Estrolet^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

L02BG04 (Letrozole)

Active Substance

Letrozole (Rec.INN registered by WHO)

Dosage Form

Estrolet®

Film-coated tablets, 2.5 mg: 10, 30, 60, 90, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-yellow in color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: magnesium aluminometasilicate – 10 mg, croscarmellose sodium – 3 mg, colloidal silicon dioxide – 3 mg, magnesium stearate – 0.5 mg; lactose/crospovidone/povidone – 81 mg, calculated on the components: lactose monohydrate – 75.3 mg, crospovidone – 2.84 mg, povidone K30 – 2.84 mg.

Film coating composition: polyvinyl alcohol – 40%, talc – 14.8%, macrogol 3350 – 20.2%, titanium dioxide – 21.65%, iron oxide yellow dye – 3.35%.

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
10 pcs. – contour cell packaging (9) – cardboard packs.
10 pcs. – contour cell packaging (10) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Aromatase inhibitor

Pharmacotherapeutic Group

Antineoplastic hormonal agents and hormone antagonists; hormone antagonists and related compounds; aromatase inhibitors

Pharmacological Action

Antitumor agent. It is a non-steroidal aromatase inhibitor – an enzyme involved in the synthesis of estrogens in postmenopausal women. Aromatase promotes the conversion of androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone and estradiol. Inhibition of aromatase activity is realized through competitive binding with the heme subunit of the cytochrome P450 enzyme, which leads to a reduction in estrogen biosynthesis in all tissues, including in estrogen-dependent tumor tissues.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal tract, the average bioavailability is approximately 99.9%. Food intake slightly reduces the rate of absorption. The mean time to reach C_max of letrozole in the blood is approximately 1 hour when letrozole is taken on an empty stomach and 2 hours when taken with food; the mean C_max is approximately 129 ± 20.3 nmol/L when taken on an empty stomach and about 98.7 ± 18.6 nmol/L when taken with food, however, the extent of letrozole absorption (as assessed by AUC) does not change.

The binding of letrozole to plasma proteins is approximately 60% (primarily with albumin – 55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. The apparent V_d at steady state is approximately 1.87 ± 0.47 L/kg. Steady-state concentration is reached within 2-6 weeks of daily administration of a 2.5 mg dose. The pharmacokinetics are non-linear. No accumulation was noted with long-term use. Letrozole is extensively metabolized by the action of CYP3A4 and CYP2A6 isoenzymes to form a pharmacologically inactive carbinol compound.

It is excreted primarily by the kidneys as metabolites, and to a lesser extent through the intestines. T_1/2 is approximately 48 hours.

Indications

Early stages of invasive breast cancer, the cells of which have hormone receptors, in postmenopausal women, as adjuvant therapy. Early stages of invasive breast cancer in postmenopausal women after completion of standard adjuvant tamoxifen therapy for 5 years as extended adjuvant therapy. Advanced hormone-dependent forms of breast cancer in postmenopausal women (first-line therapy). Advanced breast cancer in case of relapse or disease progression in postmenopausal women (natural or artificially induced) who have received prior antiestrogen therapy. Hormone-dependent HER-2 negative breast cancer in postmenopausal women as neoadjuvant therapy when chemotherapy is contraindicated and there is no need for emergency surgery.

ICD codes

Dosage Regimen

The recommended dose is 2.5 mg once daily, taken long-term.

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

If signs of disease progression appear, letrozole should be discontinued.

In the neoadjuvant (preoperative) setting, treatment with letrozole should be continued for 4-8 months to achieve optimal tumor size reduction. If an adequate tumor response to treatment is not achieved, letrozole should be discontinued, and the issue of surgical or other types of treatment should be considered.

Adverse Reactions

From the hematopoietic system infrequently – leukopenia.

From the immune system frequency unknown – anaphylactic reactions.

From the metabolism very often – hypercholesterolemia; often – anorexia, increased appetite.

From the psyche: often – depression; infrequently – anxiety (including nervousness), irritability.

From the nervous system: often – headache, dizziness; infrequently – drowsiness, insomnia, memory impairment, sensory disturbance (including paresthesia, hypesthesia), taste perception disorders, episodes of cerebrovascular accident, carpal tunnel syndrome.

From the organ of vision: infrequently – cataract, eye irritation, blurred vision.

From the cardiovascular system: very often – hot flashes; often – increased blood pressure; infrequently – palpitations, tachycardia, coronary artery disease (including newly diagnosed or worsening of existing angina, angina requiring surgery, myocardial infarction, myocardial ischemia), thrombophlebitis (including superficial and deep vein thrombophlebitis); rarely – pulmonary embolism, arterial thrombosis, stroke, ischemic attack.

From the respiratory system infrequently – dyspnea, cough.

From the digestive system often – nausea, vomiting, dyspepsia, constipation, diarrhea, abdominal pain; infrequently – stomatitis, dry mouth.

From the liver and biliary tract: infrequently – increased activity of liver enzymes; very rarely – hepatitis.

From the skin and subcutaneous tissues: very often – increased sweating; often – alopecia, dry skin, rash (including erythematous, maculopapular, psoriasiform and vesicular); infrequently – skin itching, urticaria; frequency unknown – angioedema, Lyell’s syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome (malignant multiform exudative erythema).

From the musculoskeletal system very often – arthralgia; often – myalgia, bone pain, osteoporosis, bone fractures; infrequently – arthritis; frequency unknown – trigger finger syndrome.

From the urinary system infrequently – frequent urination, urinary tract infections.

From the genital organs and mammary glands often – vaginal bleeding; infrequently – vaginal discharge, vaginal dryness, breast pain.

General disorders : very often – increased fatigue (including asthenia and malaise); often – peripheral edema; infrequently generalized edema, dryness of mucous membranes, thirst, fever, weight gain; infrequently – benign, malignant and unspecified neoplasms (including cysts and polyps), tumor pain, weight loss.

Contraindications

Hypersensitivity to letrozole; endocrine status characteristic of the premenopausal period; pregnancy, breastfeeding period; children under 18 years of age.

With caution severe hepatic impairment (Child-Pugh class C), severe renal impairment (creatinine clearance <10 ml/min), simultaneous use with potent inhibitors of CYP3A4 and CYP2A6 isoenzymes. Simultaneous use with drugs with a narrow therapeutic index, the elimination of which depends mainly on the CYP2C19 isoenzyme.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Should be used with caution in patients with severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Should be used with caution in patients with severe renal impairment (creatinine clearance < 10 ml/min). The ratio between the expected therapeutic effect and the possible risk of treatment should be carefully weighed.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Letrozole can be used in patients over 65 years of age according to indications, in recommended doses.

Special Precautions

Patients with severe liver dysfunction should be under constant supervision.

Since Letrozole is used only in postmenopausal patients, in case of an unclear status of the reproductive system hormonal regulation, it is recommended to determine the concentration of LH, FSH and/or estradiol before starting treatment.

An increase in serum FSH levels leads to stimulation of follicle growth and may cause ovulation, therefore, during letrozole therapy, there is a potential for pregnancy in women in the perimenopausal and early postmenopausal period. In such cases, reliable methods of contraception should be used until a stable postmenopausal hormonal level is established in this category of patients.

There are data on the development of osteoporosis and/or the occurrence of bone fractures during the use of letrozole, therefore, careful monitoring of the bone tissue condition is recommended throughout the entire period of letrozole use. It is recommended to avoid simultaneous use of letrozole with tamoxifen, other antiestrogenic and estrogen-containing drugs, since these agents may weaken the pharmacological action of letrozole.

Letrozole is not indicated for the treatment of breast cancer that does not contain steroid hormone receptors (estrogen or progesterone).

Effect on the ability to drive vehicles and mechanisms

Some side effects of letrozole, such as general weakness, drowsiness and dizziness, may affect the ability to perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions. In this regard, caution should be exercised when driving vehicles and working with mechanisms. If the described adverse events occur, one should refrain from performing these types of activities.

Drug Interactions

Letrozole is metabolized primarily in the liver with the participation of cytochrome P450 isoenzymes CYP3A4 and CYP2A6. The systemic elimination of letrozole can be influenced by drugs that affect these isoenzymes.

The metabolism of letrozole demonstrates low affinity for the CYP3A4 isoenzyme, since this isoenzyme in usual clinical situations at concentrations 150 times higher than the steady-state plasma levels of letrozole does not have the ability to inhibit letrozole metabolism.

Inhibitors of CYP3A4 and CYP2A6 isoenzymes can reduce the metabolism of letrozole, thereby increasing its serum concentration. Simultaneous use of potent inhibitors of these isoenzymes (for the CYP3A4 isoenzyme, these are, for example, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; for the CYP2A6 isoenzyme – methoxsalen) may lead to an increase in letrozole exposure. Caution is advised when using letrozole concomitantly with potent inhibitors of CYP3A4 and CYP2A6 isoenzymes.

Inducers of CYP3A4 and CYP2A6 isoenzymes can increase the metabolism of letrozole, thereby reducing its serum concentration. Simultaneous use of inducers of these isoenzymes (for the CYP3A4 isoenzyme, these are, for example, phenytoin, rifampicin, carbamazepine, phenobarbital, St. John’s wort) may lead to a decrease in letrozole exposure; for the CYP2A6 isoenzyme – inducers are not known.

Simultaneous use of letrozole (at a dose of 2.5 mg) and tamoxifen at a dose of 20 mg/day leads to an average decrease in letrozole serum concentration by 38%. There are no clinical data on the effect on the efficacy and safety of letrozole use after tamoxifen administration.

In vitro, Letrozole inhibits the cytochrome P450 isoenzyme CYP2A6 and slightly the isoenzyme CYP2C19. Caution is advised when using letrozole concomitantly with drugs with a narrow therapeutic index, the elimination of which depends mainly on the CYP2C19 isoenzyme (for example, phenytoin, clopidogrel).

No clinically significant interaction is observed with the simultaneous use of letrozole with cimetidine (a known non-specific inhibitor of CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often prescribed as concomitant therapy to patients taking Letrozole).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.