Femara, 2,5mg 30 pcs.

Pharmacodynamics

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

In postmenopausal women, estrogens are produced mainly by the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol.

Daily administration of letrozole at a daily dose of 0.1-5 mg leads to a decrease in plasma concentrations of estradiol, estrone and estrone sulfate by 75-95% of the initial content. Suppression of estrogen synthesis is maintained throughout treatment.

When Femara® is used in a dose range of 0.1 to 5 mg there is no disruption of steroid hormone synthesis in the adrenal glands, the ACTH test shows no disruption of aldosterone or cortisol synthesis. No additional prescription of glucocorticoids and mineralocorticoids is required.

Blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogen. No changes in plasma concentrations of luteinizing and follicle stimulating hormones, changes in thyroid function, changes in lipid profile, and increased incidence of myocardial infarctions and strokes were observed during Femara treatment.

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

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

The extended adjuvant therapy with Femara reduces the risk of progression by 42%. A significant benefit in disease-free survival was observed in the Femara group regardless of lymph node involvement. Femara® treatment reduced mortality among patients with lymph node involvement by 40%.

Pharmacokinetics

Intake

Letrozole is quickly and completely absorbed from the GI tract (average bioavailability is 99.9%). Food intake slightly reduces the absorption rate. The average value of T_max letrozole in blood is 1 h when Femara is taken on an empty stomach and 2 h when taken with food; the average value of 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, but the absorption rate of letrozole (as assessed by AUC) is unchanged. Slight changes in absorption rate are considered to be of no clinical significance, so letrozole can be taken regardless of food intake.

Distribution

The binding of letrozole to plasma proteins is approximately 60% (predominantly to albumin – 55%). The concentration of letrozole in erythrocytes is about 80% of its level in blood plasma. The apparent V_d during equilibrium is approximately 1.87±0.47 L/kg. C_ss is achieved over 2-6 weeks of daily administration of a daily dose of 2.5 mg. Pharmacokinetics are nonlinear. No cumulation has been noted with long-term use.

Metabolism

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

Extracted mainly by kidneys as metabolites, to a lesser extent – through intestine. The final T_1/2 is 48 hours.

Pharmacokinetics in special clinical cases

The pharmacokinetic parameters of letrozole are independent of patient age.

In renal insufficiency pharmacokinetic parameters do not change.

In patients with moderate hepatic impairment (Child-Pugh class B) mean AUC values, although higher by 37%, remain within the range of values observed in persons without hepatic impairment. In patients with cirrhosis and severe liver dysfunction (grade C according to Child-Pugh scale) AUC is increased 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

Active ingredient

Composition

1 tablet contains:

Active substances:

letrozole 2.5 mg.

Associates:

Lactose monohydrate,

Microcrystalline cellulose,

corn starch,

sodium carboxymethylstarch,

silicon dioxide colloidal,

magnesium stearate,

hypromellose,

talc,

macrogol 8000,

iron oxide yellow dye (17268),

titanium dioxide.

There are 10 tablets in the blister.

There are 3 blisters in the carton pack.

How to take, the dosage

For adults, the recommended dose of Femara® is 2.5 mg once daily, daily long-term.

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

Femara should be discontinued if there are signs of disease progression.

In elderly patients, there is no need to adjust the dose of Femara.

In patients with hepatic and/or renal impairment (CKR ≥ 10 ml/min) no dose adjustment is required. However, patients with severe hepatic impairment (class C on the Child-Pugh scale) should be under constant monitoring.

The tablets are taken orally, regardless of meals.

Interaction

In concomitant administration of letrozole with cimetidine and warfarin no clinically significant interaction is observed.

There is currently no clinical experience with the use of letrozole in combination with other anticancer agents.

According to the results of in vitro studies letrozole inhibits the activity of cytochrome Р450 isoenzymes – 2A6 and 2C19 (the latter moderately). When deciding on the significance of these data for the clinic it should be taken into account that CYP2A6 isoenzyme does not play a significant role in drug metabolism.

In in vitro experiments it has been shown that letrozole used in concentrations 100 times greater than the equilibrium values in plasma has no ability to significantly inhibit the metabolism of diazepam (substrate for CYP2C19).

Thus, clinically significant interactions with CYP2C19 isoenzyme are unlikely. However, caution should be exercised when co-administering letrozole and drugs metabolized predominantly with the participation of the above mentioned isoenzymes and with a narrow therapeutic index.

Special Instructions

Patients with severe hepatic impairment should be under constant monitoring.

Impact on the ability to drive and operate vehicles and other mechanisms requiring high concentration

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

In this regard, caution should be exercised when driving vehicles and operating machinery.

Contraindications

Side effects

The incidence of side effects is estimated as follows:

As a rule, adverse reactions were mild to moderate and mostly related to suppression of estrogen synthesis.

Gastrointestinal system disorders: frequently – nausea, vomiting, dyspepsia, constipation, diarrhea; sometimes – abdominal pain, stomatitis, dry mouth, increased liver enzyme activity.

CNS and peripheral nervous system disorders: frequently – headache, dizziness, depression; sometimes – anxiety, nervousness, irritability, somnolence, insomnia, memory impairment, dysesthesia, paraesthesia, hypoesthesia, sensory perception disorders, episodes of cerebral circulation disorders.

Hematopoietic system: sometimes – leukopenia.

The cardiovascular system: sometimes – palpitations, tachycardia, thrombophlebitis of superficial and deep veins, increased BP, CHD (angina, myocardial infarction, heart failure), thromboembolism; rarely – pulmonary embolism, arterial thrombosis, stroke.

Respiratory system disorders: sometimes – dyspnea, cough.

Dermatological reactions: frequently – alopecia, increased sweating, skin rash (including erythematous, maculopapular, vesicular rash, psoriasis-like rash); sometimes – skin itching, dry skin, urticaria; very rarely – angioedema, anaphylactic reactions.

Muscular system: very often – arthralgia; often – myalgia, bone pain, osteoporosis, bone fractures; sometimes – arthritis.

Senses: sometimes – cataracts, eye irritation, blurred vision, impaired sense of taste.

The urinary system: sometimes – frequent urination, urinary tract infections.

Reproductive system disorders: sometimes – vaginal bleeding, vaginal discharge, vaginal dryness, pain in the breasts.

Others: 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.

Overdose

There have been isolated reports of Femara® overdose.

Treatment: No specific treatment of overdose is known.

Symptomatic and supportive therapy is indicated. Letrozole is excreted from plasma by hemodialysis.

Pregnancy use

Femara® is contraindicated in pregnancy and lactation.

Women in the perimenopausal and early postmenopausal periods should use reliable contraception until stable postmenopausal hormone levels are established during therapy with Femara, given the potential for pregnancy.

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