intervention.

Contraindications:

- Hypersensitivity to letrozole or any other component of the drug;

- endokrinny status, characteristic of the reproductive period;

- bPregnancy, the period of breastfeeding;

- Children under 18 years of age (effectiveness and safety for children not established).

Carefully:

Severe liver failure (class C on the Child-Pugh scale), severe renal failure (creatinine clearance <10 mL / min), rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, concomitant use with potent inhibitors of isoenzymes CYP3A4 and CYP2A6.

Simultaneous use with drugs with a narrow therapeutic index, the removal of which depends mainly on isoenzyme CYP2C19.

Pregnancy and lactation:

The use of Letrozole during pregnancy and during breastfeeding is contraindicated. Letrozole should not be used in pregnant women, except when the expected benefit to the mother clearly exceeds the possible risk to the fetus.

Letrozole should not be used in women breastfeeding, except when the expected benefit clearly exceeds the risk. Women of reproductive age during treatment should constantly use effective methods of contraception.

Dosing and Administration:

Inside, regardless of food intake.

Adults: recommended dose of the drug Letrozole is 2.5 mg once daily, daily, long-term.

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

When there are signs of progression of the disease, taking the drug Letrozole should be discontinued.

In the neoadjuvant (pre-operative period), treatment with the drug should continue for 4-8 months to achieve an optimal reduction in tumor size. If there is no adequate response of the tumor to treatment, the drug should be stopped, it is necessary to decide the question of surgical or other types of treatment.

Patients with impaired hepatic function

For mild to moderate liver function disorders (class A and B on the Child-Pugh scale), dose adjustment is not required. Data on the use of the drug in patients with severe violations of the liver (class C on the scale Child-Pugh) is not enough, and therefore the use of the drug in such patients should be done with constant monitoring of the doctor.

Patients with impaired renal function

For violations of kidney function (creatinine clearance ≥ 10 ml / min), dose adjustment is not required. Data on the use of the drug in patients with creatinine clearance <10 ml / min is not enough.

Patients ≥65 years of age

In elderly patients, dose adjustment is not required.

If a dose is missed, it should be taken as soon as possible, but avoiding duplication (if the time of the next dose is practically reached).

Exceeding the daily dose> 2.5 mg threatens to increase the systemic effects of the drug.

Side effects:

As a rule, adverse reactions were mild or moderate and mainly associated with suppression of the synthesis of estrogens. The incidence of adverse reactions is estimated as follows: arising "very often" -> 10%, "often" -> 1 - <10%, "infrequently" -> 0.1% - <1%, "rarely" -> 0, 01 - <0.1%, "very rarely" - <0.01%, including individual messages.

Infectious and parasitic diseases: infrequently - urinary tract infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently - pain in the area of the tumor.

Violations from the blood and lymphatic system: infrequently, leukopenia.

Immune system disorders: frequency unknown - anaphylactic reactions.

Disorders from the metabolism and nutrition: very often hypercholesterolemia; often anorexia, increased appetite.

Disorders of the psyche: often - depression; infrequently - anxiety (including nervousness), irritability.

Impaired nervous system: often - headache, dizziness; infrequently - drowsiness, insomnia, memory impairment, impaired sensitivity (including paresthesia, hypoesthesia), eating disorders, episodes of cerebral circulation disorders, carpal tunnel syndrome.

Disorders from the side of the organ of vision: infrequently - cataract, eye irritation, "clouding" of vision.

Heart Disease: infrequent - palpitations *, tachycardia, ischemic heart disease (including newly diagnosed or worsening of the course of existing angina pectoris,angina requiring surgical intervention, myocardial infarction, myocardial ischemia).

Vascular disorders: very often - paroxysmal sensations of heat ("hot flashes"); often - increased blood pressure (BP); infrequently - thrombophlebitis (including thrombophlebitis of superficial and deep veins); rarely - embolism of the pulmonary artery, thrombosis of the arteries, stroke.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - dyspnea, cough.

Disorders from the gastrointestinal tract: often - nausea *, vomiting, indigestion, constipation, diarrhea, abdominal pain; infrequently - stomatitis, dry mouth.

Disorders from the liver and bile ducts: infrequently - increased activity of "hepatic" enzymes; very rarely - hepatitis.

Disturbances from the skin and subcutaneous tissues: very often - excessive sweating; often - alopecia, dry skin, rash (including erythematous, maculopapular, psoriasiform and vesicular); infrequently - itchy skin, hives; frequency unknown - angioedema, Lyell's syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (malignant polymorphic exudative erythema).

Disturbances from the musculoskeletal and connective tissue: very often - arthralgia; often - myalgia, bone pain *, osteoporosis, fractures of bones; infrequently - arthritis; frequency is unknown - a snapping finger syndrome.

Disorders from the kidneys and urinary tract: infrequently - rapid urination.

Violations of the genitals and mammary glands: often - vaginal bleeding; infrequently - discharge from the vagina, dryness of the vagina, pain in the mammary glands.

General disorders and disorders at the site of administration: very often - increased fatigue (including asthenia and a feeling of discomfort); often - peripheral edema; infrequently generalized edema, dry mucous membranes, thirst, fever.

Laboratory and instrumental data: often - weight gain; infrequently, weight loss.

* - adverse reactions, revealed in the metastatic period.

Separate Adverse Reactions

Adverse reactions from the heart

When adjuvant therapy with letrozole for 5 years compared with placebo treatment for 3 years following adverse reactions were observed: angina requiring surgical intervention met - in 0.8% of cases and 0.6% ofrespectively; coronary heart disease (including newly diagnosed or worsening of existing angina pectoris) - 1.4% and 1.0%, respectively; myocardial infarction - in 1.0% and in 0.7% of cases, respectively; thromboembolic events - in 0.9% and in 0.3% of cases, respectively; stroke / transient ischemic attack - in 1.5% and in 0.8% of cases, respectively.

Adverse reactions from the musculoskeletal system and connective tissue

With adjuvant therapy with Letrozole for 5 years compared with placebo therapy for 3 years, the following adverse reactions were noted: bone fractures in 10.4% and in 5.8% of cases, respectively; osteoporosis - in 12.2% and in 6.4% of cases, respectively.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

Symptoms:

There are separate reports of cases of dozethozin overdose.

Treatment:

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

Interaction:

Letrozole is metabolized predominantly in the liver with the participation of isoenzymes CYP3A4 and CYP2A6 cytochrome P450. The systemic elimination of letrozole may be affected by drugs that affect these isoenzymes.

Metabolism letrozola demonstrates a low affinity with isoenzyme CYP3A4, since this isoenzyme in conventional 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.

Drugs that lead to increased concentrations of letrozole in the blood serum

Inhibitor inhibitors CYP3A4 and CYP2A6 are able to reduce the metabolism of letrozole, thereby increasing its concentration in the blood serum. Simultaneous application of powerful inhibitors of these isoenzymes (for isoenzyme CYP3A4 are, for example, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; for the isoenzyme CYP2A6 - metoksalen) can lead to an increase in the exposure of letrozole. Care must be taken when using letrozole and powerful inhibitors of CYP3A4 and CYP2A6 isoenzymes at the same time.

Drugs that lead to a decrease in the concentration of letrozole in the blood serum

Inductors of isoenzyme CYP3A4 and CYP2A6 are able to increase the metabolism of letrozole, thereby reducing its concentration in serum. Simultaneous application of inducers of these isoenzymes (for isoenzyme CYP3A4 are, for example, phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort perforated) can lead to a decrease in the exposure of letrozole; for isoenzyme CYP2A6 - inducers are not known.

Simultaneous use of the drug Letrozole (in a dose of 2.5 mg) and tamoxifen in a dose of 20 mg / day leads to a decrease in the concentration of letrozole in the blood serum by an average of 38%. Clinical data on the effect on the efficacy and safety of the drug Letrozole after the appointment of tamoxifen, no.

Medicinal preparations, whose concentration in serum depends on the use of letrozole

In vitro letrozole inhibits isoenzyme CYP2A6 cytochrome P450 and slightly isoenzyme CYP2C19, the clinical significance of this phenomenon is not established. Care must be taken when concomitantly administering letrozole and drugs with a narrow therapeutic index, the excretion of which depends primarily on isoenzyme CYP2C19 (e.g., phenytoin, clopidogrel).

Drugs with a narrow therapeutic index for isoenzyme CYP2A6 is currently unknown.

With the simultaneous use of letrozole with cimetidine (a known non-specific inhibitor of isoenzymes CYP2C19 and CYP3A4) and warfarin (sensitive isoenzyme substrate CYP2C9 with a narrow therapeutic index, which is often prescribed as a concomitant therapy for patients taking the drug Letrozole) clinically significant interactions are not observed.

Special instructions:

Patients with severe impairment of liver function should be under constant supervision.

No data on drug use Letrozole in patients with creatinine clearance less than 10 ml / min. Before starting the preparation Letrozole in such patients, the relationship between the potential risk and the expected effect of treatment should be carefully assessed.

Since the drug Letrozole It is recommended to determine the concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and / or estradiol before the start of treatment, in the case of an unexplained hormonal regulation of the reproductive system.

An increase in the level of FSH in the serum leads to stimulation of the growth of the follicles and can cause ovulation, and therefore during therapy with the drug Letrozole there is a potential possibility of pregnancy in women in the perimenopausal and early postmenopausal period. In such cases, reliable contraceptive methods should be used before establishing a stable postmenopausal hormone level in this category of patients.

There are data on the development of osteoporosis and / or the emergence of bone fractures during the application of the drug Letrozole (see "Adverse Reactions from the Musculoskeletal System and Connective Tissue"), and therefore careful monitoring of the condition of bone tissue is recommended throughout the entire period of application of the drug.

It is recommended to avoid simultaneous application of the drug Letrozole with tamoxifen, other anti-estrogenic and estrogen-containing drugs, since these drugs can weaken the pharmacological action of letrozole (see "Interaction with other drugs").The mechanism of this interaction has not been studied.

The drug is not indicated for the treatment of breast cancer that does not contain receptors for steroid hormones (estrogen or progesterone).

Effect on the ability to drive transp. cf. and fur:

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

Form release / dosage:

Tablets, film-coated, 2.5 mg.

Packaging:

Primary packaging

For 10 tablets, coated with a film sheath, into a contoured cell packaging made of a polyvinylchloride film and aluminum foil printed lacquered.

For 10, 14, 28, 30, 60 or 100 tablets coated with a film sheath, into a jar of low-pressure polyethylene with a cover pulled with the control of the first opening. Free space in the bank is filled with cotton wool.On the bank, paste a label from paper label or writing or from polymer materials, self-adhesive.

Secondary packaging

By 1, 3, 6 or 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard for consumer containers.

50, 100, 150, 200, 300, 500 or 1000 cans, together with an equal number of instructions for use, are placed in a group box - corrugated cardboard box (for hospitals).

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004049

Date of registration:27.12.2016 / 13.11.2017

Expiration Date:27.12.2021

The owner of the registration certificate:Pharmaceuticals Nord, JSCPharmaceuticals Nord, JSC Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Biosyntez Laboratories Private Limited India

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Letrozole (Letrozole)