Instructions for Letrozole film-coated tablets 2.5 mg blister No. 30
Composition
active ingredient: letrozole;
1 tablet contains letrozole 2.5 mg in terms of 100% substance;
excipients: lactose monohydrate, corn starch, microcrystalline cellulose 101, hydroxypropyl methylcellulose (15), sodium starch glycolate (type A), magnesium stearate; film-coating composition: SepifilmTM 050 (methylhydroxypropyl cellulose, microcrystalline cellulose, acetylated (or ester acetates) mono- and diglycerides), SepisperseTM Dry 3214 Jaune (hydroxypropyl methylcellulose, microcrystalline cellulose, titanium dioxide (E 171), riboflavin (E 101)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a brownish-yellow or orange-yellow film coating.
Pharmacotherapeutic group
Agents used for hormone therapy. Hormone antagonists and similar agents. Aromatase inhibitors. Letrozole.
ATX code L02B G04.
Pharmacological properties
Pharmacodynamics
Letrozole is a nonsteroidal aromatase inhibitor (estrogen biosynthesis inhibitor); an antitumor drug.
In cases where the growth of tumor tissue depends on the presence of estrogens, the elimination of the stimulating effect mediated by them is a prerequisite for the inhibition of tumor growth.
In postmenopausal women, estrogens are produced primarily by the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) to estrone (E1) and estradiol (E2). Therefore, specific inhibition of the aromatase enzyme can be used to suppress estrogen biosynthesis in peripheral tissues and in tumor tissue.
Letrozole inhibits aromatase by competitively binding to the heme subunit of this enzyme, cytochrome P 450, which leads to a decrease in estrogen biosynthesis in all tissues.
In healthy postmenopausal women, a single dose of letrozole, 0.1 mg or 0.5 mg, or 2.5 mg, reduces serum estrone and estradiol levels (compared to baseline) by 75-78% and 78%, respectively. The maximum reduction is achieved after 48-78 hours.
In postmenopausal women with advanced breast cancer, daily administration of letrozole at a dose of 0.1 mg to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75-95% of baseline. When the drug is used at a dose of 0.5 mg or more, in many cases the concentrations of estrone and estrone sulfate are found below the sensitivity limit of the method used to determine the hormones. This indicates that with these doses of the drug a more pronounced suppression of estrogen synthesis is achieved. Estrogen suppression was maintained throughout treatment in all patients.
Letrozole is a highly specific inhibitor of aromatase activity. No impairment of adrenal steroid hormone synthesis has been observed. In postmenopausal patients treated with letrozole at a daily dose of 0.1-5 mg, no clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH, or renin activity were observed. ACTH stimulation tests performed after 6 and 12 weeks of letrozole therapy at daily doses of 0.1 mg; 0.25 mg; 0.5 mg; 1 mg; 2.5 mg, and 5 mg did not reveal any significant reduction in aldosterone or cortisol synthesis. Thus, there is no need to prescribe glucocorticoids or mineralocorticoids.
In healthy postmenopausal women, after a single dose of letrozole at doses of 0.1 mg; 0.5 mg and 2.5 mg, no changes in the concentration of androgens (androstenedione and testosterone) in the blood plasma were detected. In postmenopausal patients who received letrozole at a daily dose of 0.1 mg to 5 mg, no changes in the level of androstenedione in the blood plasma were also noted. All this indicates that the blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are precursors of estrogens. In patients receiving letrozole, no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma were noted, and no changes in thyroid function, which were assessed by the levels of thyroid-stimulating hormone T4 and T3, were noted.
Pharmacokinetics
Distribution. The binding of letrozole to plasma proteins is approximately 60% (mainly to albumin - 55%). The concentration of letrozole in erythrocytes is almost 80% of its level in plasma. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of the radioactivity in plasma was accounted for by unchanged active substance. Therefore, the systemic exposure of letrozole metabolites is insignificant. Letrozole is rapidly and widely distributed in tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 l/kg.
Metabolism and elimination. Letrozole is extensively metabolized to a pharmacologically inactive carbinol metabolite, the main route of elimination. The metabolic clearance of letrozole (CLm) is 2.1 l/h, which is less than the hepatic blood flow (approximately 90 l/h). It has been shown that the conversion of letrozole to its metabolite is mediated by the cytochrome P450 isoenzymes CYP3A4 and CYP2A6. The formation of a small number of other, as yet unidentified metabolites, as well as the excretion of unchanged drug in urine and feces, play only a minor role in the overall elimination of letrozole. The apparent terminal plasma half-life is approximately 2-4 days. After daily administration of 2.5 mg of the drug, steady-state concentrations of letrozole are reached within 2-6 weeks and are approximately 7 times higher than after a single dose of the same dose. At the same time, the steady-state concentration is 1.5-2 times higher than the equilibrium concentration that would be predicted based on calculations based on the values recorded after a single dose of the drug. This indicates that when letrozole is administered daily at a dose of 2.5 mg, its pharmacokinetics are somewhat nonlinear. Since steady-state concentrations of letrozole are maintained during long-term treatment, it can be concluded that letrozole does not accumulate.
Linearity/non-linearity. The pharmacokinetics of letrozole were dose proportional after a single oral dose of up to 10 mg (dose range 0.01 to 30 mg) and after daily doses of up to 1.0 mg (dose range 0.1 to 5 mg). A small but more than dose-proportional increase in AUC was observed after a single oral dose of 30 mg. The AUC increased approximately 3.8- and 12-fold with daily doses of 2.5 and 5 mg, respectively, compared with 2.5 and 5-fold, respectively, compared with 1.0 mg/day. Thus, the recommended dose of 2.5 mg/day may be the limit dose at which disproportionality becomes apparent, while disproportionality becomes more pronounced with 5 mg/day. The dose disproportionality is likely to be the result of saturation of metabolic elimination processes. Steady-state concentrations were reached after 1-2 months with all studied dosing regimens (0.1-5.0 mg daily).
Pharmacokinetics in specific patient groups. In studies conducted in volunteers with varying renal function (24-hour creatinine clearance ranged from 9 to 116 ml/min), it was noted that after a single dose of letrozole at a dose of 2.5 mg, its pharmacokinetics did not change. Dose adjustment is not required in patients with impaired renal function (creatinine clearance ≥ 10 ml/min). Information regarding patients with severe renal impairment (creatinine clearance < 10 ml/min) is limited.
In subjects with moderate hepatic impairment (Child-Pugh Class B), mean AUC values were 37% higher than in healthy subjects, but remained within the range of values observed in subjects without hepatic impairment. In a single-dose pharmacokinetic study in patients with cirrhosis and severe hepatic impairment (Child-Pugh Class C), AUC and t½ were increased by 95% and 187%, respectively, compared to healthy volunteers. Thus, higher levels of letrozole are expected in patients with breast cancer and severe hepatic impairment than in patients without severe hepatic impairment. Therefore, Letrozole® should be used with caution in patients with severe hepatic impairment, taking into account the benefit/risk ratio for each individual patient. Since no increase in toxicity was observed in patients receiving daily doses of 5 mg to 10 mg/day, dose adjustment in the direction of its decrease is not justified, although such patients should be under close medical supervision. In addition, no effect of renal dysfunction (estimated creatinine clearance values were 20-50 ml/min) or hepatic dysfunction on the plasma concentration of letrozole in patients with advanced breast cancer was noted. The pharmacokinetics of letrozole are independent of age.
Indication
Adjuvant therapy of hormone-positive invasive early breast cancer in postmenopausal women.
Extended adjuvant therapy for early invasive breast cancer in postmenopausal women who have received standard adjuvant tamoxifen therapy for 5 years.
Treatment of advanced forms of breast cancer in postmenopausal women (natural or induced) after recurrence or progression of the disease, who have received previous anti-estrogen therapy.
Neoadjuvant therapy in postmenopausal women with hormone-positive, HER-2-negative breast cancer who are not suitable for chemotherapy and for whom urgent surgery is not indicated.
The effectiveness of the drug for patients with hormone-negative breast cancer has not been proven.
Contraindication
Hypersensitivity to the active substance or to any other component of the drug.
Endocrine status typical of the premenopausal period.
Women of reproductive age.
Interaction with other medicinal products and other types of interactions
Letrozole is metabolised in part by CYP2A6 and CYP3A4. Therefore, the systemic clearance of letrozole may be affected by medicinal products that affect CYP3A4 and CYP2A6. Letrozole metabolism appears to have a low affinity for CYP3A4, as this enzyme is non-saturable at concentrations 150-fold higher than the plasma concentrations of letrozole observed at steady state under typical clinical conditions.
There is currently no clinical experience with letrozole in combination with estrogens or other anticancer drugs other than tamoxifen. Tamoxifen, other antiestrogens or estrogen-containing drugs may antagonize the pharmacological effects of letrozole. In addition, it has been shown that the plasma concentrations of letrozole are significantly reduced when tamoxifen and letrozole are used simultaneously. The concomitant use of letrozole with tamoxifen, other estrogen antagonists or estrogens should be avoided.
Medicinal products that may increase letrozole serum concentrations
Inhibitors of CYP3A4 and CYP2A6 activity may reduce the metabolism of letrozole and thus increase letrozole plasma concentrations. Concomitant use of medicinal products that strongly inhibit these enzymes (potent inhibitors of CYP3A4 include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; CYP2A6 (e.g. methoxsalen)) may increase letrozole exposure. Therefore, caution is advised in patients who are indicated for use of potent inhibitors of CYP3A4 and CYP2A6.
Medicinal products that may decrease letrozole serum concentrations
CYP3A4 inducers may increase the metabolism of letrozole and thus reduce the plasma concentration of letrozole. Concomitant use of medicinal products that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's wort) may reduce the exposure of letrozole. Therefore, caution is advised in patients who are indicated for potent CYP3A4 inducers. CYP2A6 inducers are unknown.
Concomitant administration of letrozole (2.5 mg) and tamoxifen 20 mg once daily resulted in an average 38% decrease in plasma levels of letrozole. Clinical experience from second-line breast cancer trials suggests that the therapeutic effect of letrozole and the incidence of adverse reactions were not increased when letrozole was administered immediately after tamoxifen. The mechanism of this interaction is unknown.
Drugs whose systemic serum concentrations may be altered by letrozole
In vitro, letrozole inhibits cytochrome P450 isoenzymes CYP2A6 and moderately CYP2C19,
but the clinical significance of this phenomenon is unknown. However, caution should be exercised when co-administering letrozole with drugs whose elimination is predominantly dependent on CYP2C19 and which have a narrow therapeutic range (such as phenytoin, clopidogrel). A substrate with a narrow therapeutic range for CYP2A6 is unknown.
Clinical interaction studies with cimetidine (a known non-specific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate for CYP2C9 with a narrow therapeutic range, which is often used as a concomitant medication in the target population of letrozole) showed that the co-administration of letrozole and these medicinal products does not cause clinically significant drug interactions.
A review of the database of these clinical studies revealed no evidence of other clinically significant interactions with other commonly prescribed drugs.
Application features
Kidney dysfunction
There are no data on the use of letrozole in patients with creatinine clearance < 10 ml/min. Before prescribing the drug to such patients, the ratio of the potential risk and the expected effect of treatment should be considered.
Cholesterol
Hypercholesterolemia was reported in patients receiving letrozole in the adjuvant setting.
Liver dysfunction
In patients with severe hepatic impairment (Child-Pugh class C), systemic exposure and half-life of letrozole are approximately twice as long as in healthy subjects. Such patients require closer monitoring.
As Letrozole® is a potent estrogen-lowering agent, in the adjuvant and extended adjuvant setting, bone mineral density should be assessed before, during, and after treatment with letrozole in women with osteoporosis and/or a history of fractures or at increased risk of osteoporosis. In the adjuvant setting, a sequential therapy regimen (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered, depending on the patient's safety profile.
Menopausal status
In patients with unclear menopausal status, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be determined before starting treatment with Letrozole. Letrozole should only be used in women with postmenopausal endocrine status.
Laboratory abnormalities
There was no dose-related effect of letrozole on any hematological or biochemical parameters. Moderate decreases in lymphocyte counts of uncertain clinical significance were observed in some patients treated with letrozole at a dose of 2.5 mg. These decreases in lymphocyte counts were transient in approximately half of the affected patients. Two patients treated with letrozole developed thrombocytopenia; the relationship to study drug was unclear. Withdrawal of patients from the study due to laboratory abnormalities, whether drug-related or not, was rare.
Other caveats
The concomitant use of Letrozole® and tamoxifen, other estrogen antagonists or estrogen-containing medicinal products should be avoided, as these substances may antagonize the pharmacological action of letrozole.
The drug contains lactose, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not take the drug.
Use during pregnancy or breastfeeding
Perimenopausal women or women of reproductive age
Letrozole® should only be used in women with a clearly established postmenopausal status. There have been reports of spontaneous abortions or congenital anomalies in newborns whose mothers took letrozole.
Given the reports of recovery of ovarian function in women treated with letrozole, despite a clear postmenopausal status at the start of therapy, the physician should discuss adequate contraceptive measures with the patient, if necessary.
Pregnancy
Based on human experience with letrozole, which includes isolated cases of congenital malformations (cleft lip, intermediate external genitalia), it is known that letrozole may cause congenital malformations when administered during pregnancy. Animal studies have shown reproductive toxicity. Letrozole® is contraindicated for use during pregnancy.
Breast-feeding
It is not known whether letrozole and its metabolites are excreted in human milk. A risk to the newborn cannot be excluded.
Letrozole® is contraindicated for use during breastfeeding.
Fertility. The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a corresponding increase in gonadotropin levels (LH, FSH). The increase in FSH levels, in turn, stimulates follicular growth, which can induce ovulation.
The ability to influence the reaction speed when driving or working with other mechanisms
Letrozole has little effect on the ability to drive and use machines. Since general weakness and dizziness, as well as drowsiness in some cases, have been observed in patients treated with letrozole, caution is recommended when driving or operating complex machinery.
Method of administration and doses
Adults, including elderly patients. The recommended dose of Letrozole® is 2.5 mg once daily. In the adjuvant and extended adjuvant setting, treatment with Letrozole® should be continued for 5 years or until disease relapse occurs. In patients with metastases, treatment with Letrozole® should be continued until signs of disease progression become evident. In the adjuvant setting, a sequential therapy regimen (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered.
In the neoadjuvant setting, Letrozole® therapy should be continued for 4-8 months to achieve optimal tumor shrinkage. If the response to treatment is inadequate, Letrozole® therapy should be discontinued and elective surgery should be performed and/or further treatment options discussed with the patient.
For elderly patients, dose adjustment of the drug is not required.
Patients with hepatic and/or renal impairment. No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B) or renal impairment (creatinine clearance ≥ 10 ml/min). There are insufficient data in patients with renal impairment with creatinine clearance < 10 ml/min or severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.
Method of application
Letrozole® should be taken orally without regard to food intake, as food does not affect the extent of absorption of the drug.
The missed dose should be taken as soon as the patient remembers. However, if the patient remembers shortly before the next dose (2-3 hours), the missed dose should be skipped and the next dose should be taken as scheduled. A double dose should not be taken, as systemic exposure greater than proportional has been observed with daily doses higher than the recommended 2.5 mg.
Children
The drug should not be used in children, as the efficacy and safety of letrozole for this category of patients have not been studied in clinical trials.
Overdose
Isolated cases of overdose with letrozole have been reported.
Specific treatment for overdose is unknown; treatment should be symptomatic and supportive.
Side effects
Overall safety profile overview
Letrozole was generally well tolerated in all studies as first- and second-line therapy for advanced breast cancer, as adjuvant therapy for early breast cancer, and as extended adjuvant therapy for breast cancer in women who had previously received standard adjuvant therapy with tamoxifen. In general, the adverse reactions observed were mostly mild to moderate in intensity and were mostly related to estrogen deficiency. The most frequently reported adverse reactions in clinical trial reports were hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important adverse reactions that may occur with letrozole treatment include musculoskeletal events such as osteoporosis and/or bone fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many adverse events may be due to the natural pharmacological effects of estrogen deficiency (e.g. hot flashes, alopecia, or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment.
Infections and infestations: urinary tract infections.
Benign, malignant and unexplained neoplasms, including cysts and polyps: pain in tumor foci(1).
Blood and lymphatic system disorders: leukopenia.
Immune system disorders: anaphylactic reactions.
Metabolic and nutritional disorders: hypercholesterolemia, anorexia, increased appetite.
Psychiatric: depression, anxiety (including nervousness), irritability.
Nervous system: headache, dizziness, drowsiness, insomnia, memory impairment, dysesthesia (including paresthesia, hypoesthesia), taste disturbance, stroke, carpal tunnel syndrome.
From the organs of vision: cataract, eye irritation, blurred vision.
Cardiac disorders: palpitations (1), tachycardia, myocardial ischemia (including new or worsening angina, angina requiring surgery, myocardial infarction, and myocardial ischemia).
Vascular disorders: hot flushes, hypertension, thrombophlebitis (including superficial and deep vein thrombophlebitis), pulmonary embolism, arterial thrombosis, cerebrovascular infarction.
Respiratory, thoracic and mediastinal disorders: dyspnea, cough.
Gastrointestinal: nausea, vomiting, dyspepsia (1), constipation, diarrhea, abdominal pain, stomatitis (1), dry mouth.
From the hepatobiliary system: increased liver enzymes, hepatitis.
Skin and subcutaneous tissue disorders: increased sweating, alopecia, rash (including erythematous, maculopapular, psoriatic and vesicular rashes), dry skin, itching, urticaria, toxic epidermal necrolysis, erythema multiforme, angioedema.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, bone pain(1), osteoporosis, bone fractures, arthritis, trigger finger syndrome.
From the urinary system and kidneys: increased frequency of urination.
Reproductive system and breast disorders: vaginal bleeding, vaginal discharge or dryness, breast pain.
General disorders and administration site conditions: fatigue (including asthenia, malaise), peripheral edema, fever, dry mucous membranes, thirst, generalized edema.
Studies: weight gain, weight loss.
(1) only in the treatment of metastatic lesions.
Expiration date
4 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Keep out of reach of children.
Packaging
10 tablets in a blister. 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
