Femara

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FEMARA® (FEMARA®)

Composition:

Active substance: letrozole;

1 tablet contains 2.5 mg of letrozole;

Excipients: colloidal anhydrous silicon dioxide; microcrystalline cellulose; lactose monohydrate; magnesium stearate; maize starch; sodium starch glycolate (type A); hydroxypropylmethylcellulose; polyethylene glycol 8000; talc; titanium dioxide (E 171); yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: dark yellow, round, slightly biconvex, film-coated tablets with beveled edges; on one side – the marking "FV", on the other – "CG".

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 growth is dependent on estrogens, elimination of their estrogen-mediated stimulatory effect is essential for tumor growth inhibition. 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 oral doses of letrozole at 0.1 mg, 0.5 mg, and 2.5 mg reduce serum levels of estrone and estradiol by 75–78% and 78%, respectively, compared to baseline. 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 often fall below the detection limit of the assay method used for hormone measurement. 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, 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 showed no significant reduction in aldosterone or cortisol synthesis. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of letrozole 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, no changes in plasma androstenedione levels were observed. This indicates that blockade of estrogen biosynthesis does not lead to accumulation of androgen precursors. No changes in plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were observed in patients receiving letrozole. Thyroid function, assessed by levels of thyroid-stimulating hormone (TSH), T4, and T3, remained unchanged.

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 in blood, t_max, is 1 hour when taken fasting and 2 hours when taken with food; mean maximum concentration in blood, C_max, 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 (assessed by the area under the concentration-time curve) remains unchanged. The minor changes in absorption rate are considered not clinically significant; therefore, letrozole can be administered independently of food intake.

Distribution. Protein binding of letrozole to plasma proteins is approximately 60% (mainly 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 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, primarily forming a pharmacologically inactive carbinol metabolite—the main elimination pathway. Metabolic clearance (CL_m) of letrozole is 2.1 L/h, which is lower than hepatic blood flow (approximately 90 L/h). 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, and excretion of unchanged drug in urine and feces play only minor roles in overall elimination. Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to postmenopausal healthy 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) 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 in plasma is approximately 2–4 days. Steady-state concentrations of letrozole are reached within 2–6 weeks after daily administration of 2.5 mg, with levels approximately 7 times higher than after a single dose. The steady-state concentration is 1.5–2 times higher than predicted from single-dose pharmacokinetic data. This indicates that the pharmacokinetics of daily 2.5 mg letrozole administration are slightly nonlinear. However, since steady-state concentrations are maintained over prolonged treatment periods, accumulation of letrozole does not occur.

Linearity/Nonlinearity. 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 30 mg oral dose, 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 nonlinearity becomes apparent, while at 5 mg/day nonlinearity is more pronounced. This nonlinearity is likely due to saturation of metabolic elimination pathways. Steady-state concentrations were achieved within 1–2 months with all tested dosing regimens (0.1–5.0 mg daily).

Pharmacokinetics in Specific Patient Populations. In a study involving 19 volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), letrozole pharmacokinetics were unchanged after a single 2.5 mg dose. Furthermore, in the same 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 correlation with minimum plasma concentrations of letrozole at steady state (C_min). 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 a similar study conducted in subjects with varying degrees of hepatic function, it was found 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 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 t_½ by 187% 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, Femara® should be used with caution in patients with severe hepatic impairment, considering the benefit-risk ratio for each individual patient. 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 monitoring. Additionally, no impact of renal impairment (calculated creatinine clearance 20–50 mL/min) or hepatic dysfunction 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 relapsed or progressed after prior antiestrogen therapy.
• Neoadjuvant therapy in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer who are not candidates for chemotherapy and in 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 and lactation.
• Reproductive potential of the patient.

Interaction with other medicinal products and other forms of interactions.

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, the metabolism of letrozole 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.

Currently, there is no clinical experience with the use of Femara® 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 inhibitors of CYP3A4, e.g., ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 inhibitors, e.g., methoxsalen) may increase exposure to letrozole. 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 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 exposure to letrozole. Therefore, caution is recommended in patients who require potent inducers of CYP3A4. Inducers of CYP2A6 are unknown.

Concomitant administration of Femara® (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 Femara® treatment, as well as the frequency of adverse reactions, was not increased when Femara® 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, to a moderate extent, CYP2C19, but the clinical relevance 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 Femara® 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 other commonly prescribed medicinal products.

Special precautions for use.

Renal impairment

There are no data on the use of Femara® 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. During an adjuvant therapy study, hypercholesterolemia was reported in 52.3% of patients receiving letrozole and in 28.6% of patients receiving tamoxifen. According to the grading criteria for 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 in total cholesterol (usually non-fasting) was observed in patients receiving monotherapy who had baseline total serum 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 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.

Effect on bones

Since Femara® 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 women with osteoporosis and/or history of fractures, as well as in those at increased risk of developing osteoporosis. In the adjuvant setting, consideration should also be given to a sequential treatment strategy (letrozole for 2 years followed by tamoxifen for 3 years), 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 Femara®. Femara® should only be administered to women with a postmenopausal endocrine status.

Tendinitis and tendon rupture

Tendinitis and tendon rupture may occur (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 Femara® on hematological or biochemical parameters have been observed. Moderate decreases in lymphocyte count of uncertain clinical significance were observed in some patients receiving Femara® at a dose of 2.5 mg. This reduction in lymphocyte count was transient in approximately half of affected patients. Thrombocytopenia developed in two patients receiving Femara®; a causal relationship with the investigational drug was not established. Discontinuation of study participation due to laboratory parameter changes, whether or not related to drug administration, was rare.

Other precautions

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

Since the tablets contain lactose, Femara® 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

Perimenopausal women or women of reproductive age

Femara® 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 Femara®. Due to reports of ovarian function recovery in women during treatment with Femara®, 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 (cleft lip, ambiguous external genitalia), it is known that Femara® may cause congenital developmental abnormalities when used during pregnancy. Animal studies have shown reproductive toxicity. Femara® 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.

Femara® 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). The rise in FSH levels, in turn, stimulates follicular growth, which may induce ovulation.

Ability to affect reaction speed when driving or operating machinery

The effect of Femara® 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.

Method of Administration and Dosage.

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

No dose adjustment is required for elderly patients.

Children. The drug is not indicated for use in children. The safety and efficacy of Femara® in pediatric patients 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 dysfunction are insufficient. Patients with severe hepatic impairment (Child–Pugh class C) require close monitoring.

Method of Administration.

Femara® 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 remembered. However, if the next scheduled dose is due within 2–3 hours, the missed dose should be omitted 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.

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 Femara® 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 Femara® was primarily determined based on data obtained from clinical trials.

Femara® 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 Femara® in metastatic and neoadjuvant settings, in approximately 75% of patients in the adjuvant setting (both groups received Femara® and tamoxifen, median treatment duration was 60 months), and in nearly 80% of patients in the extended adjuvant therapy setting (Femara® and placebo, median treatment duration was 60 months). Overall, the observed adverse reactions were predominantly mild or moderate in severity and in most cases were related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports were hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important additional adverse reactions that may occur during treatment with Femara® 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 of occurrence, with the most common listed first. The following frequency categories were used to assess the incidence of various adverse reactions: very common – (≥ 1/10), common – (≥ 1/100 to < 1/10), uncommon – (≥ 1/1,000 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

Adjuvant therapy with Femara® compared to tamoxifen monotherapy: adverse events with significantly different incidence rates

Note. The treatment period includes 30 days after the last dose. Any time includes the follow-up period after completion or discontinuation of investigational treatment.

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

Table 3

Sequential treatment compared to monotherapy with Femara®: adverse events with significantly different frequencies

* Significantly lower than in the Femara® monotherapy group

** Significantly higher than in the Femara® 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 setting, in addition to the data presented in Table 2, the following adverse events were reported for Femara® and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days): angina pectoris requiring surgical intervention (1.0% vs 1.0%); heart failure (1.1% vs 0.6%); arterial hypertension (5.6% vs 5.7%); cerebrovascular disorders/transient ischemic attack (2.1% vs 1.9%).

In the extended adjuvant setting, the following adverse events were reported for Femara® (median treatment duration 5 years) and placebo (median treatment duration 3 years), respectively: angina pectoris requiring surgical intervention (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 events* (0.9% vs 0.3%); stroke/transient ischemic attack* (1.5% vs 0.8%).

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

Musculoskeletal and connective tissue disorders.

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

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

Reporting of suspected adverse reactions.

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

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in the original packaging to protect from moisture, and in a place inaccessible to children.

Packaging.

10 tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Novartis Pharma S.p.A.

Manufacturer's address and location of its business operations.

Via Provinciale Scauri 131, 80058 Torre Annunziata (Naples Province), Italy.