Letrozole - instructions for use, dose, side effects, contraindications

Excipientslactose monohydrate (Pharmatose 200M) -85.0 mg, croscarmellose sodium (AC-Di-sol) -5.0 mg, povidone (Plasdone K-29/32) 4.0 mg, silicon dioxide colloid (Aerosil 200) -2.0 mg, magnesium stearate -1.5 mg.

Composition of the shell Opadrai yellow 03B82401: hypromellose 6 cP - 60% mg, titanium dioxide - 16%, iron oxide yellow - 11%, macrogol 400-8%, talc 5%.

Description:Round, biconvex tablets, covered with a film coating of dark yellow with a brownish hue, with a facet and an engraved "H" on one side of the tablet and "5" on the other. On the cross-section the nucleus is white.

Pharmacotherapeutic group:Antitumor agent, estrogen synthesis inhibitor

ATX: & nbsp

L.02.B.G.04 Letrozole

L.02.B.G Enzyme Inhibitors

Pharmacodynamics:

An antineoplastic agent, a non-steroidal selective aromatase inhibitor, an enzyme for the synthesis of estrogens, has an antiestrogenic effect. The activity of aromatase is reduced due to a competitive binding to the prosthetic part (heme) of cytochrome P450 (a subunit of this enzyme). In postmenopausal women, estrogens are formed predominantly with the aromatase enzyme, which turns androgens synthesized in the adrenal glands (primarily androstenedione and testosterone), into estrone and estradiol.

Daily administration to patients in postmenopause at a dose of 0.1-5 mg / day leads to a decrease in the concentration of estradiol,estrone and estrone sulfate in plasma by 75-95% of the original content; a low concentration of estrogen is maintained throughout treatment in all patients. In women with estrogen-dependent malignant breast tumors that developed during menopause, the drug, reducing the concentration of circulating estrogens and suppressing their synthesis in tumor tissue, leads to regression of tumors (in 23% of cases) and a decrease in the number of relapses and deaths. Possessing high specificity with respect to the enzyme aromatase, does not cause disturbances in the synthesis of steroid hormones in the adrenal glands.

Letrozole can be used when tamoxifen is ineffective in postmenopausal women.

Pharmacokinetics:

Absorption is high (food slows down the rate of absorption); bioavailability - 99.9%; association with plasma proteins - 60% (55% - with albumin). Concentration in erythrocytes - 80% of its content in plasma. The apparent volume of distribution during the period of stable equilibrium is about 1.87 l / kg. After daily intake at a dose of 2.5 mg / day, the equilibrium concentration in the blood is reached within 2-6 weeks. With prolonged treatment, cumulation does not occur.

Metabolism - mainly in the liver with the participation of cytochrome P450 isoenzymes with the formation of a pharmacologically inactive carbinol derivative.

Excretion is mainly by kidneys in the form of metabolites, and also through the intestine.

Half-life (T_1/2) - about 48 h. It is excreted by hemodialysis. In renal and hepatic insufficiency, the pharmacokinetic parameters do not change. With moderate hepatic insufficiency, the area under the concentration-time curve (AUC) slightly increases, but remains within the limits determined for normal liver function. With severe hepatic insufficiency (class C according to the Child-Pug classification) AUC and T_1/2 significantly increased, but given the good tolerability of high doses, dose adjustment is not required.

Indications:

Early stages of breast cancer in postmenopausal women, whose cells have receptors for hormones (as adjuvant therapy).

Early stages of breast cancer in postmenopausal women after completion of standard adjuvant therapy with tamoxifen (as an extended adjuvant therapy).

Common hormone-dependent forms of breast cancer in postmenopausal women (1st line therapy).

Common forms of breast cancer in postmenopausal women (natural or induced artificially) who received previous therapy with antiestrogens.

Contraindications:Hypersensitivity to letrozole or another component of the drug, endocrine status characteristic of the reproductive period, pregnancy, lactation, age under 18 years.

Carefully:Severe hepatic and renal insufficiency (creatinine clearance less than 10 ml / min). Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Dosing and Administration:

Inside, regardless of food intake.

The recommended dose is 2.5 mg once a day, daily, long.

As an extended adjuvant therapy treatment should last for 5 years (but not more than 5 years).

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

In elderly patients, as well as with severe renal / hepatic insufficiency, dose adjustment is not required, however, patients with severe renal / hepatic insufficiency should be under constant supervision.

Side effects:

The incidence of adverse reactions: "very often" -> 10%, "often" -> 1-10%, "infrequently" -> 0.1% - <1%, "rarely" -> 0.01-0.1 %, "very rarely" - <0.01%, including individual messages.

From the side of the digestive system: often - nausea, vomiting, indigestion, constipation, diarrhea; infrequently - abdominal pain, stomatitis, dry mouth, increased activity of "hepatic" enzymes, hepatitis.

From the nervous system: often - headache, dizziness, depression; infrequently - anxiety, nervousness, irritability, drowsiness, insomnia, memory impairment, dysesthesia, paresthesia, hypoesthesia, episodes of cerebral circulation disorders.

On the part of the organs of hematopoiesis: infrequently, leukopenia.

From the side of the cardiovascular system: infrequent - palpitation, tachycardia, thrombophlebitis of superficial and deep veins, increased blood pressure (BP), coronary heart disease (angina, myocardial infarction, heart failure), thromboembolism; rarely - embolism of the pulmonary artery, thrombosis of the arteries, stroke.

From the respiratory system: infrequently - shortness of breath, cough.

From the skin and appendages of the skin: often - alopecia, increased sweating, skin rash (incl.erythematous, maculopapular, vesicular, psoriasis-like); infrequently - itchy skin, dry skin, urticaria; very rarely - angioedema, anaphylactic reactions, Lyell's syndrome, Stevens-Johnson syndrome.

From the side of the musculoskeletal system: very often - arthralgia; often - myalgia, ossalgia, osteoporosis, fractures of bones, infrequently - arthritis, carpal tunnel syndrome, syndrome of a clicking channel.

From the sense organs: infrequently - cataract, eye irritation, blurred vision, a taste disorder.

From the side of the urinary system: infrequent - frequent urination, urinary tract infection.

From the side of the reproductive system: infrequently - vaginal bleeding, discharge from the vagina, dryness of the vagina, pain in the mammary glands.

Other: very often - sensations of heat ("hot flashes"), often - increased fatigue, asthenia, malaise, peripheral edema, increase / decrease in body weight, hypercholesterolemia, anorexia, increased appetite; infrequently - thirst, hyperthermia (pyrexia), dry mucous membranes, generalized edema, pain in tumor foci.

Overdose:

There are separate reports of cases of overdose with letrozole.

Symptomatic and supportive therapy is indicated.

Hemodialysis is effective.

Interaction:

In vitro studies letrozole It suppressed the activity of cytochrome P450-CYP2A6 and CYP2C19 isoenzymes (the latter is moderately). When deciding on the clinical significance of these data, it should be taken into account that the CYP2A6 isoenzyme does not play a significant role in the metabolism of drugs.

Clinically significant interactions with the isoenzyme CYP2C19 are unlikely. Nevertheless, caution should be exercised in the combined use of letrozole and drugs metabolized predominantly with the aforementioned isoenzymes and having a narrow therapeutic index.

Special instructions:

Before the beginning of treatment it is recommended to study the estrogen receptor status of the organism. The expediency of prescribing to patients without lymph node involvement is determined individually: the degree of malignancy, tumor size, the presence of estrogen receptors, and age are taken into account.

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

During treatment, given the potential for pregnancy, women in the perimenopausal and early postmenopausal period should use reliable contraceptive methods before establishing a stable postmenopausal hormonal status.

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

During the period of treatment, it is necessary to refrain from engaging in potentially dangerous activities that require increased attention, speed of motor and mental reactions (including driving or handling machinery).

Form release / dosage:

Tablets, film-coated 2.5 mg.

Packaging:

30 tablets per bottle of high-density polyethylene **. The bottle together with the instruction for use is placed in a pack of cardboard.

For 7 tablets in the blister A1 / A1 * or in the blister of Triplex-A1 * or in the blister of PVDC / A1 **. For 4 blisters with instructions for use are placed in a pack of cardboard.

For 10 tablets in a blister A1 / A1 * or in the blister Tprisex-Al * or in the blister PODX / A1 **. For 3 or 6 blisters with instructions for use are placed in a pack of cardboard.

At packing on Open Company MAKIZ-PHARMA ", Russia

7 tablets in a blister pack.For 4 blisters together with instructions for use in a pack of cardboard.

10 tablets in a blister pack. For 3 or 6 blisters together with instructions for use in a pack of cardboard.

1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:3 years.

Terms of leave from pharmacies:On prescription

Registration number:LP-001757

Date of registration:02.07.2012 / 28.07.2016

Expiration Date:02.07.2017

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

MAKIZ-PHARMA, LLC Russia

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Letrozole (Letrozole)