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

Excipients: lactose monohydrate 61,500 mg, microcrystalline cellulose 20,000 mg, corn starch 9.500 mg, sodium carboxymethyl starch 5,000 mg, silicon dioxide colloid 0.500 mg, magnesium stearate 1,000 mg.

Casing of the tablet: hypromellose 1.838 mg, talc 1.331 mg, macrogol 8000 0.333 mg, ferric oxide yellow oxide (17268) 0.249 mg, titanium dioxide 0.249 mg.

Description:

Round, slightly biconcave, with beveled edges, dark yellow tablets. On one side of the tablet is printed "FV", another - "CG".

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 at 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 purpose glucocorticosteroids and mineralocorticosteroids 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 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 survival rate without signs of disease 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%. Extended adjuvant therapy with letrozole after 5 years of therapy with tamoxifen resulted in a significant risk reduction progression and development of cancer of the contralateral breast as compared with placebo.

Pharmacokinetics:

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 when taken on an empty stomach and 98.7 ± 18.6 nmol / l - when taken with food, however, the degree of absorption of letrozole (when estimating the area under the curve "concentration-time" (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 reached 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 largely exposed to metabolism under the action of isoenzymes 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.

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

With renal insufficiency pharmacokinetic parameters are not are changing.

If the liver function is of moderate severity (Child-Pugh B), the average values of AUC, although higher by 37%, but remain within the range of values,which are noted in persons without violations of the liver. In patients with cirrhosis and severe impairment of its function (Child-Pugh C), AUC increases by 95% and T1 / 2 by 187%. 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:

The drug is indicated for therapy:

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

- Early stages of invasive breast cancer in postmenopausal women after completion of standard adjuvant therapy tamoxifen for 5 years as an 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 relapse or disease progression in postmenopausal women (natural or induced artificially) who received previous therapy with antiestrogens.

- Gormonependent 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.

Endocrine status characteristic of the reproductive period.

Pregnancy, the period of breastfeeding.

Age to 18 years.

Carefully:

Care should be taken when using the preparation of Femar® patients with severe hepatic Insufficiency (class C on a scale Child-Pugh), severe renal disease insufficiency (creatinine clearance less than 10 ml / min).

Dosing and Administration:

Inside, regardless of food intake.

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.

Adults. The recommended dose of Femar® is 2.5 mg once daily, daily, and for a long time.

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

When signs of progression appear disease reception of the preparation of Femar® should be discontinued.

In the neoadjuvant (preoperative) regimen, treatment with Femar® should be continued for 4-8 months to achieve an optimal reduction in tumor size.If there is no adequate response of the tumor to treatment, the preparation of Femar® should be discontinued, it is necessary to decide the question of surgical or other types of treatment.

Patients with impaired hepatic function

With violations of liver function light and moderate severity correction of the dose of the preparation of Femar® is not required (class A or B on a scale Child-Pugh). Data on the use in patients with severe impairment of liver function (grade C on a scale Child-Pugh) insufficient, in connection with which the use of the drug in such patients should be carried out 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 in patients with clearance of creatinine <10 ml / min is not enough.

Patients aged > 65 years old

In elderly patients, correction of the dose of the preparation of Femar® is not required.

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: rarely leukopenia.

Violations from the immune system: the frequency is unknown - anaphylactic reactions.

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

Mental disorders: often - depression; infrequently - anxiety (including nervousness), irritability.

Disturbances from the 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 disorders: infrequent heart palpitations *, tachycardia, coronary heart disease (including newly diagnosed or worsening of existing angina, angina requiring surgical intervention, myocardial infarction, myocardial ischemia).

Violations from the vessels: 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 increase the activity of "liver" enzymes; very rarely - hepatitis.

Disorders 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).

Disorders 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: infrequent - frequent 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 injection site: 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

With adjuvant therapy with Femar® for 5 years compared with placebo therapy for 3 years, the following adverse reactions were noted: angina pectoris requiring surgical intervention occurred in 0.8% of cases and in 0.6% of cases, respectively; ischemic heart disease (including newly diagnosed or worsening of existing angina pectoris) in 1.4% and 1.0% of cases, 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 fabrics

With adjuvant therapy with the preparation of Femar® 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, inform the doctor about it.

Overdose:

There are separate reports of cases of an overdose of Femar®.

Any specific, overdose treatment methods are unknown. Symptomatic and supportive therapy is indicated. Letrozole is removed from the plasma by hemodialysis.

Interaction:

Letrozole is metabolized mainly in the liver with the participation of isoenzymes CYP3A4 and CYP2A6 cytochrome P 450. The systemic elimination of letrozole may be affected by drugs that affect these isozymes.

Metabolism letrozola demonstrates a low affinity with isoenzyme CYP3A4, since this isoenzyme in usual clinical situations at concentrations 150 times higher than the equilibrium values letrozole in blood plasma, does not have the ability to suppress metabolism letrozole.

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

Inhibitors of isoenzymes CYP3A4 and CYP2A6 are able to reduce the metabolism of letrozole, thereby increasing its concentration in the blood serum. Simultaneous use of powerful inhibitors of these isoenzymes (for the isoenzyme CYP3A4, such 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 isoenzymes 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 the isoenzyme CYP3A4 such 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 application of the preparation of Femar® (at 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 use of the preparation of Femar® after the administration of tamoxifen is not available.

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

In vitro letrozole inhibits the isoenzyme CYP2A6 cytochrome P 450 and slightly isozyme CYP2C19, the clinical significance of this phenomenon is not established. Care should be taken when concomitantly administering letrozole and drugs with a narrow therapeutic index, the removal of which depends mainly on the isoenzyme CYP2C19 (for example, phenytoin, clopidogrel).

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

With the simultaneous administration of letrozole with cimetidine (a known nonspecific inhibitor of CYP2C19 isoenzymes and CYP3A4) and warfarin (sensitive isoenzyme substrate CYP2C9 with a narrow therapeutic index, which is often prescribed as a concomitant therapy for patients taking Femar®) clinically relevant interactions are not observed.

Special instructions:

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

There is no data on the use of the preparation of Femar® in patients with creatinine clearance less than 10 ml / min. Before starting to use Femar® in these patients, the relationship between potential risk and the expected effect of treatment should be carefully assessed.

Since the preparation of Femar® is used only in patients in postmenopausal women, in the case of an unexplained status hormonal regulation of the reproductive system recommended to determine the concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and / or estradiol before treatment.

An increase in FSH levels in the serum leads to stimulation of the growth of follicles and can cause ovulation, in with which during the therapy with the preparation of Femar®, 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 occurrence of bone fractures during the application of the preparation of Femar® (see "Adverse reactions from the musculoskeletal system and connective tissue"), and therefore careful monitoring of the bone tissue during the entire period of application is recommended preparation.

It is advisable to avoid simultaneous use of the preparation of Femar® with tamoxifen, other anti-estrogenic and estrogen-containing drugs, since these agents 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 cancer therapy The breast, which 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, 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 machinery. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Tablets, film-coated 2.5 mg.

Packaging:

10 tablets in a blister pack. For 3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

List B.

Shelf life:

5 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N015738 / 01

Date of registration:29.06.2009

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp22.10.2015

Illustrated instructions

Instructions

Femara® (Femara®)