Universal reference book for medicines
Product name: FEMARA ® (FEMARA ® )

Active substance: letrozole

Type: Antitumor drug.
Aromatase inhibitor
Manufacturer: NOVARTIS PHARMA (Switzerland) manufactured by NOVARTIS PHARMA STEIN (Switzerland)
Composition, form of production and packaging
The tablets covered with a film cover of
dark yellow color, round, slightly biconcave, with bevelled edges, "FV" is printed on one side, on the other - "CG".

1 tab.

letrozole 2.5 mg

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, sodium carboxymethyl starch, silicon colloidal dioxide, magnesium stearate, hypromellose, talc, macrogol 8000, iron dye oxide yellow (17268), titanium dioxide.

10 pieces.
- blisters (3) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2010.

PHARMACHOLOGIC EFFECT

Antitumor drug.
It 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 aromatase enzyme, which turns the androgenes synthesized in the adrenals (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 estrogen is maintained throughout the treatment.
When using the preparation of Femar ® 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 violations of the synthesis of aldosterone or cortisol.
Additional appointment of glucocorticoids and mineralocorticoids 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 Femara's acceptance, 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 Femara, the incidence of osteoporosis is slightly increased (6.9% compared with 5.5% in the placebo group).
However, the frequency of bone fractures in patients receiving the preparation of Femar ® does not differ from that of healthy people of the same age.
Adjuvant therapy with Femaroy early stages of breast cancer reduces the risk of progression, increases disease-free survival for 5 years, reduces the risk of developing a tumor of another breast.

The prolonged adjuvant therapy of Femara reduces the risk of progression by 42%.
A significant advantage over the disease-free survival in the Femara group was noted regardless of the involvement of the lymph nodes. Treatment with Femar ® reduces mortality among patients with lymph node involvement by 40%.
PHARMACOKINETICS

Suction

Letrozole is rapidly and completely absorbed from the digestive tract (the average bioavailability is 99.9%).
Food intake slightly reduces the absorption rate. The mean T max of letrozole in the blood is 1 hour with Femara on an empty stomach and 2 hours when taken with food; the mean C max is 129 ± 20.3 nmol / L for fasting and 98.7 ± 18.6 nmol / L for food intake, but the degree of absorption of letrozole (in the AUC assessment) remains unchanged. Small changes in the rate of absorption are regarded as not having clinical significance, so letrozole can be taken regardless of food intake.
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 its level in the blood plasma. The apparent V d in the period of equilibrium is about 1.87 ± 0.47 l / kg. C ss is achieved within 2-6 weeks of daily intake of a daily dose of 2.5 mg. Pharmacokinetics is nonlinear. Cumulation with prolonged use is not noted.
Metabolism

Letrozole is largely metabolized by CYP3A4 and CYP2A6 isoenzymes to form a pharmacologically inactive carbinol compound.

Excretion

It is excreted mainly by kidneys in the form of metabolites, to a lesser extent - through the intestine.
The final T 1/2 is 48 h.
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.

With a moderate impairment of liver function (class B on the Child-Pugh scale), the mean AUC values, although 37% higher, remain within the range of values ​​that are observed in individuals without impaired 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 1/2 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

- early stages of breast cancer, cells of which have receptors for hormones, in postmenopausal women, as adjuvant therapy;

- early stages of breast cancer in postmenopausal women after completion of standard adjuvant tamoxifen therapy as 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 induced artificially) who received previous therapy with antiestrogens.

DOSING MODE

For adults, the recommended dose of the preparation of Femar ® is 2.5 mg 1 time / day, daily for a long time.

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

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

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

In patients with impaired hepatic and / or renal function (CK-10 ml / min), dose adjustment is not required.
However, for severe violations of the liver (class C on the Child-Pugh scale), patients should be under constant supervision.
Tablets are taken orally, regardless of food intake.

SIDE EFFECT

The frequency of side effects is estimated as follows: very often (? 10%), often (? 1, <10%), sometimes (? 0.1%, <1%), rarely (? 0.01, <0.1%), very rare (<0.01%, including individual messages).

As a rule, adverse reactions were mild or moderate and mainly associated with suppression of the synthesis of estrogens.

From the side of the digestive system: often - nausea, vomiting, indigestion, constipation, diarrhea;
sometimes - abdominal pain, stomatitis, dry mouth, increased activity of liver enzymes.
From the side of the central nervous system and peripheral nervous system: often - headache, dizziness, depression;
sometimes - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypesthesia, eating disorders, episodes of cerebral circulation disorders.
From the hemopoietic system: sometimes - leukopenia.

From the cardiovascular system: sometimes - a feeling of palpitations, tachycardia, thrombophlebitis of superficial and deep veins, increased blood pressure, coronary artery disease (angina, myocardial infarction, heart failure), thromboembolism;
rarely - embolism of the pulmonary artery, thrombosis of the arteries, stroke.
From the respiratory system: sometimes - shortness of breath, cough.

Dermatological reactions: often - alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rashes);
sometimes - itchy skin, dry skin, urticaria; very rarely - angioedema, anaphylactic reactions.
From the musculoskeletal system: very often - arthralgia;
often - myalgia, bone pain, osteoporosis, bone fractures; sometimes - arthritis.
From the senses: sometimes - cataract, eye irritation, blurred vision, a violation of taste.

From the side of the urinary system: sometimes - frequent urination, urinary tract infections.

On the part of the reproductive system: sometimes - vaginal bleeding, vaginal discharge, vaginal dryness, pain in the mammary glands.

Other: very often - paroxysmal sensations of heat (hot flashes);
often - increased fatigue, asthenia, malaise, peripheral edema, weight gain, hypercholesterolemia, anorexia, increased appetite; sometimes - weight loss, thirst, hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor outbreaks.
CONTRAINDICATIONS

- Endocrine status characteristic of the reproductive period;

- Pregnancy;

- the period of lactation (breastfeeding);

- children and adolescence under 18;

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

There is no data on the use of the preparation of Femar ® in patients with creatinine clearance less than 10 ml / min.
Before the appointment of Femara, such patients should carefully weigh the relationship between the potential risk and the expected effect of treatment.
PREGNANCY AND LACTATION

The preparation of Femar ® is contraindicated for use during pregnancy and lactation.

During Femara's therapy, given the potential for pregnancy, women in the perimenopausal and early postmenopausal period should use reliable contraceptive methods before establishing a stable postmenopausal hormone level.

APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with impaired renal function (KK? 10 ml / min), dose adjustment is not required.

There is no data on the use of Femara in patients with SC less than 10 ml / min.
Before the appointment of Femara, such patients should carefully weigh the relationship between the potential risk and the expected effect of treatment.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with impaired liver function, dose adjustment is not required.
Nevertheless, in severe violations of liver function (class C on the Child-Pugh scale), patients should be under constant supervision.
APPLICATION FOR CHILDREN

The drug is contraindicated in children and adolescents under 18 years.

APPLICATION IN ELDERLY PATIENTS

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

SPECIAL INSTRUCTIONS

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

Impact on the ability to drive vehicles and manage mechanisms

Some of the side effects of the drug, such as general weakness and dizziness, 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.
OVERDOSE

There are separate reports of cases of overdose of the preparation of Femar ® .

Treatment: any specific treatment for overdose is unknown.
Symptomatic and supportive therapy is indicated. Letrozole is excreted from the plasma during hemodialysis.
DRUG INTERACTION

With concomitant administration of letrozole with cimetidine and warfarin, clinically significant interaction is not observed.

Clinical experience in the application of letrozole in combination with other antitumour agents is currently not available.

According to the results of in vitro studies letrozole inhibits the activity of cytochrome P450 - 2A6 and 2C19 isoenzymes (the latter is moderately).
When deciding the importance of these 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 vitro experiments, it was shown that letrozole, used in concentrations 100 times higher than the equilibrium values ​​in plasma, does not have the ability to significantly inhibit the metabolism of diazepam (a substrate for CYP2S19). Thus, clinically significant interactions with the CYP2C19 isoenzyme are unlikely. Nevertheless, caution should be exercised in the combined use of letrozole and drugs metabolized predominantly with the above isozymes and having a narrow therapeutic index.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

List B. The drug should be stored in a dry place inaccessible to children at a temperature of no higher than 30 ° C.
Shelf life - 5 years.
The drug should not be used after the expiration date.

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