Letrozole-Vista film-coated tablets 2.5 mg blister No. 100

Instructions Letrozole-Vista film-coated tablets 2.5 mg blister No. 100

Composition

active ingredient: letrozole;

1 tablet contains letrozole 2.5 mg;

Excipients: lactose monohydrate; corn starch; sodium starch glycolate (type A); microcrystalline cellulose; magnesium stearate; Opadry II 85F32410 yellow coating: polyvinyl alcohol; macrogol 3350; talc; titanium dioxide (E 171); iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated, yellow tablets, with a uniform surface and intact edges.

Pharmacotherapeutic group

Agents used for hormonal therapy. Hormone antagonists and similar agents. Aromatase inhibitors. Letrozole. ATC 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 their mediated stimulating effect is a prerequisite for the inhibition of tumor growth. In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) to estrone (E1) and estradiol (E2). Therefore, by means of specific inhibition of the aromatase enzyme, it is possible to achieve inhibition of estrogen biosynthesis in peripheral tissues and in tumor tissue.

Letrozole inhibits aromatase by competitively binding to the heme subunit of this enzyme, cytochrome P450, which leads to a decrease in estrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of letrozole, 0.1 mg, 0.5 mg and 2.5 mg, reduce 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, adrenocorticotropic hormone, or renin activity were observed. The adrenocorticotropic hormone stimulation test after 6 and 12 weeks of treatment with letrozole at a daily dose 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 and 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 estrogen precursors. 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 was 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 negligible. Letrozole is rapidly and extensively 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 major 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 cytochrome P450 isoenzymes CYP3A4 and CYP2A6 are able to metabolize letrozole to its metabolites in vitro, but their individual roles in the clearance of letrozole in vivo have not been clearly established. Drug interaction studies have shown that the simultaneous use of Letrozole-Vista and cimetidine, which is an inhibitor of the isoenzyme 3A4 only, did not cause inhibition of the clearance of letrozole, which allows us to conclude that the isoenzyme 2A6 plays an important role in the overall clearance in vivo. In this study, a slight decrease in AUC and an increase in Cmax were noted.

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. Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in the urine and 3.8 ± 0.9% in the feces. At least 75% of the radioactivity recovered in the urine over a period of up to 216 hours (84.7 ± 7.8% of the letrozole dose) was accounted for by the glucuronide conjugates of the carbinol metabolite, almost 9% by two other unidentified metabolites and 6% by unchanged letrozole.

The apparent terminal plasma half-life is approximately 2-4 days. After daily administration of 2.5 mg, steady-state concentrations of letrozole are reached within 2-6 weeks and are approximately 7-fold higher than those after a single dose. However, the steady-state concentration is 1.5-2 times higher than that predicted from calculations based on single doses. This suggests that the pharmacokinetics of letrozole at a daily dose of 2.5 mg are somewhat non-linear. Since steady-state concentrations 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. At daily doses of 2.5 and 5 mg, the AUC increased approximately 3.8- and 12-fold, instead of 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 at 5 mg/day the disproportionality becomes more pronounced. 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 selected patient groups. In studies conducted in volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 ml/min), the pharmacokinetics of letrozole and the urinary excretion of the glucuronide conjugates of its carbinol metabolite were not affected after a single 2.5 mg dose. In addition, in the above study, the effect of renal impairment on letrozole was assessed, and an analysis of covariance was performed on the basis of data from two pivotal studies (Studies AR/BC2 and AR/BC3). The estimated creatinine clearance (range in Study AR/BC2: 19-187 ml/min; in Study AR/BC3: 10-180 ml/min) did not show a statistically significant relationship with the minimum steady-state plasma levels of letrozole (Cmin). Moreover, data from the AR/BC2 and AR/BC3 studies in the second-line treatment of metastatic breast cancer demonstrated no negative effect of letrozole on creatinine clearance or deterioration of renal function.

In a similar study in volunteers with varying degrees of liver function, the mean area under the concentration-time curve (AUC) was 37% higher in subjects with moderate hepatic impairment (Child-Pugh Class B) than in healthy subjects, but remained within the range of values observed in subjects without hepatic impairment. In a single-dose pharmacokinetic study in 8 patients with cirrhosis and severe hepatic impairment (Child-Pugh Class C), AUC was increased by 95% and t½ by 187% compared with healthy subjects. 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 closely monitored. 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 was noted in 359 patients with advanced breast cancer. 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.

First-line therapy for hormone-dependent advanced breast cancer in postmenopausal women.

Treatment of advanced forms of breast cancer in postmenopausal women (natural or artificially 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 of the excipients.

Premenopausal endocrine status.

Pregnancy.

Breast-feeding.

The patient's 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 not 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 the use of Letrozole-Vista in combination with estrogens or other anticancer drugs other than tamoxifen. Tamoxifen, other antiestrogenic drugs 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 simultaneous use of letrozole with tamoxifen, other estrogen antagonists or estrogens should be avoided.

Drugs that may increase serum concentrations of letrozole.

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.

Drugs that may reduce serum concentrations of letrozole.

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.

Co-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 studies 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.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and, to a lesser extent, CYP2C19, but the clinical significance of this effect 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 drug in the target population of letrozole) showed that the combined use of Letrozole-Vista and these drugs 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-Vista in patients with creatinine clearance < 10 ml/min. Before prescribing the drug to such patients, the potential risk and the expected effect of treatment should be weighed.

Cholesterol

Monitoring of serum cholesterol levels should be considered. In the adjuvant study, hypercholesterolemia was reported in 52.3% of patients treated with letrozole and 28.6% of patients treated with tamoxifen (based on the severity of adverse reactions - STS). Grade 3-4 hypercholesterolemia was reported in 0.4% of patients in the letrozole group and 0.1% of patients in the tamoxifen group. In addition, in the adjuvant setting, increases of ≥ 1.5 × ULN in total cholesterol (usually not in the fasting state) were observed among patients receiving monotherapy and who had baseline total serum cholesterol levels within the normal range (i.e. ≤ 1.5 × ULN) in 151/1843 (8.2%) in the letrozole group versus 57/1840 (3.2%) in the tamoxifen group. The use of lipid-lowering drugs was required in 25% of patients receiving letrozole and 16% of patients receiving tamoxifen.

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.

Effect on bones

Since Letrozole-Vista is a potent estrogen-lowering agent, during adjuvant and extended adjuvant therapy with Letrozole-Vista in women with osteoporosis and/or a history of fractures or who are at increased risk of osteoporosis, bone mineral density should be assessed before, during, and after treatment with Letrozole. 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.

Tendinitis and tendon rupture.

Tendinitis and tendon rupture may occur (rarely). Patients should be carefully examined and appropriate measures (e.g. immobilization) applied to the affected tendon if necessary (see section 4.8).

Menopausal status

In patients with unclear menopausal status, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be determined before initiating treatment with Letrozole. Only women with postmenopausal endocrine status should receive Letrozole.

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 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-Vista and tamoxifen, other estrogen antagonists, or estrogen-containing drugs should be avoided, as these substances may antagonize the pharmacological action of letrozole.

As the tablets contain lactose, Letrozole-Vista is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Letrozole-Vista should only be used in women with a clearly defined postmenopausal status. There have been postmarketing reports of spontaneous abortions or congenital anomalies in newborns whose mothers took letrozole. During treatment with letrozole, regardless of a clearly defined postmenopausal status at the start of treatment, the physician should discuss appropriate contraceptive measures with the patient, if necessary.

Pregnancy

There are isolated cases of congenital defects (fusion of the labia, genitals of an intermediate type).

Letrozole-Vista may cause birth defects when used during pregnancy. Animal studies have shown reproductive toxicity. Use of Letrozole-Vista during pregnancy is contraindicated.

Breast-feeding

It is not known whether letrozole and its metabolites are excreted in human milk. A risk to the newborn/infants during breast-feeding cannot be excluded. The use of Letrozole-Vista during breast-feeding is contraindicated.

Fertility

The pharmacological action of letrozole is associated with a decrease in estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a reverse reaction of increased gonadotropin levels (LH, FSH). In turn, increased FSH levels stimulate follicular growth and may induce ovulation.

Ability to influence reaction speed when driving vehicles or other mechanisms

Letrozole-Vista has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed during the use of letrozole, and in rare cases somnolence has been reported, caution is recommended when driving or operating other machines.

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 settings, letrozole treatment should be continued for 5 years or until tumor recurrence, whichever comes first.

In patients with metastatic breast cancer or advanced breast cancer, letrozole treatment should be continued until there is evidence of tumor progression.

In the adjuvant setting, a sequential treatment regimen (letrozole for 2 years, then tamoxifen for 3 years) should also be considered.

In the neoadjuvant setting, letrozole treatment should be continued for 4 to 8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, letrozole treatment should be discontinued and surgery and/or other treatment options should be considered and discussed with the patient.

For elderly patients, dose adjustment of the drug is not required.

Patients with impaired liver and/or kidney function.

No dose adjustment of Letrozole is required for patients with renal impairment with creatinine clearance ≥10 ml/min. Limited data are available in cases of renal impairment with creatinine clearance below 10 ml/min.

No dose adjustment of Letrozole-Vista is required for patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Limited data are available in cases of severe hepatic impairment (Child-Pugh class C). Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.

Method of application

Letrozole-Vista should be taken orally regardless of 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 is not intended for use in children. The safety and efficacy of Letrozole-Vista in children (under 18 years of age) have not been established. The available data are limited, so it is not possible to make a dosage recommendation.

Overdose

Isolated cases of overdose with Letrozole-Vista have been reported. Specific treatment for overdose is unknown; treatment should be symptomatic and supportive.

Side effects

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. Adverse reactions were experienced by almost one-third of patients treated with letrozole in the metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen; median treatment period was 60 months) and almost 80% of patients in the extended adjuvant setting (both letrozole and placebo; median treatment period was 60 months). In general, the adverse reactions observed were mostly mild to moderate in nature 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 additional adverse reactions that may occur with letrozole treatment include musculoskeletal events such as osteoporosis and/or fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many adverse reactions may be due to the natural pharmacological effects of estrogen deficiency (e.g. hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment.

Adverse reactions are listed by frequency: very common: > 10%, common: > 1% to < 10%, uncommon: > 0.1% to < 1%, rare: > 0.01% to < 0.1%, very rare: < 0.01%, not known: frequency cannot be estimated from the available data. The most frequent reactions are listed first.

Table 1

* Significantly lower than with letrozole monotherapy.

** Significantly higher than with letrozole monotherapy.

Note: The reporting period includes the treatment period or the period within 30 days after treatment cessation.

Description of selected adverse reactions

Cardiac adverse reactions

In the adjuvant setting, the following adverse events were observed with letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days): angina requiring surgery (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident/transient ischemic attack (2.1% vs. 1.9%).

In the extended adjuvant setting with letrozole (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), the following adverse events were observed, respectively: angina requiring surgery (0.8% vs. 0.6%); new or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient ischemic attack* (1.5% vs. 0.8%).

Phenomena marked with * had a statistically significant difference in the two treatment groups.

Musculoskeletal adverse reactions

Musculoskeletal safety data obtained during adjuvant treatment are presented in Table 2.

In the extended adjuvant setting, significantly more patients treated with letrozole experienced bone fractures or osteoporosis (bone fractures 10.4% and osteoporosis 12.2%) compared with patients in the placebo group (5.8% and 6.4%, respectively). The median duration of treatment with letrozole was 5 years and with placebo 3 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are obliged to report any cases of suspected adverse reactions.

Tachycardia, ischemic cardiac complications (including new or worsening angina, angina requiring surgery, myocardial infarction, and myocardial ischemia)

Expiration date

4 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets in a blister. 3 or 10 blisters in a cardboard pack.

Vacation category

According to the recipe.

Producer

Sindan Pharma S.R.L.

Location of the manufacturer and address of its place of business.

11 Iona Mihalache Blvd., Sector 1, 011171, Bucharest, Romania.