Letromara®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LЕTROMARA® (LETROMARA)

Composition:

Active substance: letrozole;

1 tablet contains 2.5 mg of letrozole, calculated as 100% substance;

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose 101, hydroxypropylmethylcellulose (15), sodium starch glycolate (type A), magnesium stearate; film-coating composition: Sepifilm^TM 050 (methylhydroxypropylcellulose, microcrystalline cellulose, acetylated (or acetates of esters) mono- and diglycerides), Sepisperse^TM Dry 3214 Jaune (hydroxypropylmethylcellulose, microcrystalline cellulose, titanium dioxide (E 171), riboflavin (E 101)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets, with a brownish-yellow or orange-yellow coating.

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, eliminating their estrogen-mediated stimulatory effect is essential for suppressing tumor growth.
In postmenopausal women, estrogens are primarily formed via 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 suppress estrogen biosynthesis in peripheral tissues and in tumor tissue.

Letrozole inhibits aromatase by competitively binding to the heme subunit of cytochrome P450 within this enzyme, resulting in reduced estrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of letrozole at 0.1 mg, 0.5 mg, or 2.5 mg reduce serum levels of estrone and estradiol (compared to baseline) 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. With doses of 0.5 mg and higher, estrone and estrone sulfate concentrations often fall below the detection limit of the assay method used. This indicates that these doses achieve more pronounced suppression of estrogen synthesis. Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is a highly specific inhibitor of aromatase activity. No disruption of adrenal steroid hormone synthesis has been observed. In postmenopausal patients treated with daily doses of 0.1–5 mg of letrozole, no clinically significant changes were observed in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, adrenocorticotropic hormone (ACTH), or renin activity. 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 showed 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 letrozole at 0.1 mg, 0.5 mg, and 2.5 mg 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. No changes in plasma concentrations of luteinizing hormone and follicle-stimulating hormone were observed in patients receiving letrozole, nor were there any changes in thyroid function as assessed by TSH, T4, and T3 levels.

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 concentration of letrozole in blood (tmax) is 1 hour when administered fasting and 2 hours when administered with food; mean maximum concentration of letrozole in blood (Cmax) is 129 ± 20.3 nmol/L when fasting and 98.7 ± 18.6 nmol/L when administered with food). However, the extent of absorption (assessed by area under the concentration-time curve) remains unchanged. These minor changes in absorption rate are considered clinically insignificant; therefore, letrozole can be administered independently of food intake.

Distribution. Plasma protein binding of letrozole is approximately 60% (primarily to albumin – 55%). Erythrocyte concentrations of letrozole are about 80% of its plasma levels. 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 effects of letrozole metabolites are 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. The metabolic clearance of letrozole (CLm) is 2.1 L/h, which is lower than hepatic blood flow (approximately 90 L/h). The conversion of letrozole to its metabolite is mediated by CYP3A4 and CYP2A6 isoenzymes of cytochrome P450. Formation of small amounts of other, as yet unidentified metabolites, as well as excretion of unchanged drug in urine and feces, plays only a minor role in overall elimination. 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 urinary radioactivity detected within 216 hours (84.7 ± 7.8% of the dose) consisted of glucuronide conjugates of the carbinol metabolite, nearly 9% was attributed 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, 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 what would be predicted based on single-dose pharmacokinetic data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily dosing. However, since steady-state concentrations are 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-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 1.0 mg/day dose, instead of the expected 2.5- and 5-fold increases. Thus, the recommended dose of 2.5 mg/day may represent a 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 studied dosing regimens (0.1–5.0 mg daily).

Pharmacokinetics in Specific Patient Populations. In studies involving volunteers with varying degrees of renal function (creatinine clearance ranging from 9 to 116 mL/min), letrozole pharmacokinetics after a single 2.5 mg dose were unchanged. Furthermore, in the aforementioned study, the impact of renal impairment on letrozole was evaluated using an analysis of covariance based on data from two pivotal trials (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 association with minimum steady-state plasma concentrations of letrozole (Cmin). Moreover, data from the AR/BC2 and AR/BC3 trials in second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or worsening of 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 individuals with moderate hepatic impairment (Child-Pugh class B), mean AUC values were 37% higher than in healthy individuals but remained within the range observed in subjects without hepatic dysfunction. In a pharmacokinetic study of a single dose in patients with liver cirrhosis and severe hepatic dysfunction (Child-Pugh class C), AUC increased by 95% and t½ by 187% compared to healthy volunteers. Therefore, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment compared to those without severe liver dysfunction. Hence, Letromara® should be used with caution in patients with severe hepatic impairment, considering the individual benefit-risk ratio. Although no increase in toxicity was observed in patients receiving daily doses of 5–10 mg/day, dose reduction is not justified; however, such patients require close medical monitoring. Additionally, no impact of renal impairment (calculated creatinine clearance 20–50 mL/min) or hepatic impairment on plasma letrozole concentrations was observed in patients with advanced breast cancer. Letrozole pharmacokinetics 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 completed standard 5-year adjuvant therapy with tamoxifen.
• 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, 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 excipients.

• Endocrine status characteristic of the premenopausal period.

• Pregnancy, breastfeeding.

• Contraindicated in women of reproductive potential.

Interaction with other medicinal products and other forms of interaction.

Metabolism of letrozole occurs partially via 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 antiestrogens, 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 (strong CYP3A4 inhibitors include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g., methoxsalen)) may increase letrozole exposure. Therefore, caution is recommended in patients who require 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 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 in patients who require strong inducers of CYP3A4. Inducers of CYP2A6 are unknown.

Concomitant administration of letrozole (2.5 mg) and tamoxifen 20 mg once daily resulted in a mean 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 known non-specific 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 co-administration of letrozole with these medicinal products does not cause clinically significant drug interactions.

A review of the database from these clinical studies revealed no 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 considered before prescribing the drug to such patients.

Cholesterol

Serum cholesterol monitoring should be considered. In an adjuvant treatment study, hypercholesterolemia was reported in 52.3% of patients receiving letrozole and in 28.6% of patients receiving tamoxifen. Grade 3–4 hypercholesterolemia [according to the Common Terminology Criteria for Adverse Events (CTCAE)] was reported in 0.4% of patients in the letrozole group and in 0.1% of patients in the tamoxifen group. Furthermore, in adjuvant therapy, an increase ≥ 1.5 × ULN in total cholesterol (usually non-fasting) was observed in patients receiving monotherapy and who had normal baseline serum total cholesterol levels (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 agents were required in 25% of patients receiving letrozole and in 16% of patients receiving tamoxifen.

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.

Effects on bone

Since Lētromarā® is a potent agent that reduces estrogen concentrations, bone mineral density should be assessed before initiating treatment, during treatment, and after completion of treatment with letrozole in women with osteoporosis and/or history of fractures or those at increased risk of developing osteoporosis. In the adjuvant setting, sequential treatment regimens (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 uncertain menopausal status, levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol should be determined before initiating treatment with Lētromarā®. Lētromarā® should only be administered to women with a postmenopausal endocrine status.

Tendinitis and tendon rupture

Tendinitis and tendon rupture are possible (rare). Careful evaluation of patients and appropriate management (e.g., immobilization) of the affected tendon are required.

Laboratory test changes

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

Other precautions

Concomitant use of Lētromarā® with tamoxifen, other antiestrogens, or estrogen-containing medicinal products should be avoided, as these agents may counteract the pharmacological effect of letrozole.

Lētromarā® contains lactose — if you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Perimenopausal women or women of reproductive age

Lētromarā® should only be used in women with a clearly established postmenopausal status. There are reports of spontaneous abortions and congenital anomalies in newborns whose mothers took letrozole.

Due to reports of ovarian function recovery in women during letrozole treatment, despite a clearly defined postmenopausal status at the start of therapy, the physician should discuss appropriate contraceptive methods with the patient as needed.

Pregnancy

Based on human experience with letrozole, including individual cases of congenital malformations (cleft lip, ambiguous external genitalia), letrozole is known to cause fetal malformations when used during pregnancy. Animal studies have shown reproductive toxicity. Lētromarā® is contraindicated during pregnancy.

Breastfeeding

It is unknown whether letrozole and its metabolites are excreted in human breast milk. Risk to the newborn/infant cannot be excluded.

Lētromarā® is contraindicated 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). Increased FSH levels, in turn, stimulate follicular growth, which may induce ovulation.

Ability to influence reaction rate when driving or operating machinery.

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

Dosage and Administration

Adults, including elderly patients. The recommended dose of Letromara® is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with Letromara® should continue for 5 years or until disease recurrence. For patients with metastatic disease, treatment with Letromara® should be continued until evidence of disease progression becomes apparent. In adjuvant settings, sequential treatment regimens should also be considered (letrozole for 2 years followed by tamoxifen for 3 years).

In the neoadjuvant setting, treatment with Letromara® should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, therapy with Letromara® 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. Letromara® is not indicated for use in pediatric patients. The safety and efficacy of letrozole in children 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 for 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.

Administration

Letromara® should be taken orally, independently 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 scheduled dose (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 administration of daily doses higher than the recommended 2.5 mg resulted in greater than proportional systemic exposure.

Children.

Letromara® is not recommended for use in children, as the efficacy and safety of letrozole in this patient population have not been studied in clinical trials.

Overdose.

Single cases of letrozole overdose have been reported.

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

Adverse Reactions

Overview of Safety Profile

The frequency of adverse reactions to letrozole was primarily determined based on data obtained from clinical trials.

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 nearly 1/3 of patients treated with letrozole in metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen, with a median treatment duration of 60 months), and nearly 80% of patients in the extended adjuvant therapy setting (letrozole and placebo, with a median treatment duration of 60 months). Overall, the observed adverse reactions were mostly mild or moderate in severity and were in most cases related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports included hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important 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 attributable 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. Frequency categories for these adverse reactions are described in Table 1.

Adverse reactions are listed by frequency, with the most common listed first. The following terms are used to classify the frequency of occurrence 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).

Table 1

(1) Only in the treatment of metastatic disease.

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

Table 2

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

Note. During treatment – includes 30 days after the last dose. At any time – includes the follow-up period after completion or discontinuation of the investigational treatment.

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

Table 3

Sequential treatment compared with 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 adverse reactions

In the adjuvant treatment setting, the following adverse events were reported for letrozole and tamoxifen, respectively (with a median duration of treatment of 60 months plus 30 days): 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 for letrozole (median treatment duration 5 years) and placebo (median treatment duration 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 adverse reactions

Safety data for the musculoskeletal system obtained in the adjuvant treatment setting are presented in Table 2.

In the extended adjuvant treatment setting, bone fractures or osteoporosis were observed in a statistically significantly higher number 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. 4 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.