Letrovista

INSTRUCTION FOR MEDICAL USE OF MEDICINAL PRODUCT LЕТROVISTA (LETROVISTA)

Composition:

Active ingredient: letrozole;

1 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: hypromellose (E 464), talc (E 553b), macrogol 8000, titanium dioxide (E 171), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex film-coated tablets, with embossing "L9ОО" 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 inhibitor of estrogen biosynthesis) and 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 (mainly 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 component of cytochrome P450, a subunit of this enzyme, thereby reducing 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 concentrations of estrone and estradiol (compared to baseline levels) by 75% and 78%, respectively. Maximum reduction is achieved within 48–78 hours.

In postmenopausal women with advanced breast cancer, daily administration of letrozole at doses of 0.1–5 mg reduces plasma concentrations 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, in many cases the concentrations of estrone and estrone sulfate fall below the detection limit of the assay method used for hormone measurement. 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 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 (ACTH), or renin activity were observed. ACTH 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 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 of 0.1 mg, 0.5 mg, and 2.5 mg did not alter plasma concentrations of androgens (androstenedione and testosterone). In postmenopausal patients receiving daily doses of letrozole of 0.1–5 mg, 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 (LH) or follicle-stimulating hormone (FSH) were observed, nor were there any changes in thyroid function as assessed by levels of thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4).

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 fasting and 2 hours when administered with food; mean maximum plasma concentration of letrozole (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 [AUC]) remains unchanged. The minor changes in absorption rate are considered not clinically significant; therefore, letrozole can be administered independently of food intake.

Distribution. Plasma protein binding of letrozole is approximately 60% (mainly 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 extensively distributes into tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 L/kg.

Metabolism and elimination. Letrozole is extensively metabolized to form an inactive carbinol metabolite—the primary 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 small amounts of other, as yet unidentified metabolites, as well as excretion of unchanged drug in urine and feces, plays 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 the 216-hour period (84.7 ± 7.8% of the 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 elimination half-life (t1/2) from plasma is approximately 2–4 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. Concurrently, 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 over prolonged treatment periods, accumulation of the drug 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 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, instead of 2.5- and 5-fold, compared to the 1.0 mg/day dose. Thus, the recommended dose of 2.5 mg/day may represent a threshold dose at which non-proportionality becomes apparent, while at a dose of 5 mg/day non-proportionality becomes 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 a study involving 19 volunteers with varying degrees of 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 this study, the impact of impaired renal function on the action of letrozole was evaluated; a covariate analysis 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 association with minimum steady-state plasma concentrations of letrozole (Cmin). Additionally, data from the AR/BC2 and AR/BC3 studies on second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or worsening of renal function.

Therefore, 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 subjects with varying degrees of hepatic function, it was established 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 impairment. In a pharmacokinetic study 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. Thus, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment compared to patients without severe liver dysfunction. Therefore, the drug 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. 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. The pharmacokinetics of letrozole are not influenced by 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 completed 5 years of standard adjuvant therapy with tamoxifen.
• First-line therapy of hormone-dependent advanced breast cancer in postmenopausal women.
• Treatment of advanced breast cancer in postmenopausal women (naturally or artificially induced) 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 in 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.
• Endocrine status characteristic of the premenopausal period.
• Pregnancy, breastfeeding.
• Women of reproductive age.

Interaction with other medicinal products and other forms of interaction.

Letrozole metabolism is partially mediated by CYP2A6 and CYP3A4. Therefore, medicinal products affecting CYP3A4 and CYP2A6 enzymes may influence the systemic elimination of letrozole. Apparently, letrozole metabolism has low affinity for CYP3A4, as this enzyme does not become saturated at concentrations 150 times higher than the plasma concentration of letrozole observed at steady state under typical clinical conditions.

To date, there is no clinical experience with the use of letrozole 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 letrozole metabolism and thereby increase plasma concentrations of letrozole. Concomitant use of medicinal products that strongly inhibit these enzymes (potent CYP3A4 inhibitors, e.g., ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 inhibitors, e.g., methoxsalen) may increase letrozole exposure. Therefore, caution is recommended in patients who require potent CYP3A4 and CYP2A6 inhibitors.

Medicinal products that may decrease serum concentrations of letrozole. Inducers of CYP3A4 activity may enhance letrozole metabolism 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 potent CYP3A4 inducers. CYP2A6 inducers are not known.

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 LetroVista and the frequency of adverse reactions were not increased when the medicinal product was administered immediately after tamoxifen. The mechanism of this interaction is unknown.

Medicinal products whose systemic serum concentrations may be altered by letrozole administration.

In vitro, letrozole inhibits the cytochrome P450 isoenzyme CYP2A6 and moderately inhibits CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when co-administering letrozole with medicinal products whose elimination primarily depends on CYP2C19 and which have a narrow therapeutic index (e.g., phenytoin, clopidogrel). No substrate with a narrow therapeutic index for CYP2A6 is known. Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate of CYP2C9 with a narrow therapeutic index, commonly used as a concomitant medication in the target population for letrozole) showed that co-administration of letrozole with these medicinal products does not result in clinically significant drug interactions.

A review of the clinical study database 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 the medicinal product letrozole for the treatment of patients with creatinine clearance < 10 ml/min. The benefit-risk ratio should be carefully considered before prescribing the medicinal product to such patients.

Cholesterol.

Serum cholesterol monitoring 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. Grade 3–4 hypercholesterolemia (according to the Common Terminology Criteria for Adverse Events — CTCAE) was reported in 0.4% of patients in the letrozole group and in 0.1% of patients in the tamoxifen group. Additionally, during adjuvant therapy, an increase ≥ 1.5 × ULN (upper limit of normal) 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 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. These patients require closer monitoring.

Effect on bones.

Since LetroVista is a potent medicinal product that reduces estrogen concentrations, bone mineral density should be assessed before starting treatment, during treatment, and after completion of treatment with letrozole in women with osteoporosis and/or history of fractures or those at increased risk of developing osteoporosis during adjuvant or extended adjuvant therapy. In the setting of adjuvant treatment, sequential treatment regimens (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered 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 if necessary (see section "Adverse reactions").

Menopausal status.

In patients with unclear menopausal status, levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol should be determined before initiating treatment with LetroVista. The medicinal product letrozole should only be administered to women with a postmenopausal endocrine status.

Laboratory test abnormalities.

No dose-dependent effect of the medicinal product LetroVista on any hematological or biochemical parameters has been observed. A moderate decrease in lymphocyte count of uncertain clinical significance was observed in some patients treated with the drug at a dose of 2.5 mg. This lymphocyte reduction was transient in approximately half of the patients affected by letrozole. Thrombocytopenia developed in two patients, although a causal relationship with the investigational drug was not established. Patients rarely discontinued the study due to laboratory parameter changes, whether or not related to the use of the medicinal product.

Other warnings.

Concomitant use of the medicinal product letrozole 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 medicinal product contains lactose, it is not recommended for use in patients with rare hereditary problems such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Perimenopausal women or women of reproductive age. LetroVista should only be administered to women with a clearly established postmenopausal status. Post-marketing reports exist of spontaneous abortions and congenital anomalies in newborns whose mothers took letrozole.

Due to reports of ovarian function recovery in women treated with LetroVista, despite a clearly defined postmenopausal status at the start of therapy, the physician should discuss appropriate contraception with the patient if necessary.

Pregnancy. The medicinal product LetroVista may cause fetal developmental abnormalities if used during pregnancy (e.g., cleft lip, ambiguous external genitalia). Animal studies have shown reproductive toxicity. Therefore, the drug 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. The medicinal product LetroVista is contraindicated during breastfeeding.

Fertility. The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a compensatory increase in gonadotropin levels (LH, FSH). The increase in FSH primarily stimulates follicular growth, which may induce ovulation.

Ability to influence reaction speed when driving or operating machinery.

The effect of the medicinal product LetroVista on the ability to drive or operate machinery is negligible. However, since general weakness and dizziness, and in some cases somnolence, have been observed in patients during treatment, caution is recommended when driving or operating machinery.

Method of Administration and Dosage.

Adults, including elderly patients. The recommended dose of LetroVista is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with the medicinal product should continue for 5 years or until tumor recurrence, whichever occurs first.

For patients with metastatic disease, therapy with LetroVista 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 LetroVista should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, letrozole therapy 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.

Patients with hepatic and/or renal impairment. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child–Pugh class A or B) or renal impairment (with creatinine clearance ≥ 10 mL/min). Data are insufficient for patients with severe renal impairment (creatinine clearance < 10 mL/min) or severe hepatic dysfunction. Patients with severe hepatic impairment (Child–Pugh class C) require careful monitoring. Method of Administration.

LetroVista 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 next scheduled dose is due 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 following daily doses exceeding the recommended 2.5 mg.

Children.

The medicinal product is not intended for use in children, as its efficacy and safety have not been studied in this patient population within clinical trials. Available data are limited; therefore, dosage recommendations cannot be established.

Overdose.

Isolated cases of letrozole overdose have been reported.

There is no specific antidote for overdose; treatment should be symptomatic and supportive.

Adverse reactions.

The frequency of adverse reactions associated with the use of letrozole was primarily determined based on data obtained from clinical trials.

The medicinal product was generally well tolerated in all studies, both 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, approximately in 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen, with a median treatment duration of 60 months), and in almost 80% of patients in the extended adjuvant therapy setting (both letrozole 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. Serious adverse reactions potentially associated with treatment with LetroVista include musculoskeletal events such as osteoporosis and/or bone fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many of the 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. The frequency categories of these adverse reactions are presented in Table 1.

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

Table 1

1 Only in the treatment of metastatic disease.

Some adverse reactions were observed at significantly different frequencies under adjuvant treatment conditions. The tables below provide information on significant differences in therapy 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 events with significantly different frequencies.

Note.

During treatment — includes 30 days after the last dose.

At any time — includes the follow-up period after completion or discontinuation of the investigational treatment.

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

Table 3.

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

* Significantly lower than in the letrozole monotherapy group.

** Significantly higher than in the letrozole monotherapy group.

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

Description of selected adverse reactions.

Cardiac disorders.

In the adjuvant treatment setting, the following adverse events were observed with letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days), in addition to those presented in Table 2: angina pectoris requiring surgical treatment (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); arterial hypertension (5.6% vs. 5.7%); cerebrovascular disorders / transient ischemic attack (2.1% vs. 1.9%).

In the extended adjuvant treatment setting, the following adverse events were reported with letrozole (median treatment duration 5 years) and placebo (median treatment duration 3 years), respectively: angina pectoris requiring surgical treatment (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 for the musculoskeletal system from the adjuvant treatment setting are presented in Table 2.

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

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 3 years.

Storage conditions.

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

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

Prescription status. Prescription only.

Manufacturer. Sintong España, S.L.

Manufacturer's address and location of its business operations.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.