Letrozole - vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETROZOLE-VISTA (LETROZOLE-VISTA)

Composition:

Active substance: letrozole;

1 tablet contains 2.5 mg of letrozole;

Excipients: lactose monohydrate; corn starch; sodium starch glycolate (type A); microcrystalline cellulose; magnesium stearate; coating Opadry II 85F32410 yellow: polyvinyl alcohol; polyethylene glycol 3350; talc; titanium dioxide (E 171); iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets of yellow color, with a uniform surface and intact edges.

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

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

In healthy postmenopausal women, a single dose of letrozole at 0.1 mg, 0.5 mg, or 2.5 mg reduces 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 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 assay method used for hormone determination. This indicates that these doses of the drug 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, or renin activity were observed. Administration of an adrenocorticotropic hormone stimulation test at 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg of letrozole revealed no notable reduction in aldosterone or cortisol synthesis. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of 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 androgen precursors of estrogens. In patients receiving letrozole, no changes in plasma concentrations of luteinizing hormone and follicle-stimulating hormone 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 of letrozole (tmax) is 1 hour when administered on an empty stomach and 2 hours when administered with food; mean maximum plasma concentration (Cmax) is 129 ± 20.3 nmol/L when administered fasting and 98.7 ± 18.6 nmol/L when administered with food). However, the extent of absorption of letrozole (assessed by the area under the concentration-time curve) is 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 a pharmacologically inactive carbinol metabolite – the main 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 can convert letrozole into its metabolites in vitro, but their individual roles in in vivo clearance of letrozole have not been precisely established. Drug interaction studies have shown that concomitant administration of Letrozole-Vista and cimetidine, an inhibitor of only the 3A4 isoenzyme, did not inhibit letrozole clearance, suggesting the important role of the 2A6 isoenzyme in overall in vivo clearance. In this study, a slight decrease in AUC and an increase in Cmax were observed.

Formation of small amounts of other, yet unidentified metabolites, as well as excretion of unchanged drug in urine and feces, play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of radioactivity was recovered in urine and 3.8 ± 0.9% in feces. At least 75% of the radioactivity detected in urine over 216 hours (84.7 ± 7.8% of the administered 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. After daily administration of 2.5 mg, steady-state concentration is reached within 2–6 weeks, being 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 has slightly nonlinear characteristics. However, since steady-state concentration is maintained throughout prolonged treatment, 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 times, respectively, instead of 2.5 and 5 times, compared to the 1.0 mg/day dose. 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. In studies involving volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), pharmacokinetics of letrozole and urinary excretion of glucuronide conjugates of its carbinol metabolite were unchanged after a single 2.5 mg dose. Furthermore, in the aforementioned study, the impact of impaired renal function 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 (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 a similar study involving volunteers with varying degrees of hepatic function, it was found that in individuals with moderate hepatic impairment (Child-Pugh class B), the mean area under the concentration-time curve (AUC) was 37% higher than in healthy subjects 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 t½ by 187% compared to healthy volunteers. However, since no increase in toxicity was observed in patients receiving daily doses of 5–10 mg/day, dose reduction is not justified, although such patients should be closely monitored. Additionally, no impact of renal impairment (calculated creatinine clearance 20–50 mL/min) or hepatic impairment on plasma concentrations of letrozole was observed in 359 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 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 (natural or 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.
• Premenopausal endocrine status.
• Pregnancy.
• Breastfeeding.
• Women of reproductive potential.

Interaction with other medicinal products and other forms of interaction.

Metabolism of letrozole occurs partially via CYP2A6 and CYP3A4 enzymes. Therefore, medicinal products affecting CYP3A4 and CYP2A6 enzyme activity may influence the systemic elimination of letrozole. However, the metabolism of letrozole appears to have 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 Letrozole-Vista 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 (strong CYP3A4 inhibitors include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 inhibitors, e.g., methoxsalen) may increase letrozole exposure. Therefore, caution is recommended in patients who require strong CYP3A4 and CYP2A6 inhibitors.

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 CYP3A4 inducers. Inducers of CYP2A6 are unknown.

Concomitant administration of Letrozole-Vista (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-Vista, as well as the frequency of adverse reactions, was not increased when Letrozole-Vista 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 significance of this effect is unknown. However, caution should be exercised when administering letrozole concomitantly 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 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-Vista 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-Vista in patients with creatinine clearance < 10 ml/min. The potential risks and expected benefits of treatment should be carefully considered before prescribing the medicinal product to such patients.

Cholesterol

Monitoring of serum cholesterol levels should be considered. During the 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. Furthermore, during adjuvant therapy, an increase ≥ 1.5 × ULN in total cholesterol (usually non-fasting) was observed among patients receiving monotherapy who had baseline normal 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.

Effect on bones

Since Letrozole-Vista is a potent agent that reduces estrogen concentrations, bone mineral density should be evaluated 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, consideration should also be given to the use of a sequential treatment regimen (letrozole for 2 years followed by tamoxifen for 3 years), depending on the patient's safety profile.

Tendinitis and tendon rupture

Tendinitis and tendon rupture may occur (rarely). Patients should be carefully evaluated and appropriate measures (e.g., immobilization) applied if necessary (see section "Adverse reactions").

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 Letrozole-Vista. Letrozole-Vista should only be administered to women with a confirmed postmenopausal endocrine status.

Laboratory test abnormalities

No dose-dependent effects of Letrozole-Vista on any hematological or biochemical parameters have been observed. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Letrozole-Vista at a dose of 2.5 mg. This reduction in lymphocyte count was transient in approximately half of the affected patients. Thrombocytopenia developed in two patients receiving Letrozole-Vista; 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 warnings

Concomitant use of Letrozole-Vista 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, Letrozole-Vista 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-Vista should only be used in women with a clearly defined postmenopausal status. There are post-marketing reports of spontaneous abortions and congenital anomalies in newborns whose mothers took letrozole. During treatment with letrozole, despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive measures with the patient as necessary.

Pregnancy

Isolated cases of congenital malformations (labial fusion, ambiguous genitalia) have been reported.

Letrozole-Vista may cause fetal malformations when used during pregnancy. Animal studies have demonstrated reproductive toxicity. The use of Letrozole-Vista during pregnancy is contraindicated.

Breastfeeding

It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to newborns/infants during breastfeeding cannot be excluded. The use of Letrozole-Vista during breastfeeding is contraindicated.

Fertility

The pharmacological action of letrozole is associated with reduced estrogen production through inhibition of aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a compensatory increase in gonadotropin levels (LH, FSH). In turn, elevated FSH levels stimulate follicular growth and may induce ovulation.

Ability to affect reaction speed when driving or operating machinery. Letrozole-Vista has a minor influence on the ability to drive or operate machinery. Since fatigue and dizziness have been observed during letrozole use, and somnolence has been reported rarely, caution is recommended when driving or operating machinery.

Dosage and Administration

Adults, including elderly patients. The recommended dose of letrozole is 2.5 mg once daily.

In the adjuvant and extended adjuvant setting, treatment with letrozole should continue for 5 years or until tumor recurrence, whichever occurs first.

For patients with metastatic breast cancer or advanced-stage breast cancer, treatment with letrozole should continue until evidence of tumor progression.

In the adjuvant setting, consideration should also be given to a sequential treatment regimen (letrozole for 2 years followed by tamoxifen for 3 years).

In the neoadjuvant setting, treatment with letrozole should continue for 4 to 8 months to achieve optimal tumor shrinkage. If the response to treatment is inadequate, letrozole therapy should be discontinued and surgical intervention and/or other treatment options should be considered and discussed with the patient.

Dose adjustment is not required for elderly patients.

Patients with hepatic and/or renal impairment.

Dose adjustment of Letrozole-Vista is not required for patients with renal impairment and creatinine clearance ≥10 mL/min. Data are limited in cases of renal impairment with creatinine clearance below 10 mL/min.

Dose adjustment of Letrozole-Vista is not required for patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Data are limited in cases of severe hepatic impairment (Child-Pugh class C). Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.

Administration

Letrozole-Vista should be administered orally, independent of food intake, as food does not affect the extent of drug absorption.

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

Pediatric population.

The medicinal product is not intended for use in children. The safety and efficacy of Letrozole-Vista in children (under 18 years of age) have not been established. Available data are limited; therefore, dosage recommendations cannot be provided.

Overdose.

There have been isolated reports of overdose with Letrozole-Vista. There is no specific antidote for overdose; treatment should be symptomatic and supportive.

Adverse reactions

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 in the treatment of advanced breast cancer, as adjuvant therapy for early-stage breast cancer, and as extended adjuvant therapy in women who had previously received standard adjuvant therapy with tamoxifen. Adverse reactions were observed in approximately
1/3 of patients treated with letrozole in metastatic and neoadjuvant settings, in about 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen; median treatment duration was 60 months), and in nearly 80% of patients in the extended adjuvant therapy setting (both letrozole and placebo; median treatment duration was 60 months). Overall, the observed adverse reactions were mostly mild or moderate in severity and in most cases were related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports included hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Other important potential adverse reactions associated with letrozole treatment include musculoskeletal disorders such as osteoporosis and/or bone fractures, and cardiovascular disorders (including cerebrovascular and thromboembolic events). Many adverse effects may be attributed to the natural pharmacological consequences of estrogen deficiency (e.g., hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred during the first few weeks of treatment.

Adverse reactions are listed by frequency of occurrence: very common: > 10%, common: > 1% to < 10%, uncommon: > 0.1% to < 1%, rare: > 0.01% to < 0.1%, very rare: < 0.01%, unknown: frequency cannot be estimated from available data. The most frequent reactions are listed first.

Table 1

1 Adverse reactions to the medicinal product reported only in metastatic cancer.

Some adverse reactions have been reported at significantly different frequencies under adjuvant therapy conditions. The tables below provide information on significant differences of letrozole compared to tamoxifen monotherapy and the sequential treatment regimen of letrozole followed by tamoxifen:

Table 2

Adjuvant therapy with letrozole compared to tamoxifen monotherapy:

adverse effects with significantly different frequencies

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

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

Table 3

Sequential treatment regimen compared to letrozole monotherapy:

adverse events with significantly different frequencies

* Significantly lower than with letrozole monotherapy.

** Significantly higher than with letrozole monotherapy.

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

Description of selected adverse reactions

Cardiac adverse reactions

During adjuvant therapy, the following adverse effects of letrozole and tamoxifen, respectively, were observed (with a median treatment duration 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 complications/transient ischemic attack (2.1% vs. 1.9%).

During extended adjuvant therapy with letrozole (median treatment duration 5 years) and placebo (median treatment duration 3 years), the following adverse effects were observed, respectively: angina requiring surgical intervention (0.8% vs. 0.6%); onset or worsening of angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic complications* (0.9% vs. 0.3%); stroke/transient ischemic attack* (1.5% vs. 0.8%).

Events marked with * showed a statistically significant difference between the two treatment groups.

Musculoskeletal adverse reactions

Safety data for the musculoskeletal system obtained during adjuvant therapy are presented in Table 2.

During extended adjuvant therapy, a significantly higher number of patients receiving letrozole experienced bone fractures or osteoporosis (bone fractures 10.4% and osteoporosis 12.2%, respectively) compared to patients in the placebo group (5.8% and 6.4%, respectively). The median treatment duration was 5 years with letrozole and 3 years with placebo.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product 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.

Shelf life. 4 years.

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 or 10 blisters in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

Sindan Pharma S.R.L.

Manufacturer's address and place of business.

Bd. Ion Mihalache no. 11, Sector 1, 011171, Bucharest, Romania.