Letero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETERO (LETERO)

Composition:

Active substance: letrozole;

One film-coated tablet contains 2.5 mg of letrozole;

Excipients: lactose monohydrate; colloidal anhydrous silicon dioxide; sodium croscarmellose; magnesium stearate; povidone; coating: Opadry yellow 03B82401 (hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), polyethylene glycol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: dark yellow, round, slightly biconvex tablets with beveled edges, film-coated, with engraved markings «Н» on one side and «5» on the other.

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

ATC code L02B G04.

Pharmacological Properties

Pharmacodynamics

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

In cases where tumor growth is dependent on estrogens, elimination of their estrogen-mediated stimulatory effect is essential for suppression of tumor growth. In postmenopausal women, estrogens are primarily synthesized via the enzyme aromatase, which converts androgens produced in the adrenal glands (primarily androstenedione and testosterone) into estrone (E1) and estradiol (E2). Therefore, specific inhibition of the aromatase enzyme can suppress estrogen biosynthesis in peripheral tissues and in tumor tissue.

Letrozole inhibits aromatase by competitively binding to the heme subunit of cytochrome P450, a component 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% of baseline levels. With doses of 0.5 mg and higher, concentrations of estrone and estrone sulfate are often below the detection limit of the assay method used for hormone determination. This indicates that these doses achieve pronounced and sustained suppression of estrogen synthesis throughout the treatment period in these 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 daily doses of 0.1–5 mg, no clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, adrenocorticotropic hormone (ACTH), or renin activity were observed. ACTH stimulation tests performed at 6 and 12 weeks of therapy with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg revealed no notable reduction in aldosterone or cortisol synthesis. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg of letrozole did not alter plasma concentrations of androgens (androstenedione and testosterone). Similarly, in postmenopausal patients receiving daily doses of 0.1–5 mg of letrozole, no changes in plasma androstenedione levels were observed. This indicates that blockade of estrogen biosynthesis does not lead to accumulation of estrogen precursor androgens. In patients receiving letrozole, no changes in plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were observed, and no alterations in thyroid function were noted, as assessed by levels of thyroid-stimulating hormone (TSH), 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 fasting and 2 hours when administered with food; mean maximum plasma concentration (Cmax) is 129 ± 20.3 nmol/L when administered fasting and 98.7 ± 18.6 nmol/L when administered with food). However, the extent of absorption (as assessed by the area under the concentration-time curve) remains unchanged. The minor changes in absorption rate are considered not clinically significant; therefore, LETRO may 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 approximately 80% of its plasma level. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of radioactivity in plasma was attributed to the unchanged active substance. Thus, systemic activity of letrozole metabolites is negligible. Letrozole rapidly and extensively 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 metabolite – the primary elimination pathway. Metabolic clearance of letrozole is 2.1 L/h, which is lower than hepatic blood flow (approximately 90 L/h). It has been shown that CYP3A4 and CYP2A6 isoenzymes of cytochrome P450 are capable of converting letrozole into its metabolite. Formation of small amounts 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 radioactivity was recovered in urine and 3.8 ± 0.9% in feces. At least 75% of the radioactivity detected in urine within 216 hours (84.7 ± 7.8% of the dose of letrozole) was attributed to glucuronide conjugates of the carbinol metabolite, nearly 9% to two other unidentified metabolites, and 6% to unchanged letrozole.

The expected terminal half-life from plasma is approximately 2–4 days. After daily administration of 2.5 mg, steady-state concentration is reached within 2–6 weeks, and is approximately 7 times higher than after a single dose of the same amount. Concurrently, the steady-state concentration is 1.5–2 times higher than the value predicted based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily dosing. However, since steady-state concentration is maintained over prolonged treatment periods, accumulation of letrozole does not occur.

Linearity/Non-linearity. Letrozole pharmacokinetics 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 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-fold, respectively, compared to a 2.5- and 5-fold increase expected from a 1.0 mg/day dose. Thus, the recommended dose of 2.5 mg/day may represent the threshold 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 dosing regimens studied (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), letrozole pharmacokinetics were unchanged after a single 2.5 mg dose. Furthermore, in this study, the impact of impaired renal function was assessed – letrozole, an analysis of covariance was performed based on data from two pivotal studies (AR/BC2 and AR/BC3). Calculated creatinine clearance (range in AR/BC2: 19–187 mL/min; in AR/BC3: 10–180 mL/min) showed no statistically significant relationship with minimum plasma concentrations of letrozole at steady state (Cmin). Additionally, data from AR/BC2 and AR/BC3 studies in second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or renal function.

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

In a similar study conducted in subjects 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 cirrhosis and severe hepatic impairment (Child-Pugh class C), AUC increased by 95% and t½ by 187% compared to healthy volunteers. Thus, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment than in those without severe liver dysfunction. Therefore, LETRO 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 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 20–50 mL/min) or hepatic impairment on plasma letrozole concentrations was observed in 359 patients with advanced breast cancer. Letrozole pharmacokinetics are independent of age.

Clinical characteristics.

Indications.

• Adjuvant therapy of hormone receptor-positive early-stage 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 experienced disease recurrence or progression after prior antiestrogen therapy.
• Neoadjuvant therapy in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer who are not suitable for chemotherapy and for whom immediate surgical intervention is not indicated.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Endocrine status typical of the premenopausal period.
• Pregnancy and breastfeeding.
• Contraindicated in women of reproductive age.

Interaction with other medicinal products and other forms of interaction.

Metabolism of letrozole is partially mediated by CYP2A6 and CYP3A4. Therefore, medicinal products affecting CYP3A4 and CYP2A6 enzymes may influence the systemic clearance of letrozole. Apparently, the metabolism of letrozole has low affinity for CYP3A4, as this enzyme does not become saturated at concentrations 150 times higher than the 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 thereby increase plasma concentrations of letrozole. Concomitant use of medicinal products that strongly inhibit these enzymes (potent CYP3A4 inhibitors include: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6, e.g., methoxsalen) may increase letrozole exposure. Therefore, caution is recommended when using potent inhibitors of CYP3A4 and CYP2A6.

MEDICINAL PRODUCTS THAT MAY DECREASE SERUM CONCENTRATIONS OF LETROZOLE

Inducers of CYP3A4 activity may enhance the metabolism of letrozole and thereby reduce plasma concentrations of letrozole. Concomitant use of medicinal products that induce CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's wort) may reduce letrozole exposure. Therefore, caution is recommended when using potent 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 reduction of 38% in plasma levels of letrozole. Clinical experience from second-line breast cancer treatment studies indicates that the therapeutic effect of letrozole, 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 co-administering 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 non-specific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate of CYP2C9 with a narrow therapeutic index, frequently used as a concomitant medication in the target population for letrozole) showed that co-administration of Letrozole with these medicinal products does not cause clinically significant drug interactions.

A review of the database from these clinical studies did not reveal any evidence of other clinically significant interactions with other commonly prescribed medicinal products.

Special precautions for use.

Renal impairment

There are no data on the use of letrozole for the treatment of patients with creatinine clearance < 10 mL/min. The benefit-risk ratio should be carefully evaluated before prescribing LETERO 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 treatment with letrozole in women with osteoporosis and/or a history of fractures, or those at increased risk of developing osteoporosis during adjuvant or extended adjuvant therapy. In the adjuvant setting, a sequential treatment regimen (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered depending on the patient's safety profile (see sections “Posology and method of administration”, “Undesirable effects”).

Menopausal status

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

Tendinitis and tendon rupture

Rare cases of tendinitis and tendon ruptures have been reported in patients receiving letrozole. Careful monitoring of patients is required, and appropriate measures (e.g., immobilization) should be taken if tendon involvement occurs (see section “Undesirable effects”).

Cholesterol

Monitoring of serum cholesterol levels should be considered. Hypercholesterolemia has been reported in patients receiving letrozole as well as in those receiving tamoxifen. In addition, increased total cholesterol (usually non-fasting) has been reported in patients receiving letrozole monotherapy who had normal baseline serum total cholesterol levels. Some of these patients required treatment with lipid-lowering agents.

Laboratory test abnormalities

No dose-dependent effect of letrozole on any hematological or biochemical parameters has been observed. A mild decrease in lymphocyte count of uncertain clinical significance was observed in some patients receiving letrozole 2.5 mg. This lymphocyte decrease was transient in approximately half of the affected patients. Thrombocytopenia has been reported in two patients receiving letrozole; a causal relationship with letrozole has not been established.

Other warnings

Concomitant use of letrozole with tamoxifen, other antiestrogens, or estrogen-containing products 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”).

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

Use during pregnancy or breastfeeding.

Pregnancy

Human experience with letrozole (isolated cases of congenital malformations: labial fusion, intermediate-type external genitalia) suggests that letrozole may cause congenital developmental abnormalities when used during pregnancy. Animal studies have revealed reproductive toxicity of the drug.

Letrozole is contraindicated during pregnancy.

Breastfeeding

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

Therefore, letrozole is contraindicated during breastfeeding.

Perimenopausal women or women of reproductive potential

Letrozole should only be used in women with a clearly established postmenopausal status. Spontaneous abortions and congenital abnormalities in newborns have been reported in mothers who received letrozole. Due to reports of ovarian function recovery in women receiving letrozole despite a clearly defined postmenopausal status at the start of therapy, the physician should discuss appropriate contraceptive measures with the patient, if necessary.

Fertility

The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition 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 driving and use of machines.

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

Method of Administration and Dosage

Adults and Elderly Patients. The recommended dose of LETERO is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with LETERO should continue for 5 years or until disease recurrence. In patients with metastatic disease, treatment with LETERO 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, treatment with LETERO should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, treatment with LETERO should be discontinued and planned surgical intervention initiated and/or alternative treatment options discussed with the patient.

Dose adjustment is not required for elderly patients.

Children. LETERO 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 dysfunction are insufficient. Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.

Method of Administration

The medicinal product LETERO should be administered orally, independent of food intake, as food does not affect the extent of drug absorption.

If a dose is missed, it should be taken as soon as the patient remembers. However, if the patient remembers close to the time of the next dose (within 2–3 hours), the missed dose should not be taken, and the next dose should be taken according to the regular schedule. A double dose should not be taken, as administration of daily doses higher than the recommended 2.5 mg has been associated with disproportionately higher systemic exposure.

Children.

The medicinal product is not intended for use in children, as the efficacy and safety of the drug have not been studied in this patient population within clinical trials.

Overdose.

Isolated cases of letrozole overdose have been reported.

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

Adverse reactions.

Letrozole was generally well tolerated in all studies as first- and second-line therapy for advanced breast cancer, as adjuvant therapy for early-stage 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 letrozole in metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received letrozole and tamoxifen, median treatment duration was 60 months), and nearly 80% of patients in the extended adjuvant therapy setting (both letrozole and placebo, median treatment duration was 60 months). The observed adverse reactions were predominantly mild or moderate in severity and were mostly related to estrogen deficiency. The most commonly reported adverse reactions in clinical trials included hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important additional adverse reactions that may occur during letrozole treatment include musculoskeletal events such as osteoporosis and/or bone fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many adverse effects may be attributed to the natural pharmacological consequences of estrogen deficiency (e.g., hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred during the first few weeks of treatment.

Adverse reactions are listed by frequency, 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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000); frequency not known (cannot be estimated from 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: decreased appetite, 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 irritation, blurred vision.

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

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

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnea, cough.

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

Hepatobiliary disorders. Uncommon: elevated 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: tendinitis. 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 body temperature, dry mucous membranes, thirst, generalized edema.

Investigations. Common: weight increased. Uncommon: weight decreased.

¹ Only in 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 to letrozole monotherapy: adverse events with significantly different frequencies

* Significantly lower than in the letrozole monotherapy group.

** Significantly higher than in the letrozole monotherapy group.

Note. The reporting period includes the treatment period or 30 days after discontinuation of treatment.

Description of selected adverse reactions

Cardiac disorders

In the adjuvant treatment setting, the following adverse events were reported with letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days), in addition to the data presented in Table 1: angina 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%).

In the extended adjuvant treatment setting, the following adverse events were reported with letrozole (median treatment duration of 5 years) and placebo (median treatment duration of 3 years), respectively: angina requiring surgical intervention (0.8% vs. 0.6%); newly diagnosed angina or worsening of 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 incidence of events marked with * differed significantly between the two treatment groups.

Musculoskeletal and connective tissue disorders

Safety data for the musculoskeletal system from the adjuvant treatment setting are presented in Table 1.

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

Shelf life. 3 years.

Storage conditions. Store in the original manufacturer’s packaging at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister; 1 or 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

HETERO LABS LIMITED.

HETERO LABS LIMITED.

Address.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.