Letrozole krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETROZOLE KRKA (Letrozole KRKA)

Composition:

Active substance: letrozole;

One film-coated tablet contains 2.5 mg of letrozole;

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

Film coating: hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), polyethylene glycol 400, talc, purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, smooth on both sides, film-coated tablets.

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 dependent on estrogen, eliminating the estrogen-mediated stimulatory effect is essential for inhibiting 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 and tumor tissues.

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 at 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% from baseline. With doses of 0.5 mg and higher, concentrations of estrone and estrone sulfate in many cases fall below the detection limit of the hormone 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 letrozole at daily doses of 0.1–5 mg, 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 letrozole (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 female volunteers, 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, no changes in plasma androstenedione levels were observed in postmenopausal patients receiving daily doses of 0.1–5 mg of letrozole. These findings indicate that blockade of estrogen biosynthesis does not lead to accumulation of estrogen precursors, the androgens. In patients receiving letrozole, no changes were observed in plasma concentrations of luteinizing hormone (LH) or follicle-stimulating hormone (FSH), 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 concentration (Cmax) of letrozole in blood is 129 ± 20.3 nmol/L when administered fasting and 98.7 ± 18.6 nmol/L when taken with food). However, the extent of absorption of letrozole (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%). Concentration in erythrocytes is about 80% of the level in plasma. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of radioactivity in plasma corresponded to unchanged active substance. Therefore, systemic effects of letrozole metabolites are 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 metabolite (the primary elimination pathway). The metabolic clearance (CLm) of letrozole is 2.1 L/hour, which is less than hepatic blood flow (approximately 90 L/hour). Cytochrome P450 isoenzymes CYP3A4 and CYP2A6 have been shown to convert 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 excreted in urine within 216 hours (84.7 ± 7.8% of the administered dose) was accounted for by glucuronide conjugates of the carbinol metabolite, nearly 9% by two other unidentified metabolites, and 6% by unchanged letrozole.

The apparent terminal half-life (t1/2) 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. Meanwhile, the steady-state concentration is 1.5–2 times higher than what would be expected based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole at a daily dose of 2.5 mg is slightly nonlinear. However, since steady-state concentration is maintained during prolonged administration, it can be concluded that accumulation of letrozole does not occur.

Linearity/Non-linearity

Letrozole pharmacokinetics were dose-proportional after administration of 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 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

Letrozole pharmacokinetics 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 letrozole pharmacokinetics were observed after a single 2.5 mg dose. Additionally, in the aforementioned study, the effect of impaired renal function on letrozole was evaluated by analysis of covariance 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 steady-state plasma concentration of letrozole (Cmin). Furthermore, 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 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 volunteers with varying degrees of hepatic function, it was found that in individuals 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 subjects 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 t1/2 by 187%, respectively, compared to healthy volunteers. Thus, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment compared to those without severe liver dysfunction. Therefore, letrozole Krka 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 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 5 years of standard 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 menopause) 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 candidates for chemotherapy and for whom immediate surgery 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 age.

Interaction with other medicinal products and other forms of interaction.

Letrozole metabolism is partially mediated by CYP2A6 and CYP3A4. Therefore, medicinal products affecting the activity of 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 its plasma concentrations. Concomitant administration 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 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 its plasma concentrations. Concomitant administration 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 (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 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 isoenzyme CYP2A6 and moderately inhibits CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when co-administering letrozole with medicinal products whose elimination is primarily dependent 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 with these medicinal products does not result in clinically significant drug interactions.

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

Special precautions for use.

Renal function

There are no data on the use of Letrozole KRKA in 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 treated with letrozole and in 28.6% of patients treated with tamoxifen. According to the severity criteria of adverse reactions (CTC), 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 × ULN (upper limit of normal) in total cholesterol (usually non-fasting) was observed in patients treated with the drug as 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. Hypolipidemic agents were required in 25% of patients treated with letrozole and in 16% of patients treated with tamoxifen.

Hepatic function

In patients with severe hepatic impairment (Child–Pugh class C), systemic exposure and t1/2 of letrozole are approximately twice as long as in healthy individuals. These patients require closer monitoring.

Effect on bones

Since Letrozole KRKA is a potent agent that reduces estrogen concentrations, bone mineral density should be assessed before initiating treatment, during treatment, and after completion of letrozole therapy in postmenopausal women with osteoporosis and/or a 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 unclear menopausal status, levels of LH, FSH, and/or estradiol should be determined before initiating treatment with Letrozole KRKA. Only women with a postmenopausal endocrine status should receive Letrozole KRKA.

Tendonitis and tendon rupture

Tendonitis and tendon rupture are possible (rare). Careful examination of patients and appropriate measures (e.g., immobilization) for the affected tendon should be undertaken (see section "Adverse reactions").

Laboratory test abnormalities

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

Other warnings

Concomitant use of Letrozole KRKA 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 drug contains lactose, it should not be used in patients with rare hereditary problems such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Perimenopausal women or women of reproductive age

Letrozole KRKA should only be used in women with a clearly established postmenopausal status. Post-marketing reports have documented spontaneous abortions and congenital anomalies in newborns whose mothers took this drug. Due to reports of ovarian function recovery in women treated with Letrozole KRKA despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss the use of contraception with patients as appropriate.

Pregnancy

Based on human experience, including isolated cases of congenital malformations (cleft lip, ambiguous external genitalia), it is known that letrozole may cause developmental malformations when used during pregnancy. Animal studies have shown reproductive toxicity. Letrozole KRKA is contraindicated during pregnancy.

Lactation

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

Letrozole KRKA 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). The increase in FSH, in turn, stimulates follicular growth, which may induce ovulation.

Ability to affect reaction speed when driving or operating machinery.

The effect of Letrozole KRKA 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

Adult patients, including elderly patients. The recommended dose of Letrozole KRKA is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with Letrozole KRKA should continue for 5 years or until disease recurrence.

In patients with metastatic disease, treatment with Letrozole KRKA should be continued until signs of disease progression become evident. In the adjuvant setting, sequential treatment regimens should also be considered (letrozole for 2 years followed by tamoxifen for 3 years).

In the neoadjuvant setting, treatment with Letrozole KRKA should continue for 4–8 months to achieve optimal tumor shrinkage. If the response to treatment is inadequate, therapy with Letrozole KRKA 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. Letrozole KRKA is not indicated for use in children. The safety and efficacy of Letrozole KRKA 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 classes A and B) or renal impairment (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

Letrozole KRKA is 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 within 2–3 hours before the next scheduled dose, the missed dose should not be taken; instead, 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 resulted in systemic exposure disproportionate to the dose increase.

Children.

The drug is not used in children, as the efficacy and safety of the drug in this patient population have not been studied in 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

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

Adverse reactions were observed in nearly 1/3 of patients treated with letrozole in metastatic and neoadjuvant settings, and in nearly 80% of patients in both adjuvant and extended adjuvant therapy. Most adverse reactions occurred during the first few weeks of treatment.

The most commonly reported adverse reactions in clinical studies were hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue.

Important adverse reactions that may occur during treatment with Letrozole KRKA include musculoskeletal disorders such as osteoporosis and/or bone fractures, and cardiovascular disorders (including cerebrovascular and thromboembolic events). Many of the adverse effects may be related 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. The frequency of these adverse reactions is shown in Table 1.

The frequency of adverse reactions is mainly based on data obtained from clinical trials.

The adverse reactions listed in Table 1 were observed during clinical trials and post-marketing use of letrozole.

Adverse reactions are listed by frequency, with the most common ones listed first. The following categories were used to assess the frequency of occurrence of various adverse reactions: very common – ≥ 10%; common – ≥ 1% to < 10%; uncommon – ≥ 0.1% to < 1%; rare – ≥ 0.01% to < 0.1%; very rare – < 0.01%; frequency not known (cannot be estimated from available data).

Table 1

(1) Only in the treatment of metastatic disease.

The frequency of certain adverse reactions differed significantly under adjuvant treatment conditions.

Table 2

Adjuvant therapy with letrozole compared to tamoxifen monotherapy: 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 investigational treatment.

Differences were determined by risk ratios and 95% confidence intervals.

Table 3

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, in addition to the data presented in Table 2, the following adverse events were reported during treatment with letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days): surgically treated angina pectoris (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 5 years) and placebo (median treatment duration 3 years), respectively: surgically treated angina pectoris (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 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 disorders

Safety data for the musculoskeletal system from 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 the placebo group (5.8% and 6.4%, respectively). Median treatment duration was 5 years for letrozole compared to 3 years for placebo.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

TAD Pharma GmbH.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.