Letrozole genefarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETROZOLE GENEPHARM (LETROZOLE GENEPHARM)

Composition:

Active substance: letrozole;

1 tablet contains 2.5 mg of letrozole;

Excipients: lactose monohydrate; microcrystalline cellulose; maize starch; sodium starch glycolate (type A); colloidal anhydrous silicon dioxide; magnesium stearate;

Tablet coating: titanium dioxide (E 171); yellow iron oxide (E 172); macrogol 4000; red iron oxide (E 172); talc; hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow-colored, round, biconvex film-coated tablets.

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

ATC code L02BG04.

Pharmacological Properties.

Pharmacodynamics.

Letrozole is a nonsteroidal aromatase inhibitor (an estrogen biosynthesis inhibitor) and an antineoplastic agent.

In cases where tumor tissue growth is dependent on the presence of estrogens, eliminating their estrogen-mediated stimulatory effect is essential for suppressing tumor growth.
In postmenopausal women, estrogens are primarily formed through the action 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 suppress estrogen biosynthesis in peripheral tissues and within 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 from 0.1 mg to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75–95% compared to baseline levels. With doses of 0.5 mg and higher, concentrations of estrone and estrone sulfate often fall below the detection limit of the assay method used for hormone determination. 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 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 detected. 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. Thus, 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). In postmenopausal patients receiving daily doses of 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. In patients receiving letrozole, no changes in plasma concentrations of luteinizing hormone (LH) or follicle-stimulating hormone (FSH) 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 taken on an empty stomach and 2 hours when taken with food; mean maximum plasma concentration (Cmax) is 129 ± 20.3 nmol/L when taken fasting 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 (AUC)) remains 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 was attributed to unchanged active substance. Therefore, 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 an inactive carbinol metabolite – the primary elimination pathway. The metabolic clearance of letrozole (CLm) is 2.1 L/h, which is less 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 a small amount of other, 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 excreted 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 apparent terminal half-life in plasma is approximately 2–4 days. Steady-state concentration of letrozole is reached within 2–6 weeks after daily administration of 2.5 mg, and is approximately 7 times higher than after a single dose of the same amount. At the same time, steady-state concentrations are 1.5–2 times higher than those predicted based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole at a daily dose of 2.5 mg are slightly nonlinear. However, since steady-state concentrations are maintained over prolonged treatment periods, it can be concluded that accumulation of letrozole does not occur.

Linearity/Nonlinearity. The pharmacokinetics of letrozole were dose-proportional after single oral doses up to 10 mg (dose range 0.01–30 mg), as well as 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 proportional increase in AUC was observed. 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 groups.

The pharmacokinetics of letrozole are not influenced by age.

In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), no changes in the pharmacokinetics of letrozole were observed after administration of a single 2.5 mg dose. Furthermore, in the same study, the impact of renal impairment on letrozole was evaluated using covariance analysis 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 correlation with minimum plasma concentrations of letrozole at steady state (Cmin). Additionally, data from the AR/BC2 and AR/BC3 trials of second-line treatment for 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 degrees of hepatic function, it was established that in patients with moderate hepatic impairment (Child-Pugh class B), mean AUC values were 37% higher than in healthy volunteers but remained within the range observed in patients without hepatic impairment. In a pharmacokinetic study of a single dose in 8 patients with liver cirrhosis and severe hepatic dysfunction (Child-Pugh class C), AUC increased by 95% and elimination half-life (t1/2) by 187% compared to healthy volunteers. Therefore, Letrozole Jenefarm should be used with caution in patients with severe hepatic impairment, considering the benefit-risk ratio for each individual patient.

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 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.

• Reproductive potential of the patient.

Interaction with other medicinal products and other forms of interaction.

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

Clinical experience with the use of Letrozole GenePharm in combination with estrogens or other anticancer agents, apart from tamoxifen, is currently lacking. Tamoxifen, other antiestrogens, or estrogen-containing medicinal products may counteract the pharmacological effect of letrozole. Furthermore, 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 its plasma concentrations. Concomitant use of medicinal products that strongly inhibit these enzymes (potent CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 inhibitors, e.g., methoxsalen) may increase letrozole exposure. Therefore, caution is recommended in patients who require potent CYP3A4 and CYP2A6 inhibitors.

Medicinal products that may decrease serum concentrations of letrozole

Inducers of CYP3A4 activity may enhance the metabolism of letrozole and thereby reduce its plasma concentrations. 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 potent CYP3A4 inducers. Inducers of CYP2A6 are unknown.

Concomitant administration of Letrozole GenePharm (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 GenePharm and the frequency of adverse reactions were not increased when this medicinal product 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 (e.g., 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 of CYP2C9 with a narrow therapeutic index, commonly used as a concomitant medication in the target population for letrozole) showed that co-administration of Letrozole GenePharm with these medicinal products does not result in clinically significant drug interactions.

A review of the database from these clinical studies revealed no evidence of other clinically significant interactions with commonly prescribed medicinal products.

Special precautions for use.

Renal impairment

There are no data on the use of Letrozole Jenepharmed 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. 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% of patients in the tamoxifen group. Additionally, in adjuvant therapy, an increase ≥ 1.5 × upper limit of normal (ULN) in total cholesterol (usually non-fasting) was observed in patients receiving monotherapy who had baseline serum total cholesterol levels within normal limits (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), the AUC and t1/2 of letrozole are approximately twice as long as in healthy individuals. Such patients require closer monitoring.

Effect on bones

Since Letrozole Jenepharmed is a potent agent that reduces estrogen concentrations, in patients with osteoporosis and/or a history of fractures, as well as in those at increased risk of developing osteoporosis, bone mineral density should be assessed before initiating, during, and after completion of adjuvant or extended adjuvant therapy with letrozole. In the adjuvant setting, a sequential treatment strategy (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, serum LH, FSH, and/or estradiol levels should be determined before initiating treatment with Letrozole Jenepharmed. Letrozole Jenepharmed should only be administered to women with a postmenopausal endocrine status.

Tendinitis and tendon rupture

Tendinitis and tendon rupture have been reported rarely. Patients should be carefully evaluated and appropriate measures (e.g., immobilization) taken if tendon involvement is suspected (see section "Adverse reactions").

Laboratory test abnormalities

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

Other warnings

Concomitant use of Letrozole Jenepharmed with tamoxifen, other estrogen antagonists, or estrogen-containing medicinal products should be avoided, as these substances may counteract the pharmacological effect of letrozole.

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

Use during pregnancy or breastfeeding.

Perimenopausal women or women of reproductive age

Letrozole Jenepharmed should only be used in women with a clearly established postmenopausal status. Post-marketing reports have documented spontaneous abortions and congenital malformations in newborns whose mothers received Letrozole Jenepharmed.

Due to reports of ovarian function recovery in women treated with Letrozole Jenepharmed, despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive methods with patients as needed.

Pregnancy

Based on human experience, including individual cases of congenital malformations (such as cleft lip, ambiguous external genitalia), Letrozole Jenepharmed may cause developmental abnormalities when used during pregnancy. Animal studies have shown reproductive toxicity. Letrozole Jenepharmed is contraindicated during pregnancy.

Breastfeeding

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

Letrozole Jenepharmed 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 compensatory increase in gonadotropin levels (LH, FSH). Elevated FSH levels stimulate follicular growth, which may induce ovulation.

Ability to influence reaction speed when driving or operating machinery

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

Dosage and Administration.

Adults, including elderly patients. The recommended dose of Letrozole GenePharm is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with Letrozole GenePharm should continue for 5 years or until disease recurrence. For patients with metastatic disease, treatment with Letrozole GenePharm should be continued until signs of disease progression become evident. In the adjuvant setting, sequential therapy regimens should also be considered (treatment with letrozole for 2 years followed by tamoxifen for 3 years).

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

Children. The drug is not indicated for use in children and adolescents. The safety and efficacy of Letrozole GenePharm in children and adolescents under 17 years of age have not been established. Available data are limited; therefore, dosage recommendations cannot be provided.

Patients with hepatic and/or renal impairment. No dose adjustment is required for patients with mild to moderate hepatic impairment (Child–Pugh classes 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 GenePharm should be administered orally, independent of food intake.

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 systemic exposure higher than proportional has been observed with daily doses exceeding the recommended 2.5 mg.

Children.

The drug is not indicated 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.

Overview of safety profile

The frequency of adverse reactions for Letrozole GenePharm was primarily determined based on data obtained from clinical studies.

Letrozole was generally well tolerated in all studies as first- and second-line therapy in the treatment of advanced breast cancer, as adjuvant therapy for early-stage breast cancer, and as extended adjuvant therapy in women previously treated with standard adjuvant tamoxifen. Adverse reactions were observed in nearly
1/3 of patients treated with Letrozole GenePharm in metastatic and neoadjuvant settings, in approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen, with a median treatment duration of 60 months), and in nearly 80% of patients receiving extended adjuvant therapy (both letrozole and placebo, with a median treatment duration of 60 months). Overall, 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 study reports included hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important additional adverse reactions that may occur during treatment with Letrozole GenePharm 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 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).

Table 1

(1) Only in the treatment of metastatic disease.

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

Table 2

Adverse reactions with significantly different frequencies in adjuvant therapy with Letrozole compared to monotherapy with tamoxifen:

Note. "During treatment" includes 30 days after administration of 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 to letrozole monotherapy (Letrazole Jenefarm): adverse reactions with significantly different frequencies

* Significantly lower than in the monotherapy group with Letrozole Jenepharm.

** Significantly higher than in the monotherapy group with Letrozole Jenepharm.

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

Description of selected adverse reactions

Adverse reactions of the cardiac system

In the adjuvant treatment setting, in addition to the data presented in Table 2, the following adverse reactions were reported for Letrozole Jenepharm and tamoxifen, respectively (with a median duration of treatment of 60 months plus 30 days): angina pectoris requiring surgical treatment (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 reactions were reported for Letrozole Jenepharm (median treatment duration 5 years) and placebo (median treatment duration 3 years), respectively: angina pectoris requiring surgical treatment (0.8% vs. 0.6%); newly diagnosed angina or worsening of angina symptoms (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.

Adverse reactions of the musculoskeletal system

Safety data regarding 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 Jenepharm treatment group (bone fractures – 10.4% and osteoporosis – 12.2%) compared to the placebo group (5.8% and 6.4%, respectively). Median duration of treatment was 5 years for Letrozole Jenepharm compared to 3 years for placebo.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 film-coated tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Jenepharm S.A., Greece.

Manufacturer's address and location of operations.

18th km Marathona Avenue, Pallini Attiki, 15351, Greece.