Loreta - instructions for use, doses, side effects, contraindications

Excipients: lactose monohydrate 61.50 mg, cellulose microcrystalline 20.00 mg, corn pregelatinized corn starch 9.50 mg, sodium carboxymethyl starch 5.00 mg, magnesium stearate 1.00 mg, silicon dioxide colloid 0.50 mg.

Shell: Fell yellow (03F32518) 4.00 mg (macrogol 8000 0.33 mg, talc 1.33 mg, hypromellose 1.84 mg, titanium dioxide 0.25 mg, iron oxide dye yellow 0.25 mg).

Description:Round, biconvex tablets, film-coated, yellow, engraved "L900" on one side of the tablet and "2.5" on the other. On the cross-section the nucleus is white.

Pharmacotherapeutic group:Antineoplastic, an inhibitor of the synthesis of estrogens

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 glands (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 adenocorticotropic hormone (ACTH) does not reveal violations of the synthesis of aldosterone or cortisol. Additional appointment 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 taking letrozole, 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 were not observed.

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

Adjuvant therapy with letrozole early stages of breast cancer reduces the risk of relapse, increases the disease-free survival for 5 years, reduces the risk of developing secondary tumors.With prolonged adjuvant therapy letrozol reduces the risk of relapse by 42%. 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:

Suction and distribution

Letrozole is quickly and completely absorbed from the gastrointestinal tract (GIT), the average bioavailability is 99.9%. Food intake slightly reduces the absorption rate. The mean time to reach the maximum concentration of letrozole in the blood (T_m_Oh) is 1 hour when taking letrozole on an empty stomach and 2 hours - when taking with food; the mean value of the maximum concentration (C_m_Oh) is 129 ± 20.3 nmol / L for fasting and 98.7 ± 18.6 nmol / L for food intake, but the extent of letrozole absorption (in the area estimate 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 about 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.

Metabolism and excretion

Letrozole is largely metabolized by isozymes CYP3A4 and CYP2A6 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 (T1 / 2) is 48 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of letrozole do not depend on the age of the patient. In renal failure pharmacokinetic parameters do not change. When the liver function of moderate severity (Child-Pugh class B), the average values 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 and severe impairment of liver function (Child-Pugh class C) AUC increases by 95% and T1 / 2 by 187%. However, in these cases, given the good tolerability of high doses of the drug (5-10 mg / day), do not change the dose of letrozole.

Indications:

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

- 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.

- 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 forms of 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.

Contraindications:

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

- Endocrine status characteristic of the reproductive period.

- Pregnancy; the period of breastfeeding;

- Age to 18 years.

Carefully:

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Severe hepatic insufficiency (Child-Pugh class C).

Severe renal insufficiency (creatinine clearance <10 ml / min).

Simultaneous application with powerful inhibitors of isoenzymes CYP3A4 and CYP2A6 or drugs with a narrow therapeutic index.

Pregnancy and lactation:

Contraindicated because there are no clinical studies for this group of patients.

The results of preclinical studies showed that letrozole possesses embryotoxic and fetotoxic effect, therefore, in case of pregnancy during therapy with letrozole, the patient should be warned about the potential hazard to the fetus while continuing therapy with the drug.

Dosing and Administration:

Inside, regardless of food intake.

The recommended dose of the drug LORETA 2.5 mg once a day, daily, long.

If a dose is missed, it should be used as soon as possible, but avoiding duplication (if the time of the next dose is practically reached). Exceeding the daily dose> 2.5 mg provokes an increase in the systemic effects of the drug.

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 the tumor does not reach an adequate response to treatment, the drug should be stopped, it is necessary to decide the question of surgical or other types of treatment. As an extended adjuvant therapy treatment should last for 5 years (not more than 5 years).

If signs of disease progression appear, use of LORET should be discontinued.

Patients with impaired hepatic function

In the case of violations of the liver function of mild and moderate severity, dose adjustment is not required (Child-Pugh classes A, B). The therapy with letrozole in patients with severe impairment of liver function (Child-Pugh class C) should be carried out with constant monitoring of the doctor.

Patients with impaired renal function

If there is a violation of kidney function (creatinine clearance> 10 ml / min) dose correction of letrozole is not required. Therapy with letrozole in patients with severe renal impairment creatinine clearance <10 ml / min (Child-Pugh class C) should be carried out with the constant monitoring of the doctor.

Patients over 65 years of age

In elderly patients, correction of the dose of LORET is not required.

Side effects:

The frequency of adverse reactions is estimated as follows: "very often" occurring -> 10%, "often" -> 1 - <10%, "infrequently" -> 0.01% - - <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 polyps cysts): 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.

Mental disturbance: 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 organs of vision: infrequently - cataract, eye irritation, "clouding" of vision.

Disorders from the heart: infrequently - palpitation, tachycardia, coronary heart disease (including the first time detected or worsening of the existing angina, angina requiring surgery, 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.

Violation of the respiratory system, chest and mediastinum: 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.

Disorders from the rut 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.

Violation of the genitals and mammary glands: often - vaginal bleeding; infrequent - 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 indicators: often - weight gain; infrequently, weight loss.

Overdose:

Symptoms: there are some reports of cases of dozethrosin overdose, specific symptomatology is not described.

Treatment: symptomatic and supportive therapy. Letrozole is displayed during dialysis.

Interaction:

Letrozole is metabolized predominantly in the liver with the participation of isoenzymes CYP2A6 and CYP2C19 cytochrome P450. The systemic elimination of letrozole may be affected by drugs that affect these isozymes.

Drugs that lead to an increase in the concentration of letrozole in the blood serum.

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

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

Inductors of isoenzymes CYP3A4 and CYP2A6 are able to increase the metabolism of letrozole, thereby reducing its concentration in the blood serum. Simultaneous application of inducers of these isoenzymes (for isoenzyme CYP3A4 such are, for example, phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort pitted) may lead to a decrease in the exposure of letrozole; for isoenzyme CYP2A6 - Inductors are unknown.

Simultaneous use with tamoxifen

With the simultaneous use of letrozole and tamoxifen at a dose of 20 mg / day, the concentration of letrozole in the serum is reduced by an average of 38%.

Simultaneous use with drugs that have a narrow therapeutic index

In vitro letrozole inhibits isoenzyme CYP2A6 cytochrome P450 and slightly CYP2C19, the clinical significance of this phenomenon is not established. Care should be taken when applying letrozole simultaneously with drugs with a narrow therapeutic index, the administration of which depends primarily on isoenzyme CYP2C19 (eg, phenytoin, clopidogrel).

Simultaneous use with cimetidine and warfarin

With the simultaneous use of letrozole with cimetidine (a known nonspecific inhibitor of isoenzymes CYP2C19 and CYP3A4) and warfarin (sensitive isoenzyme substrate CYP2C9c narrow therapeutic index, which is often prescribed as a concomitant therapy for patients receiving letrozole) clinically significant interactions are not observed.

Special instructions:

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

During therapy with letrozole, given the potential for pregnancy, women in the perimenopausal and early postmenopausal periods should use reliable contraceptive methods before establishing a stable postmenopausal hormone level.

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 in such patients, the relationship between the potential risk and the expected effect of treatment should be carefully evaluated.

- As 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 FSH levels in the serum leads to stimulation of the growth of follicles and can cause ovulation, and therefore, during therapy with the drug, 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 group of patients.

- There are data on the development of osteoporosis and / or bone fractures during the application of letrozole (see "Disturbances from the musculoskeletal system and connective tissue"), therefore careful monitoring of the bone tissue during the entire period of application of the drug is recommended. It is recommended to avoid simultaneous use of the drug with tamoxifen, other antiestrogenic 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 and progesterone).

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

Some of the side effects of the drug, such as general weakness, dizziness and drowsiness, can affect the ability to perform potentially dangerous activities requiring attention concentration and rapid reactions.

In this regard, care should be taken when driving vehicles and mechanisms, and when these undesirable phenomena appear, one should refrain from carrying out these activities.

Form release / dosage:Film coated tablets 2.5 mg.

Packaging:

For 10 tablets in blisters of polyamide / aluminum foil / PVC // aluminum foil. 3 or 9 blisters packed with instructions for use in a cardboard box.

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 expiry date.

Terms of leave from pharmacies:On prescription

Registration number:PL-000733

Date of registration:29.09.2011 / 06.02.2017

Expiration Date:Unlimited

The owner of the registration certificate:ESCO PHARMA, LLCESCO PHARMA, LLC

Manufacturer: & nbsp

SYNTHON HISPANIA, S.L. Spain

Representation: & nbspESCO PHARMA, LLCESCO PHARMA, LLC

Information update date: & nbsp13.11.2017

Illustrated instructions

Instructions

Loreta (Loreta)