Femara film-coated tablets 2.5 mg blister No. 30

Instructions for Femara film-coated tablets 2.5 mg blister No. 30

Composition

active ingredient: letrozole;

1 tablet contains 2.5 mg of letrozole;

Excipients: colloidal anhydrous silica; microcrystalline cellulose; lactose, monohydrate; magnesium stearate; corn starch; sodium starch glycolate (type A); hydroxypropyl methylcellulose; polyethylene glycol 8000; talc; titanium dioxide (E 171); iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: dark yellow, round, slightly biconvex tablets, film-coated, with beveled edges; on one side - marking "FV", on the other - "CG".

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 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 of 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 more pronounced suppression of estrogen synthesis is achieved with these doses of the drug. 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 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, changes in the level of androstenedione in the blood plasma were also not 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 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 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 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). Cytochrome P450 isoenzymes CYP3A4 and CYP2A6 have been shown to metabolize letrozole to its metabolite. 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 urine over a period of up to 216 hours (84.7 ± 7.8% of the letrozole dose) was due to glucuronide conjugates of the carbinol metabolite, almost 9% to two other unidentified metabolites, and 6% to 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 times 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, respectively, compared to 2.5- and 5-fold, respectively, compared to 1.0 mg/day. Thus, the recommended dose of 2.5 mg/day may be the limit 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 dosage regimens studied (0.1–5.0 mg daily).

Pharmacokinetics in selected patient groups. In a study conducted in 19 volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 ml/min), the pharmacokinetics of letrozole were not affected after a single dose of 2.5 mg. 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 plasma levels of letrozole at steady state (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 conducted in subjects with varying degrees of hepatic function, mean AUC values were 37% higher in patients 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 subjects with cirrhosis and severe hepatic impairment (Child-Pugh Class C), AUC and t½ were increased by 95% and 187%, respectively, compared with healthy subjects. Thus, higher levels of letrozole are expected in breast cancer patients with severe hepatic impairment than in subjects without severe hepatic impairment. Therefore, Femara® should be used with caution in patients with severe hepatic impairment, taking into account the benefit/risk balance for each individual patient. Since no increase in toxicity was observed in patients receiving daily doses of 5 mg to 10 mg/day, a dose adjustment in the direction of its decrease is not justified, although such patients should be closely monitored. In addition, no effect of renal impairment (estimated creatinine clearance values were 20–50 ml/min) or hepatic impairment on the plasma concentration of letrozole was observed 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 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.

Pregnancy, breastfeeding period.

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 Femara® 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.

Application features

Kidney dysfunction

There are no data on the use of Femara® 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.

Monitoring of serum cholesterol should be considered. In the adjuvant treatment study, hypercholesterolemia was reported in 52.3% of patients treated with letrozole and 28.6% of patients treated with tamoxifen. Grade 3-4 hypercholesterolemia was reported in 0.4% of patients treated with letrozole and 0.1% of patients treated with tamoxifen. In addition, in the adjuvant treatment setting, increases of ≥ 1.5 × ULN in total cholesterol (usually not in the fasting state) were observed in patients treated with monotherapy with normal baseline total cholesterol (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 using letrozole and 16% of patients using 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.

Since Femara® is a potent estrogen-lowering agent, during adjuvant and extended adjuvant therapy with Femara® in women with osteoporosis and/or a history of fractures and in those 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.

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 Femara®. Only women with postmenopausal endocrine status should take Femara®.

Tendinitis and tendon rupture.

Tendinitis and tendon rupture are possible (rarely). Patients should be carefully examined and appropriate measures (e.g. immobilization) should be taken for the affected tendon (see section "Adverse reactions").

Violations of laboratory parameters.

There was no dose-related effect of Femara® on any hematological or biochemical parameters. Moderate decreases in lymphocyte counts of uncertain clinical significance were observed in some patients receiving Femara® at a dose of 2.5 mg. These decreases in lymphocyte counts were transient in approximately half of the affected patients. Two patients receiving Femara® developed thrombocytopenia; the relationship to the study drug was not clear. Withdrawal of patients from the study due to laboratory changes, whether or not related to the drug, was rare.

Other caveats.

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

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

Use during pregnancy or breastfeeding

Women in perimenopausal state or women of reproductive age.

Femara® should only be used in women with a clearly established postmenopausal status. There have been postmarketing reports of spontaneous abortions or congenital anomalies in newborns whose mothers took Femara®. Given the reports of recovery of ovarian function in women treated with Femara® despite a clear postmenopausal status at the start of therapy, the physician should discuss adequate contraceptive methods with the patient, as appropriate.

Pregnancy.

Based on human experience, which includes isolated cases of congenital malformations (cleft lip, intermediate external genitalia), Femara® is known to cause congenital malformations when administered during pregnancy. Animal studies have shown reproductive toxicity. Femara® is contraindicated during pregnancy.

Breast-feeding.

It is not known whether letrozole and its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded.

Femara® 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.

Ability to influence reaction speed when driving vehicles or other mechanisms

The effect of Femara® on the ability to drive and use machines is negligible. Since patients treated with the drug experienced general weakness and dizziness, as well as drowsiness in some cases, caution is recommended when driving and operating complex machinery.

Method of administration and doses

In the neoadjuvant setting, Femara® therapy should be continued for 4–8 months to achieve optimal tumor shrinkage. If the response to treatment is inadequate, Femara® 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.

Children. The drug is not used to treat children. The safety and efficacy of Femara® in children have not been established. The available data are limited, so it is not possible to make dosage recommendations.

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.

Femara® 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 is not used in children, as the efficacy and safety of the drug for this category of patients have not been studied in clinical trials.

Overdose

Isolated cases of overdose with Femara® have been reported.

Specific treatment for overdose is unknown; treatment should be symptomatic and supportive.

Side effects

General overview of the safety profile.

The frequency of adverse reactions for Femara® was determined mainly on the basis of data obtained during clinical trials.

Femara® was generally well tolerated in all studies as first- and second-line therapy in the treatment of 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 observed in almost one-third of patients treated with Femara® in the metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received both Femara® and tamoxifen, median treatment period 60 months) and almost 80% of patients in the extended adjuvant setting (both Femara® and placebo, median treatment period 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 flashes, hypercholesterolemia, arthralgia, nausea, increased sweating and fatigue. Important additional adverse reactions that may occur with Femara® treatment include musculoskeletal events such as osteoporosis and/or bone 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 flashes, alopecia or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment. The frequency categories for these adverse reactions are described in Table 1.

Adverse reactions are listed by frequency, with the most frequent first. The following gradations were used to estimate the frequency of various adverse reactions: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1,000 - < 1/100), rare (≥ 1/10,000 - < 1/1,000), very rare (< 1/10,000); unknown frequency (cannot be estimated from the available data).

Table 1

(1) Only when treating metastatic disease.

Some adverse reactions were reported with significantly different frequencies in the adjuvant setting.

Table 2

Adjuvant therapy with Femara® compared with tamoxifen monotherapy: adverse events with significantly different frequencies

Note: During treatment includes 30 days after the last dose. Anytime includes the follow-up period after completion or discontinuation of study treatment.

The difference is based on risk ratios and 95% confidence intervals.

Table 3

Sequential treatment compared to Femara® monotherapy: adverse events with significantly different frequencies

* Significantly less than in the Femara® monotherapy group

** Significantly higher than in the Femara® monotherapy group

Note: The notification period includes the treatment period or 30 days after treatment is discontinued.

Description of selected adverse reactions.

In the adjuvant setting, in addition to those presented in Table 2, the following adverse events were reported with Femara® 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%); cerebral circulation disorder/transient ischemic attack (2.1% vs. 1.9%).

In the extended adjuvant setting, the following adverse events were reported for Femara® (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), respectively: angina requiring surgery (0.8% vs. 0.6%); new angina 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%).

The frequency of events marked with * was statistically significantly different between the two treatment groups.

Adverse reactions from the musculoskeletal system.

Musculoskeletal safety data obtained in the adjuvant setting are presented in Table 2.

In the extended adjuvant setting, bone fractures or osteoporosis were observed in a statistically significantly higher number of patients in the Femara® treatment group (bone fractures – 10.4% and osteoporosis – 12.2%) than in the placebo group (5.8% and 6.4%, respectively). The median duration of treatment was 5 years for Femara® compared to 3 years for placebo.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the pharmacovigilance system.

Expiration date

5 years.

Storage conditions

Store at a temperature not exceeding 30 °C in the original packaging to protect from moisture and out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Novartis Pharma S.p.A.

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

Provinciale Skito 131, 80058 Torre Annunziata, (province of Naples), Italy.