Etrucil

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETRUZIL (ETRUZIL®)

Composition:

Active substance: letrozole;

One film-coated tablet contains 2.5 mg of letrozole;

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized corn starch, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, talc, macrogol 8000, titanium dioxide (E171), iron oxide yellow (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets, engraved with "L9OO" on one side and "2.5" on the other.

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 estrogen-dependent, elimination of the estrogen-mediated stimulatory effect is a prerequisite for suppression of tumor growth.

In postmenopausal women, estrogens are primarily formed via the enzyme aromatase, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone (E1) and estradiol (E2). Therefore, specific inhibition of the aromatase enzyme can achieve suppression of estrogen biosynthesis in peripheral tissues and in tumor tissue.

Letrozole inhibits aromatase by competitively binding to the non-protein heme portion of the aromatase cytochrome P450, resulting in reduced estrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of letrozole of 0.1, 0.5, 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 ranging from 0.1 to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75–95% compared to baseline levels.

When the drug is administered at a dose of 0.5 mg or higher, concentrations of estrone and estrone sulfate are often below the detection limit of the assay method used for hormone determination. This indicates that with these doses of the drug, a more pronounced suppression of estrogen synthesis is achieved, which is maintained throughout the treatment period in these patients.

Letrozole is a highly specific inhibitor of aromatase activity. No impairment of steroid hormone synthesis in the adrenal glands 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 in renin activity were observed. ACTH stimulation tests performed at 6 and 12 weeks of therapy with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg of letrozole revealed no significant reduction in the synthesis of aldosterone or cortisol. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, after single doses of 0.1, 0.5, and 2.5 mg of letrozole, no changes in plasma concentrations of androgens (androstenedione and testosterone) were observed.

In postmenopausal patients receiving daily doses of 0.1 to 5 mg of letrozole, no changes in plasma levels of androstenedione 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 (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 on an empty stomach 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)) is unchanged. The minor changes in absorption rate are considered not clinically significant; therefore, letrozole can be taken independently of food intake.

Distribution. Protein binding of letrozole to plasma proteins 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 the unchanged active substance. Therefore, the systemic effect of letrozole metabolites is negligible. Letrozole rapidly and completely 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 are capable of converting letrozole into its metabolite. The formation of a small amount 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 within 216 hours (84.7 ± 7.8% of the administered dose) 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 days. After daily administration of 2.5 mg of the drug, steady-state concentration is reached within 2–6 weeks, and is approximately 7 times higher than after a single dose of the same amount. At the same time, the steady-state concentration values 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 a slightly non-linear character. Since the steady-state concentration of letrozole is maintained during long-term treatment, it can be concluded that accumulation of letrozole does not occur.

Linearity/Non-linearity. The pharmacokinetics of letrozole were dose-proportional after administration of 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 dose-proportional increase in AUC was observed. With daily doses of 2.5 and 5 mg, AUC values 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 a dose of 5 mg/day non-proportionality becomes more pronounced. The 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 a study involving 19 volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), no change in the pharmacokinetics of letrozole was observed after a single 2.5 mg dose. Furthermore, in the aforementioned study, the impact of impaired renal function on letrozole was evaluated; an analysis of covariance was performed 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 relationship with minimum plasma concentrations of letrozole at steady state (Cmin). Moreover, data from studies AR/BC2 and AR/BC3 on second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or worsening of renal function.

Thus, 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 hepatic function, it was established that in patients with moderate hepatic impairment (Child-Pugh class B), mean values of the area under the concentration-time curve (AUC) were 37% higher than in healthy volunteers, but remained within the range observed in patients without hepatic impairment. In a study evaluating the pharmacokinetics of a single dose in 8 patients with liver cirrhosis and severe hepatic dysfunction (Child-Pugh class C), AUC increased by 95% and t½ by 187%, respectively, compared to values in healthy volunteers. Therefore, higher plasma levels of letrozole are expected in patients with breast cancer and severe hepatic impairment compared to patients without severe liver dysfunction. Hence, Femara® should be used with caution in patients with severe hepatic impairment, considering the benefit-risk ratio for each individual patient. Although dose reduction is not justified, as no increase in toxicity has been observed in patients receiving daily doses of 5–10 mg/day, such patients require close monitoring. Additionally, no effect of renal impairment (calculated creatinine clearance values of 20–50 mL/min) or hepatic impairment on plasma concentrations of letrozole was observed in 359 patients with advanced breast cancer. The pharmacokinetics of letrozole are not age-dependent.

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 received standard 5-year adjuvant therapy with tamoxifen.
• First-line therapy for 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, HER2-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 letrozole or to any of the excipients of the drug.
• Endocrine status characteristic of the premenopausal period.
• Pregnancy, breastfeeding.
• Women of childbearing potential.

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. 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 the plasma concentrations of letrozole observed at steady state under typical clinical conditions.

Currently, there is no clinical experience with the use of letrozole in combination with estrogens or other anticancer agents, except tamoxifen. Tamoxifen, other antiestrogens, or estrogen-containing medicinal products may counteract the pharmacological effect of letrozole. Moreover, it has been demonstrated that concomitant administration of tamoxifen and letrozole significantly reduces plasma concentrations of letrozole.

Concomitant use of letrozole with tamoxifen, other estrogen antagonists, or estrogens should be avoided.

MEDICINAL PRODUCTS THAT MAY INCREASE SERUM CONCENTRATIONS OF LETROZOLE

Inhibitors of CYP3A4 and CYP2A6 activity may reduce the metabolism of letrozole and thereby increase plasma concentrations of letrozole. Concomitant use of medicinal products that strongly inhibit these enzymes (potent CYP3A4 inhibitors include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g., methoxsalen)) may increase letrozole exposure. Therefore, caution is recommended when administering such potent inhibitors of CYP3A4 and CYP2A6 to patients.

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 letrozole exposure. Therefore, caution is recommended when administering such potent inducers of CYP3A4 to patients. Inducers of CYP2A6 are unknown.

Concomitant administration of letrozole (2.5 mg) and tamoxifen (20 mg once daily) resulted in an average 38% reduction 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, did not increase when letrozole was administered immediately after tamoxifen. The mechanism of this interaction is unknown.

MEDICINAL PRODUCTS WHOSE SYSTEMIC SERUM CONCENTRATIONS MAY BE ALTERED BY LETROZOLE

In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and moderately CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when co-administering letrozole with medicinal products whose elimination primarily depends on CYP2C19 and which have a narrow therapeutic index (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 CYP2C9 substrate with a narrow therapeutic index, frequently used as a concomitant medication in the target population for letrozole) showed that concomitant administration of letrozole 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 function

There are no data regarding the use of letrozole in patients with creatinine clearance <10 mL/min. The potential risks and benefits of treatment 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 grading criteria for severity 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 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%) patients 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 function

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 is a potent agent that reduces estrogen concentrations, bone mineral density should be assessed before initiation, during, and after completion of adjuvant and extended adjuvant therapy with letrozole in 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 a sequential treatment regimen (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 letrozole therapy. Letrozole should only be administered to women with a postmenopausal endocrine status.

Tendinitis and tendon rupture

Tendinitis and tendon rupture may occur (rarely). Careful evaluation of patients and appropriate management (e.g., immobilization) of the affected tendon are required (see section "Adverse reactions").

Laboratory test abnormalities

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

Other precautions

Concomitant use of letrozole 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, Etruzil is not recommended for patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Perimenopausal women or women of reproductive age

Etruzil should be used only in women with a clearly established postmenopausal status. Post-marketing reports have documented spontaneous abortions and congenital anomalies in newborns whose mothers were exposed to letrozole during pregnancy. Due to reports of ovarian function recovery in women treated with Etruzil, despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive methods with patients, if necessary.

Pregnancy

Based on human experience, including individual cases of congenital malformations (cleft lip, ambiguous external genitalia), letrozole is known to cause developmental abnormalities when used during pregnancy. Animal studies have demonstrated reproductive toxicity. Letrozole is contraindicated during pregnancy.

Breastfeeding

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

Etruzil 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 rise in FSH, in turn, stimulates follicular growth, which may induce ovulation.

Ability to affect reaction speed when driving or operating machinery

The effect of Etruzil on the ability to drive or operate machinery is negligible. However, since general weakness and dizziness have been observed in patients during treatment, and somnolence has occurred 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 Etruzil is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with Etruzil should continue for 5 years or until disease recurrence. For patients with metastases, treatment with Etruzil should be continued until evidence of disease progression becomes apparent. 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 Etruzil should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, therapy with Etruzil should be discontinued and planned surgical intervention initiated and/or alternative treatment options discussed with the patient.

No dose adjustment is required for elderly patients.

Children

Etruzil is not indicated for use in children. The safety and efficacy of Etruzil 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 class A or B) or renal impairment (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

Etruzil should be administered orally, independently of food intake, as food does not affect the extent of drug absorption.

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

Children

Etruzil should not be used in children, as the efficacy and safety of letrozole 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

Overview of Safety Profile

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

Etruzil was generally well tolerated in all studies as first- and second-line therapy for advanced breast cancer, as adjuvant therapy for early-stage breast cancer, and as extended adjuvant therapy for breast cancer in women who had previously received standard adjuvant therapy with tamoxifen. Adverse reactions were observed in nearly 1/3 of patients treated with Etruzil in metastatic and neoadjuvant settings, in approximately 75% of patients in the adjuvant setting (both groups received Etruzil and tamoxifen, with a median treatment duration of 60 months), and in nearly 80% of patients receiving extended adjuvant therapy (Etruzil and placebo, with a median treatment duration of 60 months).

Overall, the observed adverse reactions were predominantly mild or moderate in severity and were in most cases related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports included hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important adverse reactions that may occur during treatment with letrozole include musculoskeletal disorders such as osteoporosis and/or bone fractures, and cardiovascular disorders (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 occurrence of various adverse reactions: very common – (≥ 1/10), common – (≥ 1/100 to < 1/10), uncommon – (≥ 1/1,000 to < 1/100), rare – (≥ 1/10,000 to < 1/1,000), very rare – (< 1/10,000); frequency not known (cannot be estimated from available data).

Table 1

(1) Only in the treatment of metastatic disease.

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

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

Table 2

Note. The treatment period includes 30 days after the last dose. 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.

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

Table 3

* Significantly lower than in the monotherapy group with Etruzil

** Significantly higher than in the monotherapy group with Etruzil

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 events were reported for Etruzil and tamoxifen, respectively (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 disorders/transient ischemic attack (2.1% vs 1.9%).

In the extended adjuvant treatment setting, the following adverse events were reported for Etruzil (median treatment duration 5 years) and placebo (median treatment duration 3 years), respectively: angina requiring surgical intervention (0.8% vs 0.6%); newly diagnosed angina or worsening of angina (1.4% vs 1.0%); myocardial infarction (1.0% vs 0.7%); thromboembolic event* (0.9% vs 0.3%); stroke/transient ischemic attack* (1.5% vs 0.8%).

The incidence of events marked with * was statistically significantly different 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 Etruzil 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 Etruzil 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 use of the medicinal product. Healthcare professionals are required to report any cases of suspected adverse reactions through the pharmacovigilance system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging. 10 film-coated tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Egis Pharmaceuticals PLC, Hungary.
2. Sinten Spain, S.L., Spain.

Manufacturer's address and place of business.

1. Responsible for the complete manufacturing process, including batch release:

Sinten Spain, S.L.

C/ Castello, No. 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.

2. Responsible for batch release:

Egis Pharmaceuticals PLC

Bekenyfoldi u. 118-120, Budapest, H-1165, Hungary.