Letrozole-Teva film-coated tablets 2.5 mg blister No. 30

Instructions for use Letrozole-Teva film-coated tablets 2.5 mg blister No. 30

Composition

active ingredient: letrozole;

1 tablet contains letrozole 2.5 mg;

excipients: microcrystalline cellulose, corn starch, magnesium stearate, lactose monohydrate, colloidal anhydrous silica, sodium starch glycolate (type A), yellow iron oxide (E 172), macrogol, titanium dioxide (E 171), talc, indigo carmine (E 132), polyvinyl alcohol, tartrazine (E 102).

Dosage form

Film-coated tablets.

Main physicochemical properties: dark yellow, round, biconvex, film-coated tablets, embossed with “93” on one side and “B1” on the other.

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 stimulatory effect mediated by them 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 with these doses of the drug a more pronounced suppression of estrogen synthesis is achieved. Estrogen suppression was maintained in all patients during the treatment period.

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, 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 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 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 compound, the major route of elimination. The metabolic clearance of letrozole is 2.1 l/h, which is less than the hepatic blood flow (approximately 90 l/h). It has been shown that letrozole is converted to its metabolite by the cytochrome P450 isoenzymes CYP3A4 and CYP2A6. The formation of a small number of other, as yet unidentified metabolites, as well as 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, 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 a study conducted in 19 volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 ml/min), it was noted that the pharmacokinetics of letrozole were not altered after a single dose of 2.5 mg. In addition, in the above study, the effect of renal impairment on letrozole was evaluated, and a covariate analysis was performed based on 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, letrozole 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 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 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 or breastfeeding.

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 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 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

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 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 administering letrozole concomitantly 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 concomitant use of letrozole and these medicinal products does not cause clinically significant drug interactions.

No evidence of other clinically significant interactions with other commonly prescribed drugs was found.

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.

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

As letrozole is a potent estrogen-lowering agent, during adjuvant and extended adjuvant therapy with letrozole 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. Osteoporosis treatment should be initiated as appropriate and patients should be closely monitored during letrozole therapy.

In the adjuvant setting, sequential therapy (2 years of letrozole followed by 3 years of tamoxifen) may also be considered depending on the patient's safety profile (see sections 4.8 and 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 starting treatment with letrozole. Only women with postmenopausal endocrine status should receive letrozole.

Cholesterol

Monitoring of serum cholesterol levels 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 in the letrozole group and 0.1% of patients in the tamoxifen group, according to the Adverse Reaction Severity Assessment (ADR) criteria. Additionally, in the adjuvant setting, increases of ≥ 1.5 × ULN in total cholesterol (usually not in the fasting state) were observed in patients receiving monotherapy and with baseline total 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. Lipid-lowering medication was required in 25% of patients receiving letrozole and 16% of patients receiving tamoxifen.

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. Thrombocytopenia was reported in two patients treated with letrozole; the relationship to letrozole was unclear. Withdrawal of patients from the study due to laboratory changes, whether or not related to the drug, was rare.

Tendinitis and tendon ruptures

Tendinitis and tendon rupture may occur (rarely). Patients require close medical supervision and appropriate measures (e.g. immobilization) for the affected tendon (see section "Adverse reactions").

Other

The drug contains lactose, therefore patients with rare hereditary forms of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption syndrome should not use the drug.

The drug contains tartrazine (E 102), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

Based on human experience with letrozole and isolated cases of congenital malformations (fusion of labia minora, intermediate external genitalia), 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 or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded.

Therefore, letrozole is contraindicated during breastfeeding.

Perimenopausal women and women of reproductive age

Letrozole should only be used in women who are clearly postmenopausal. Spontaneous abortions or congenital anomalies have been reported in infants born to mothers who took letrozole. Given the reports of ovarian function returning to normal in women treated with letrozole despite clearly postmenopausal status at the start of therapy, the physician should discuss adequate contraception with the patient as appropriate.

Fertility

The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to increased levels of gonadotropins (LH, FSH). In turn, increased levels of FSH stimulate follicular growth and may induce ovulation.

Ability to influence reaction speed when driving vehicles or other mechanisms

Letrozole has little effect on the ability to drive and use machines. Since general weakness and dizziness, as well as drowsiness in isolated cases, have been observed during treatment with the drug, caution is recommended when driving or operating complex machinery.

Method of administration and doses

Adults and 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, letrozole therapy 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.

Children. The drug is not used to treat children. The safety and efficacy of letrozole 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

Letrozole should be taken orally without regard to food intake, as food does not affect the extent of its absorption.

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.

Letrozole is not used in pediatric practice, as the efficacy and safety of the drug for this category of patients have not been studied.

Overdose

Isolated cases of overdose with letrozole have been reported.

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

Side effects

The frequency of adverse reactions to letrozole was determined mainly on the basis of data obtained during clinical trials. The drug was generally well tolerated in all studies as first- and second-line therapy in the treatment of advanced breast cancer, as adjuvant therapy in early breast cancer and as extended adjuvant therapy in breast cancer in women who had previously received standard adjuvant therapy with tamoxifen.

Almost one-third of patients treated with letrozole in the metastatic and neoadjuvant settings, and approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen, median treatment period 60 months), and almost 80% of patients in the extended adjuvant setting (both letrozole and placebo, median treatment period 60 months) experienced adverse reactions. Overall, adverse reactions were mostly mild to moderate in nature and were mostly related to estrogen deficiency. The most common adverse reactions reported in clinical trials were hot flashes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important adverse reactions that may occur during treatment with letrozole 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 below.

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

Infections and infestations: Uncommon: urinary tract infections.

Benign, malignant and unspecified neoplasms, including cysts and polyps. Uncommon: pain in tumor foci1.

Blood and lymphatic system disorders: Uncommon: leukopenia.

Immune system disorders: Frequency not known: anaphylactic reactions.

Metabolism and nutrition disorders: Very common: hypercholesterolemia. Common: anorexia, increased appetite.

Psychiatric disorders: Common: depression. Uncommon: anxiety (including nervousness), irritability.

Nervous system disorders: Common: headache, dizziness. Uncommon: drowsiness, insomnia, memory impairment, dysesthesia (including paresthesia, hypoesthesia), taste disturbance, stroke, carpal tunnel syndrome.

On the part of the organs of vision. Uncommon: cataract, irritation of the mucous membrane of the eye, blurred vision.

Cardiac disorders: Common: palpitations1. Uncommon: tachycardia, myocardial ischaemia (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia).

Vascular disorders: Very common: hot flushes. Common: hypertension. Uncommon: thrombophlebitis (including superficial and deep vein thrombophlebitis). Rare: pulmonary embolism, arterial thrombosis, cerebrovascular infarction.

Respiratory system: Uncommon: dyspnea, cough.

Gastrointestinal disorders: Common: nausea, vomiting, dyspepsia1, constipation, diarrhoea, abdominal pain. Uncommon: stomatitis1, dry mouth.

Hepatobiliary system disorders: Uncommon: increased liver enzymes, hyperbilirubinemia, jaundice. Not known: hepatitis.

Skin and subcutaneous tissue disorders: Very common: increased sweating. Common: alopecia, rash (including erythematous, maculopapular, psoriatic and vesicular rashes), dry skin. Uncommon: pruritus, urticaria. Not known: toxic epidermal necrolysis, erythema multiforme, angioedema.

Musculoskeletal and connective tissue disorders Very common: arthralgia Common: myalgia, bone pain1, osteoporosis, bone fractures, arthritis Uncommon: tendinitis Rare: tendon rupture Not known: trigger finger syndrome

Urinary system: Uncommon: frequent urination.

Reproductive system and breast disorders: Common: vaginal bleeding. Uncommon: vaginal discharge or dryness, breast pain.

General disorders: Very common: fatigue (including asthenia and malaise). Common: peripheral oedema, chest pain. Uncommon: fever, dry mucous membranes, thirst, anasarca.

Investigations: Common: weight gain. Uncommon: weight loss.

1 Only when treating metastatic disease.

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

Table 1

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

Table 2

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

Description of selected adverse reactions

From the heart

In the adjuvant setting, in addition to those presented in Table 1, the following adverse events were reported with letrozole and tamoxifen, respectively (with a median duration of treatment 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 with letrozole (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.

Musculoskeletal system

Musculoskeletal safety data obtained in the adjuvant setting are presented in Table 1.

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

Expiration date

3 years.

Storage conditions

Keep out of the reach of children. The medicinal product does not require any special storage conditions.

Packaging

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

Vacation category

According to the recipe.

Producer

1. Teva Pharmaceutical Industries Ltd.

2. Teva Pharmaceutical Plant JSC.

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

1. 18 Eli Hurwitz St., Ind. Zone, Kfar Saba, Israel.

2. Precinct 1; H-4042 Debrecen, Pallagi utca 13, Hungary.