Femara pills 2,5mg №30

pharmachologic effect

Pharmacodynamics

Antitumor drug. It has an anti-estrogenic effect, selectively inhibits aromatase (an estrogen synthesis enzyme) by highly specific competitive binding to the subunit of this enzyme - the heme of cytochrome P450. Blocks the synthesis of estrogen in both peripheral and tumor tissues.

In women in the postmenopausal period, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens (primarily androstenedione and testosterone) synthesized into the adrenal glands 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 the blood plasma by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout the treatment.

At use of the drug Femara® 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 administration of glucocorticoids and mineralocorticoids is not required.

The blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen.No changes in luteinizing and follicle-stimulating hormones in the blood plasma, changes in thyroid function, changes in the lipid profile, an increase in the incidence of myocardial infarction and stroke were observed during the administration of Femara.

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

Adjuvant therapy with Femara in early stages of breast cancer reduces the risk of progression, increases survival without signs of disease for 5 years, reduces the risk of developing a tumor of another breast.

Extended adjuvant therapy Femara reduces the risk of progression by 42%. A significant survival benefit with no signs of disease in the Femara group was noted regardless of the involvement of lymph nodes. Treatment with Femara® reduces mortality among patients with lymph node involvement by 40%.

Pharmacokinetics

Suction

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (the average bioavailability is 99.9%). Food intake slightly reduces the rate of absorption. Average t_max letrozole in the blood is 1 hour when taking Femara on an empty stomach and 2 hours when taken with food; mean C_max 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 (as measured by AUC) does not change.Small changes in the rate of absorption are regarded as having no clinical significance, therefore letrozole can be taken regardless of the meal.

Distribution

The binding of letrozole to plasma proteins is approximately 60% (mainly with albumin - 55%). The concentration of letrozole in red blood cells is about 80% of its level in the blood plasma. Seeming v_d during the period of equilibrium it is about 1.87 ± 0.47 l / kg. C_ss 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 marked.

Metabolism

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

Removal

Excreted mainly by the kidneys in the form of metabolites, to a lesser extent - through the intestines. Final t_1/2 is 48 hours

Pharmacokinetics in special clinical situations

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

In renal failure, the pharmacokinetic parameters do not change.

In moderately severe liver dysfunction (Child-Pugh class B), the average AUC values, although 37% higher, remain within the range of values ​​observed in individuals without liver dysfunction. In patients with cirrhosis of the liver and severely impaired function (class C on the Child-Pugh scale), the 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

• The early stages of breast cancer, whose cells have hormone receptors in postmenopausal women, as an adjuvant therapy;
• early stages of breast cancer in postmenopausal women after the completion of standard adjuvant therapy with Tamoxifen as an 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 artificially induced) who received prior anti-estrogen therapy.

Contraindications

• Endocrine status characteristic of the reproductive period;
• pregnancy;
• lactation period (breastfeeding);
• children and adolescents up to 18 years;
• hypersensitivity to letrozole or any other component of the drug.
• There are no data on the use of Femara® in patients with creatinine clearance less than 10 ml / min. Before prescribing femara, such patients should carefully weigh the ratio between the potential risk and the expected effect of treatment.

Use during pregnancy and lactation

The drug Femara® is contraindicated for use during pregnancy and lactation.

During therapy with Femara,Considering the potential for pregnancy, women in the perimenopausal and early postmenopausal period should use reliable methods of contraception until a stable postmenopausal hormone level is established.

special instructions

Patients with severely impaired liver function should be under constant supervision.

Influence on the ability to drive vehicles and other mechanisms that require high concentration of attention

Some side effects of the drug, such as general weakness and dizziness, can affect the ability to perform potentially hazardous activities that require concentration and quick reactions. In this regard, care should be taken when driving vehicles and machinery.

Composition

1 pill contains:

Active substances: letrozole 2.5 mg.

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

Dosage and administration

For adults The recommended dose of Femara® is 2.5 mg 1 time / day, daily for a long time.

As extended adjuvant therapy, treatment should continue for 5 years (not longer than 5 years).

If there are signs of disease progression, Femara should be stopped.

Elderly patients dose adjustment femara not required.

In patients with impaired liver and / or kidney function (CC ≥ 10 ml / min) dose adjustment of the drug is not required. However, with severe violations of the liver (class C on the Child-Pugh scale) patients should be under constant surveillance.

Tablets are taken orally, regardless of the meal.

Side effects

The incidence of side effects is assessed as follows:

• occur very often (≥10%);
• often (≥1, <10%);
• sometimes (≥0.1%, <1%);
• rarely (≥0.01, <0.1%);
• very rarely (<0.01%, including individual messages).

As a rule, adverse reactions were mild or moderately pronounced and were mainly associated with the suppression of estrogen synthesis.

From the digestive system: often - nausea, vomiting, dyspepsia , 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, hypoesthesia, gustatory disturbances, episodes of cerebral circulation.

From the hemopoietic system: sometimes - leukopenia.

Since the cardiovascular system: sometimes - palpitations, tachycardia, superficial and deep vein thrombophlebitis, increased blood pressure, coronary heart disease (angina, myocardial infarction, heart failure), thromboembolism; rarely - pulmonary embolism, arterial thrombosis, stroke.

On the part of the respiratory system: sometimes - shortness of breath, cough.

Dermatological reactions: often - alopecia, excessive sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rash); sometimes - itching, 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, disturbed taste sensations.

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

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

Other: very often hot flashes (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 foci.

Drug interaction

With the simultaneous appointment of letrozole with cimetidine and Warfarin , there is no clinically significant interaction.

Clinical experience on the use of letrozole in combination with other anticancer agents is currently not available.

According to the results of in vitro studies, letrozole suppresses the activity of cytochrome P450 isoenzymes - 2A6 and 2C19 (the latter is moderate).When deciding on the significance of this 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 CYP2C19). Thus, clinically significant interactions with the CYP2C19 isoenzyme are unlikely. However, caution should be exercised in the combined use of letrozole and drugs that are metabolized mainly with the participation of the above isoenzymes and have a narrow therapeutic index.

Overdose

There are separate reports of cases of overdose of the drug Femara®.

Treatment: no specific treatment for overdose is known. Symptomatic and supportive therapy is indicated. Letrozole is derived from plasma during hemodialysis.

Storage conditions

Store in a dry place inaccessible to children at a temperature not exceeding 30 ° C.