Letrozole-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETROZOLE-TEVA (LETROZOLE-TEVA)

Composition:

Active substance: letrozole;

1 tablet contains 2.5 mg of letrozole;

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Agents used in hormonal therapy. Hormone antagonists and related agents. Aromatase inhibitors. Letrozole.

ATC code L02BG04.

Pharmacological properties.

Pharmacodynamics.

Letrozole is a non-steroidal aromatase inhibitor (an estrogen biosynthesis inhibitor) and an antineoplastic agent.

In cases where tumor tissue growth is estrogen-dependent, elimination of the stimulatory effect mediated by estrogens is a prerequisite for tumor growth suppression. In postmenopausal women, estrogens are primarily formed with the participation of the enzyme aromatase, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone (E1) and estradiol (E2). Therefore, specific inhibition of the aromatase enzyme can achieve suppression of estrogen biosynthesis in peripheral tissues and tumor tissue.

Letrozole inhibits aromatase by competitively binding to the heme subunit of cytochrome P450 of this enzyme, resulting in reduced 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 levels of estrone and estradiol (compared to baseline levels) by 75–78% and 78%, respectively. Maximum reduction is achieved within 48–78 hours.

In postmenopausal women with advanced breast cancer, daily administration of letrozole at doses ranging from 0.1 mg to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75–95% from baseline levels. With doses of 0.5 mg and higher, concentrations of estrone and estrone sulfate in many cases fall below the detection limit of the assay method used for hormone determination. This indicates that more pronounced suppression of estrogen synthesis is achieved with these doses. In all patients, estrogen suppression was maintained throughout 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 daily doses of 0.1–5 mg, no clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH, or renin activity were detected. ACTH stimulation tests performed at 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg of letrozole revealed no significant reduction in aldosterone or cortisol synthesis. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of letrozole of 0.1 mg, 0.5 mg, and 2.5 mg did not alter plasma concentrations of androgens (androstenedione and testosterone). In postmenopausal patients receiving daily doses of letrozole from 0.1 mg to 5 mg, no changes in plasma androstenedione levels were observed. This indicates that blockade of estrogen biosynthesis does not lead to accumulation of androgen precursors of estrogens. In patients receiving letrozole, no changes in plasma concentrations of luteinizing hormone and follicle-stimulating hormone were observed, nor were there any changes in thyroid function, as assessed by levels of thyroid-stimulating hormone, T4, and T3.

Pharmacokinetics.

Absorption. Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean bioavailability is 99.9%). Food slightly reduces the rate of absorption (mean time to reach maximum plasma concentration (tmax) is 1 hour when administered on an empty stomach and 2 hours when taken with food; mean maximum plasma concentration (Cmax) is 129 ± 20.3 nmol/L when administered on an empty stomach and 98.7 ± 18.6 nmol/L when taken with food). However, the extent of absorption of letrozole (as assessed by the area under the concentration-time curve) is unchanged. The minor changes in absorption rate are considered not clinically significant; therefore, letrozole can be administered independently of food intake.

Distribution. Plasma protein binding of letrozole is approximately 60% (primarily to albumin – 55%). The concentration of letrozole in erythrocytes is about 80% of its plasma level. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of radioactivity in plasma corresponded to unchanged active substance. Therefore, the systemic effect of letrozole metabolites is negligible. Letrozole rapidly and widely distributes into tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 L/kg.

Metabolism and elimination. Letrozole undergoes extensive metabolism, forming a pharmacologically inactive carbinol compound – the main elimination pathway. The metabolic clearance of letrozole is 2.1 L/h, which is less than hepatic blood flow (approximately 90 L/h). It has been shown that conversion of letrozole to its metabolite is mediated by CYP3A4 and CYP2A6 isoenzymes of cytochrome P450. Formation of a small amount of other, as yet unidentified metabolites, as well as excretion of unchanged drug in urine and feces, plays 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 radioactivity was recovered in urine and 3.8 ± 0.9% in feces. At least 75% of the radioactivity recovered in urine within 216 hours (84.7 ± 7.8% of the dose of letrozole) corresponded to glucuronide conjugates of the carbinol metabolite, nearly 9% to two other unidentified metabolites, and 6% to unchanged letrozole.

The apparent terminal half-life in plasma is approximately 2–4 days. After daily administration of 2.5 mg of the drug, steady-state concentration is reached within 2–6 weeks, and is approximately 7 times higher than after a single dose of the same amount. At the same time, the steady-state concentration is 1.5–2 times higher than the value expected based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily dosing at 2.5 mg. Since the steady-state concentration of letrozole is maintained over a prolonged treatment period, it can be concluded that accumulation of letrozole does not occur.

Linearity/Non-linearity. The pharmacokinetics of letrozole were dose-proportional after single oral doses up to 10 mg (dose range 0.01–30 mg) and after daily doses up to 1.0 mg (dose range 0.1–5 mg). After administration of a single oral dose of 30 mg, a slight but more than dose-proportional increase in AUC was observed. With daily doses of 2.5 mg and 5 mg, AUC increased approximately 3.8 and 12 times, respectively, instead of 2.5 and 5 times, compared to the 1.0 mg/day dose. Thus, the recommended dose of 2.5 mg/day may represent the threshold dose at which non-proportionality becomes apparent, while at 5 mg/day non-proportionality is more pronounced. This non-proportionality is likely due to saturation of metabolic elimination processes. Steady-state concentrations were achieved within 1–2 months with all studied dosing regimens (0.1–5.0 mg daily).

Pharmacokinetics in specific patient populations. In a study involving 19 volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), pharmacokinetics of letrozole were unchanged after a single 2.5 mg dose. Furthermore, in the aforementioned study, the impact of impaired renal function on letrozole was evaluated; a covariate analysis was performed based on data from two pivotal studies (AR/BC2 and AR/BC3). Calculated creatinine clearance (range in study AR/BC2: 19–187 mL/min; in study AR/BC3: 10–180 mL/min) showed no statistically significant correlation with minimum plasma concentrations of letrozole at steady state (Cmin). Moreover, data from studies AR/BC2 and AR/BC3 in second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or worsening of renal function.

Thus, dose adjustment in patients with impaired renal function (creatinine clearance ≥ 10 mL/min) is not required. Information regarding patients with severe renal impairment (creatinine clearance < 10 mL/min) is limited.

In a similar study conducted in individuals with varying hepatic function, it was established that in patients with moderate hepatic impairment (Child-Pugh class B), mean values of the area under the concentration-time curve (AUC) were 37% higher than in healthy volunteers, but remained within the range observed in patients without hepatic dysfunction. In a pharmacokinetic study of a single dose in 8 patients with liver cirrhosis and severe hepatic impairment (Child-Pugh class C), AUC increased by 95% and t½ by 187%, respectively, compared to values in healthy volunteers. Thus, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment compared to patients without severe liver dysfunction. Therefore, letrozole should be used with caution in patients with severe hepatic impairment, considering the benefit-risk ratio for each individual patient. Although dose reduction is not justified, as no increase in toxicity parameters was observed in patients receiving daily doses of 5–10 mg/day, such patients require close monitoring. Furthermore, no impact of renal impairment (calculated creatinine clearance values of 20–50 mL/min) or hepatic impairment on plasma concentrations of letrozole was observed in 359 patients with advanced breast cancer.

The pharmacokinetics of letrozole are independent of age.

Clinical characteristics.

Indications.

• Adjuvant therapy of early-stage hormone receptor-positive invasive breast cancer in postmenopausal women.
• Extended adjuvant therapy of early-stage invasive breast cancer in postmenopausal women who have received standard adjuvant therapy with tamoxifen for 5 years.
• First-line therapy of hormone-dependent advanced breast cancer in postmenopausal women.
• Treatment of advanced breast cancer in postmenopausal women (naturally or artificially induced) who have relapsed or progressed after prior antiestrogen therapy.
• Neoadjuvant therapy in postmenopausal women with hormone receptor-positive, HER-2-negative breast cancer who are not candidates for chemotherapy and for whom immediate surgical intervention is not indicated.

The efficacy of the drug has not been demonstrated in patients with hormone receptor-negative breast cancer.

Contraindications.

• Hypersensitivity to the active substance or to any of the other components of the drug.
• Endocrine status characteristic of the premenopausal period.
• Pregnancy or breastfeeding.
• Women of reproductive age.

Interaction with other medicinal products and other forms of interaction.

Metabolism of letrozole occurs partially via CYP2A6 and CYP3A4 enzymes. Therefore, medicinal products affecting CYP3A4 and CYP2A6 enzymes may influence the systemic elimination of letrozole. Apparently, the metabolism of letrozole has low affinity for CYP3A4, as this enzyme is not saturated at concentrations 150 times higher than plasma concentrations of letrozole observed at steady-state under typical clinical conditions.

Currently, there is no clinical experience with the use of letrozole in combination with estrogens or other anticancer agents, except tamoxifen. Tamoxifen, other antiestrogenic agents, or estrogen-containing medicinal products may counteract the pharmacological effect of letrozole. Moreover, it has been demonstrated that concomitant administration of tamoxifen and letrozole significantly reduces plasma concentrations of letrozole. Concomitant use of letrozole with tamoxifen, other estrogen antagonists, or estrogens should be avoided.

Medicinal products that may increase serum concentrations of letrozole

Inhibitors of CYP3A4 and CYP2A6 activity may reduce the metabolism of letrozole and thus increase plasma concentrations of letrozole. Concomitant administration of medicinal products that strongly inhibit these enzymes (strong inhibitors of CYP3A4 include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g., methoxsalen)) may increase exposure to letrozole. Therefore, caution is recommended in patients requiring strong inhibitors of CYP3A4 and CYP2A6.

Medicinal products that may decrease serum concentrations of letrozole

Inducers of CYP3A4 activity may increase the metabolism of letrozole and thus reduce plasma concentrations of letrozole. Concomitant administration of medicinal products that induce CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's wort) may reduce exposure to letrozole. Therefore, caution is recommended in patients requiring strong inducers of CYP3A4. Inducers of CYP2A6 are unknown.

Concomitant administration of letrozole (2.5 mg) and tamoxifen 20 mg once daily resulted in an average 38% reduction in plasma levels of letrozole. Clinical experience from studies of second-line breast cancer therapy indicates that the therapeutic effect of letrozole treatment, as well as the frequency of adverse reactions, was not increased when letrozole was administered immediately after tamoxifen. The mechanism of this interaction is unknown.

Medicinal products whose systemic serum concentrations may be altered by letrozole

In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and moderately CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when coadministering letrozole with medicinal products whose elimination primarily depends on CYP2C19 and which have a narrow therapeutic index (such as phenytoin, clopidogrel). A substrate with a narrow therapeutic index for CYP2A6 is unknown.

Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate for CYP2C9 with a narrow therapeutic index, commonly used as a concomitant medication in the target population for letrozole) showed that concomitant administration of letrozole with these medicinal products does not result in clinically significant drug interactions.

There is no evidence of other clinically significant interactions with other commonly prescribed medicinal products.

Special precautions for use.

Renal impairment

There are no data regarding the use of letrozole in patients with creatinine clearance < 10 mL/min. The benefit-risk ratio should be carefully considered before prescribing the drug to such patients.

Hepatic impairment

In patients with severe hepatic impairment (Child-Pugh class C), systemic exposure and elimination half-life of letrozole are approximately twice as long as in healthy individuals. These patients require closer monitoring.

Bone effects

Since letrozole is a potent agent that reduces estrogen concentrations, bone mineral density should be assessed before starting, during, and after completion of adjuvant or extended adjuvant therapy with letrozole in women with osteoporosis and/or history of fractures or those at increased risk of developing osteoporosis. If necessary, treatment for osteoporosis should be initiated 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 "Dosage and administration" and "Undesirable effects").

Menopausal status

In patients with uncertain menopausal status, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol should be determined before initiating letrozole therapy. Letrozole should only be administered to women with a confirmed postmenopausal endocrine status.

Cholesterol

Serum cholesterol levels should be monitored. In a clinical trial of adjuvant treatment, hypercholesterolemia was reported in 52.3% of patients receiving letrozole and in 28.6% of patients receiving tamoxifen. According to the Common Terminology Criteria for Adverse Events (CTCAE), grade 3–4 hypercholesterolemia was reported in 0.4% of patients in the letrozole group and in 0.1% in the tamoxifen group. Additionally, in the adjuvant setting, an increase ≥ 1.5 × ULN in total cholesterol (usually non-fasting) was observed in patients receiving monotherapy who had baseline total cholesterol levels within normal limits (i.e., ≤ 1.5 × ULN): in 151/1843 (8.2%) patients in the letrozole group versus 57/1840 (3.2%) in the tamoxifen group. Lipid-lowering agents were required in 25% of patients receiving letrozole and in 16% of those receiving tamoxifen.

Laboratory test abnormalities

No dose-dependent effects of letrozole on any hematological or biochemical parameters have been observed. Mild decreases in lymphocyte count of uncertain clinical significance were observed in some patients receiving letrozole 2.5 mg. This lymphocyte reduction was transient in approximately half of affected patients. Thrombocytopenia was reported in two patients receiving letrozole; a causal relationship with letrozole was not established. Discontinuation of the study due to laboratory abnormalities, whether or not related to the drug, was rare.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (rare) may occur. Patients require careful medical supervision and appropriate management (e.g., immobilization) of the affected tendon (see section "Undesirable effects").

Other

Concomitant use of letrozole with tamoxifen, other antiestrogens, or estrogen-containing medications should be avoided, as these agents may reduce the pharmacological effect of letrozole (see section "Interaction with other medicinal products and other forms of interaction").

The product contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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

Use during pregnancy or breastfeeding.

Pregnancy

Based on human experience and isolated cases of congenital malformations (labial fusion, ambiguous external genitalia), letrozole may cause congenital developmental abnormalities when used during pregnancy. Animal studies have shown reproductive toxicity of the drug.

Letrozole is contraindicated during pregnancy.

Breastfeeding

It is unknown whether letrozole or its metabolites are excreted in human breast milk. A risk to newborns/infants cannot be ruled out.

Therefore, letrozole is contraindicated during breastfeeding.

Perimenopausal women and women of reproductive age

Letrozole should only be used in women with a clearly established postmenopausal status. Spontaneous abortions and congenital anomalies in newborns have been reported in mothers who took letrozole. Due to reports of ovarian function restoration in women during letrozole treatment, despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive methods with patients as needed.

Fertility

The pharmacological action of letrozole involves reducing estrogen production by inhibiting aromatase. In premenopausal women, suppression of estrogen synthesis leads to increased gonadotropin levels (LH, FSH). In turn, elevated FSH levels stimulate follicular growth and may induce ovulation.

Ability to affect reaction speed when driving or operating machinery.

The effect of letrozole on the ability to drive or operate machinery is negligible. However, since fatigue and dizziness, and in some cases somnolence, have been observed during treatment, caution is recommended when driving or operating complex machinery.

Dosage and Administration.

Adults and elderly patients. The recommended dose of letrozole is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with Letrozole-Teva should continue for 5 years or until disease recurrence. In patients with metastases, letrozole therapy should be continued until signs of disease progression become evident.

In the adjuvant setting, sequential therapy regimens should also be considered (letrozole for 2 years followed by tamoxifen for 3 years).

In the neoadjuvant setting, letrozole therapy should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, letrozole therapy should be discontinued and planned surgical intervention initiated and/or further treatment options discussed with the patient.

Dose adjustment is not required for elderly patients.

Children. The drug is not indicated for use in children. The safety and efficacy of letrozole in pediatric patients have not been established. Available data are limited; therefore, dosage recommendations cannot be provided.

Patients with hepatic and/or renal impairment. Dose adjustment is not required in patients with mild to moderate hepatic impairment (Child–Pugh class A and B) or renal impairment (with creatinine clearance ≥10 mL/min). Data in patients with severe renal impairment (creatinine clearance <10 mL/min) or severe hepatic impairment are insufficient. Patients with severe hepatic impairment (Child–Pugh class C) require close monitoring.

Administration method

Letrozole should be administered orally, independent of food intake, as food does not affect its extent of absorption.

If a dose is missed, it should be taken as soon as remembered. However, if the next scheduled dose is due within 2–3 hours, the missed dose should be skipped and the next dose taken according to the regular schedule. A double dose should not be taken, as systemic exposure higher than proportional has been observed with daily doses exceeding the recommended 2.5 mg.

Children.

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

Overdose.

Isolated cases of letrozole overdose have been reported.

There is no specific antidote for letrozole overdose; treatment should be symptomatic and supportive.

Adverse Reactions

The frequency of adverse reactions to letrozole was primarily determined based on data obtained from clinical trials. The medicinal product was generally well tolerated in all studies, both as first- and second-line therapy in the treatment of advanced breast cancer, as adjuvant therapy for early-stage breast cancer, and as extended adjuvant therapy in women who had previously received standard adjuvant therapy with tamoxifen.

Adverse reactions were observed in almost ⅓ of patients treated with letrozole in metastatic and neoadjuvant settings, in approximately 75% of patients receiving adjuvant therapy (both groups received letrozole and tamoxifen, with a median treatment duration of 60 months), and in nearly 80% of patients undergoing extended adjuvant therapy (letrozole and placebo, median treatment duration of 60 months). Overall, adverse reactions were mostly mild or moderate in severity and, in most cases, related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports include hot flashes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important adverse reactions that may occur during letrozole treatment include musculoskeletal disorders such as osteoporosis and/or bone fractures, and cardiovascular events (particularly cerebrovascular and thromboembolic events). Many adverse effects may be attributed to the natural pharmacological consequences of estrogen deficiency (e.g., hot flashes, alopecia, or vaginal bleeding). Most adverse reactions occurred during the first few weeks of treatment. Frequency categories for these adverse reactions are described below.

Adverse effects are listed by frequency of occurrence, with the most common listed first. The following frequency categories were used to assess the incidence of various adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

Infections and infestations. Uncommon: urinary tract infections.

Benign, malignant and unspecified neoplasms, including cysts and polyps. Uncommon: pain in tumor sites¹.

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: somnolence, insomnia, memory impairment, dysesthesia (including paresthesia, hypoesthesia), taste disturbances, stroke, carpal tunnel syndrome.

Eye disorders. Uncommon: cataract, eye mucous membrane irritation, blurred vision.

Cardiac disorders. Common: palpitations¹. Uncommon: tachycardia, myocardial ischemia events (including onset or worsening of angina, angina requiring surgical intervention, myocardial infarction, and myocardial ischemia).

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

Respiratory system disorders. Uncommon: dyspnea, cough.

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

Hepatobiliary disorders. Uncommon: increased liver enzymes, hyperbilirubinemia, jaundice. Frequency not known: hepatitis.

Skin and subcutaneous tissue disorders. Very common: increased sweating. Common: alopecia, rash (including erythematous, maculopapular, psoriasiform, and vesicular rashes), dry skin. Uncommon: pruritus, urticaria. Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema.

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

Renal and urinary disorders. Uncommon: urinary frequency.

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

General disorders and administration site conditions. Very common: fatigue (including asthenia and malaise). Common: peripheral edema, chest pain. Uncommon: increased temperature, dryness of mucous membranes, thirst, anasarca.

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

¹ Only during treatment of metastatic disease.

Some adverse reactions were reported at significantly different frequencies under adjuvant treatment conditions.

Table 1

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

Table 2

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

Description of individual adverse reactions

Cardiac disorders

Under adjuvant treatment conditions, in addition to the data presented in Table 1, the following adverse events were reported during treatment with letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days): angina pectoris requiring surgical intervention (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); arterial hypertension (5.6% vs. 5.7%); cerebrovascular disorders/transient ischemic attack (2.1% vs. 1.9%).

Under extended adjuvant treatment conditions, the following adverse events were reported for letrozole (median treatment duration of 5 years) and placebo (median treatment duration of 3 years), respectively: angina pectoris requiring surgical intervention (0.8% vs. 0.6%); newly diagnosed angina or worsening of existing angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic events* (0.9% vs. 0.3%); stroke/transient ischemic attack* (1.5% vs. 0.8%).

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

Musculoskeletal and connective tissue disorders

Safety data for the musculoskeletal system obtained under adjuvant treatment conditions are presented in Table 1.

Under extended adjuvant treatment conditions, bone fractures or osteoporosis were observed statistically significantly more frequently in patients treated with letrozole (bone fractures – 10.4% and osteoporosis – 12.2%) compared to patients 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.

Shelf life. 3 years.

Storage conditions.

Store out of reach of children. No special storage conditions are required for this medicinal product.

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

1. Teva Pharmaceutical Industries Ltd.
2. AT Pharmaceutical Plant Teva.

Manufacturer's address and location of business operations.

1. 18 Eli Hurvitz Street, Industrial Zone, Kfar Saba, Israel.
2. Unit 1; H-4042 Debrecen, Pallagi Street 13, Hungary.