Letrozole - vista ac

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

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;

Coating: OPADRY® 03F32518 Yellow (hypromellose (E 464), talc (E 553b), polyethylene glycol 8000, titanium dioxide (E 171), yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: Yellow, round, biconvex film-coated tablets, embossed with "L900" on one side and "2.5" on the other.

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); an antineoplastic medicinal agent.

In cases where tumor tissue growth is estrogen-dependent, eliminating the estrogen-mediated stimulatory effect is essential for suppressing 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 heme subunit of cytochrome P450, a component of this enzyme, resulting in reduced estrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of letrozole of 0.1 mg, 0.5 mg, and 2.5 mg reduce serum levels of estrone and estradiol (compared to baseline levels) by 75−78% and 78%, respectively. Maximum reduction is achieved within 48−78 hours.

In postmenopausal women with advanced breast cancer, daily administration of letrozole at doses ranging from 0.1 mg to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75−95% from baseline. With administration of the drug at doses 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 the specified 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 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, adrenocorticotropic hormone, or renin activity were detected. Adrenocorticotropic hormone stimulation tests performed at 6 and 12 weeks of therapy with daily doses of letrozole of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg revealed no significant reduction in aldosterone or cortisol synthesis. Thus, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, after a single administration of letrozole at doses of 0.1 mg, 0.5 mg, and 2.5 mg, no changes in plasma concentrations of androgens (androstenedione and testosterone) were observed. In postmenopausal patients receiving letrozole at daily doses of 0.1 mg to 5 mg, no changes in plasma levels of androstenedione were noted. 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 concentration of letrozole in blood [tmax] is 1 hour when administered fasting and 2 hours when administered with food; mean maximum concentration of letrozole in blood [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) 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% (primarily to albumin—55%). 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, systemic effects of letrozole metabolites are negligible. Letrozole rapidly and extensively distributes into tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 L/kg.

Metabolism and elimination. Letrozole undergoes extensive metabolism, forming an inactive carbinol metabolite—the primary elimination pathway. 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 cytochrome P450 isoenzymes CYP3A4 and CYP2A6 are capable of converting letrozole into its metabolites in vitro, but their individual roles in the clearance of letrozole in vivo have not been precisely established. Drug interaction studies have shown that concomitant administration of letrozole and cimetidine, an inhibitor of only the 3A4 isoenzyme, did not cause inhibition of 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 a small amount 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 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 from plasma is approximately 2−4 days. Steady-state concentration of letrozole is reached within 2−6 weeks after daily administration of 2.5 mg, and is approximately 7 times higher than after a single dose of the same amount. At the same time, the steady-state concentration is 1.5−2 times higher than the value that would be expected based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily administration of 2.5 mg. Since steady-state concentrations of letrozole are maintained during prolonged treatment, it can be concluded that accumulation of letrozole does not occur.

Linearity/Non-linearity. Pharmacokinetics of letrozole were dose-proportional after single oral doses up to 10 mg (dose range 0.01 to 30 mg), as well as after daily doses up to 1.0 mg (dose range 0.1 to 5 mg). After 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 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 a dose of 5 mg/day non-proportionality becomes more pronounced. The non-proportionality of dose 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 a covariate analysis 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). Additionally, 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 in patients with impaired renal function (creatinine clearance ≥ 10 mL/min) is not required. 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 established 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 individuals, but remained within the range observed in individuals without hepatic impairment. In a pharmacokinetic study of a single dose in 8 patients with liver cirrhosis and severe hepatic dysfunction (Child-Pugh class C), an increase in AUC by 95% and t½ by 187% was observed compared to healthy volunteers. However, since no increase in toxicity parameters was observed in patients receiving daily doses of 5 mg to 10 mg/day, dose reduction is not justified, although such patients should be closely monitored. Furthermore, no impact 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. Pharmacokinetics of letrozole are independent of age.

Clinical characteristics.

Indications.

• For adjuvant therapy of hormone receptor-positive early-stage invasive breast cancer in postmenopausal women.
• For extended adjuvant therapy of early-stage invasive breast cancer in postmenopausal women who have received standard 5-year adjuvant therapy with tamoxifen.
• For first-line treatment of hormone-dependent advanced breast cancer in postmenopausal women.
• For treatment of advanced breast cancer in postmenopausal women (natural or induced) who have experienced disease recurrence or progression after prior antiestrogen therapy.
• For neoadjuvant therapy in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer who are not suitable candidates for chemotherapy and for whom immediate surgical intervention is not indicated.

The efficacy of the medicinal product 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.
• Reproductive potential in female patients.

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 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 antiestrogenic medicinal products, 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: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6, e.g., methoxsalen) may increase letrozole exposure. Therefore, caution is recommended in patients who require strong 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 letrozole exposure. Therefore, caution is recommended in patients who require strong inducers of CYP3A4. 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 studies of second-line breast cancer therapy 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 (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 for 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 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 letrozole for the treatment of 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 therapy study, hypercholesterolemia was reported in 52.3% of patients receiving letrozole and in 28.6% of patients receiving tamoxifen (according to the Common Terminology Criteria for Adverse Events — CTCAE). Grade 3–4 hypercholesterolemia was reported in 0.4% of patients in the letrozole group and in 0.1% of patients in the tamoxifen group. Additionally, in the adjuvant therapy setting, an increase of ≥ 1.5 × ULN (upper limit of normal) in total cholesterol (usually non-fasting) was observed among patients receiving monotherapy who had baseline serum total cholesterol levels within normal limits (i.e., ≤ 1.5 × UL, ULN), in 151/1843 (8.2%) in the letrozole group versus 57/1840 (3.2%) in the tamoxifen group. Hypolipidemic medicinal products 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. Such patients require closer monitoring.

Effect on bones.

Since Letrozole-Vista AC is a potent medicinal product 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 or those at increased risk of developing osteoporosis. In the adjuvant setting, consideration should also be given to sequential treatment regimens (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). Careful evaluation of patients and appropriate management (e.g., immobilization) of the affected tendon should be performed as needed (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 AC. Letrozole-Vista AC should only be administered to women with a postmenopausal endocrine status.

Laboratory test abnormalities.

No dose-dependent effects of letrozole on any hematological or biochemical parameters have been observed. Moderate decreases in lymphocyte count of uncertain clinical significance were observed in some patients receiving letrozole 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; the relationship to the investigational drug was not established. Discontinuation of the study due to laboratory abnormalities, whether related to the medicinal product or not, was rare.

Other warnings.

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

Important information on excipients.

Since the tablets contain lactose, Letrozole-Vista AC 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.

Letrozole-Vista AC should be used only in women with a clearly defined postmenopausal status. Post-marketing reports have described spontaneous abortions and congenital anomalies in newborns whose mothers were exposed to letrozole. During treatment with letrozole, despite a clearly defined postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive measures with patients as necessary.

Pregnancy.

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

Letrozole-Vista AC may cause fetal harm when administered during pregnancy. Animal studies have demonstrated reproductive toxicity. Administration of Letrozole-Vista AC during pregnancy is contraindicated.

Breastfeeding.

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

Fertility.

The pharmacological action of letrozole is related to decreased 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 influence reaction speed while driving or operating machinery.

Letrozole-Vista AC has a minor influence on the ability to drive or operate machinery. Since fatigue and dizziness have been reported during treatment with letrozole, 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 disease, treatment with Letrozole-Vista AS should continue until evidence of disease progression becomes apparent.

In the adjuvant setting, sequential treatment regimens should also be considered (e.g., 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 reduction. If the treatment response is inadequate, letrozole therapy should be discontinued and surgical intervention and/or other treatment options should be planned, as discussed with the patient. Dose adjustment of the medicinal product is not required for elderly patients.

Patients with hepatic and/or renal impairment.

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

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

Administration method.

Letrozole-Vista AS 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 systemic exposure higher than proportional has been observed following daily doses exceeding the recommended 2.5 mg.

Pediatric population.

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

Overdose.

Cases of letrozole overdose have been reported. There is no specific antidote for letrozole 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 nearly 1/3 of patients treated with letrozole in metastatic and neoadjuvant settings, in approximately 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 receiving extended adjuvant therapy (both letrozole and placebo; median treatment duration was 60 months). Overall, the observed adverse reactions were mostly mild to 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 additional 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.

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 in treatment with 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 period after completion or discontinuation of the investigational treatment.

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

Table 3

Sequential treatment regimen compared with 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 treatment are presented in Table 2.

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

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

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

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Synthon España, S.L.

Manufacturer's location and address of its business site.

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