Letrozole astra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETROZOL ASTRA (LETROZOL ASTRA)

Composition:

active substance: letrozole;

1 tablet contains 2.5 mg of letrozole;

excipients: colloidal anhydrous silicon dioxide; microcrystalline cellulose; lactose monohydrate; magnesium stearate; maize starch; sodium starch glycolate; coating: hypromellose; polyethylene glycol 6000; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets.

Pharmacotherapeutic group

Agents used in hormonal therapy. Hormone antagonists and related agents. Aromatase inhibitors. Letrozole. ATC code L02B G04.

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 estrogen, 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, by specifically inhibiting the aromatase enzyme, it is possible to suppress 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 of 0.1 to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75–95% compared to baseline levels. With doses of 0.5 mg and higher, the concentrations of estrone and estrone sulfate in many cases fall below the detection limit of the assay 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 (ACTH), or renin activity were observed. ACTH stimulation tests performed at 6 and 12 weeks of therapy with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg showed no significant reduction in aldosterone or cortisol synthesis. Therefore, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of letrozole at 0.1 mg, 0.5 mg, and 2.5 mg did not alter plasma concentrations of androgens (androstenedione and testosterone). 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. No changes in plasma concentrations of luteinizing hormone and follicle-stimulating hormone were observed in patients receiving letrozole, 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 (as assessed by the area under the concentration-time curve (AUC)) remains unchanged. The minor changes in absorption rate are considered clinically insignificant; therefore, letrozole can be administered independently of food intake.

Distribution

Plasma protein binding of letrozole is approximately 60% (primarily to albumin – 55%). Erythrocyte concentrations of letrozole are nearly 80% of its plasma levels. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of plasma radioactivity was attributed to 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

Letrozole undergoes extensive metabolism, forming a pharmacologically 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 cytochrome P450 isoenzymes CYP3A4 and CYP2A6 are capable of converting letrozole into its metabolite. Formation of small amounts 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.

Elimination

The apparent terminal half-life in plasma is approximately 2–4 days. After daily administration of 2.5 mg, steady-state concentration of letrozole 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 predicted based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily dosing of 2.5 mg. Since steady-state concentrations are maintained throughout prolonged treatment, it can be concluded that 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. This dose 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

Older patients

Letrozole pharmacokinetics are not age-dependent.

Patients with impaired renal function

In studies involving volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), no changes in letrozole pharmacokinetics were observed after a single 2.5 mg dose. 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.

Patients with impaired hepatic function

In studies conducted in individuals with varying degrees of hepatic function, it was reported that patients with moderate hepatic impairment (Child-Pugh class B) had mean AUC values 37% higher than in healthy volunteers, but remained within the range observed in patients without hepatic impairment. Therefore, Letrozole Astra should be used with caution in patients with severe hepatic impairment, considering the benefit-risk ratio for each individual patient.

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 receptor-positive 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, 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.
• Endocrine status characteristic of the premenopausal period.
• Pregnancy or breastfeeding.
• Women of reproductive age.

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. Apparently, the metabolism of letrozole has low affinity for CYP3A4, as this enzyme is not 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. Furthermore, 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 administration 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 (e.g., methoxsalen)) may increase exposure to letrozole. 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 administration of medicinal products that induce CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s wort) may reduce exposure to letrozole. Therefore, caution is recommended in patients who require strong CYP3A4 inducers. Inducers of CYP2A6 are unknown.

Concomitant administration of Letrozole Astra (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 and the frequency of adverse reactions were not increased when Letrozole Astra 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 of CYP2C9 with a narrow therapeutic index, frequently 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 letrozole in patients with creatinine clearance below 10 mL/min. The benefit-risk ratio should be carefully considered before prescribing the drug to such patients.

Cholesterol

Monitoring of serum cholesterol levels should be considered. Hypercholesterolemia has been reported in patients treated with letrozole as well as in those treated with tamoxifen. In addition, increases in total cholesterol (usually non-fasting) have been observed in patients receiving letrozole as monotherapy who had normal baseline serum total cholesterol levels. Some of these patients required treatment with lipid-lowering agents.

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.

Bone effects

Since letrozole is a potent agent that reduces estrogen concentrations, bone mineral density should be assessed before initiating, during, and after completion of adjuvant and extended adjuvant therapy with letrozole in women with osteoporosis and/or history of fractures or those at increased risk of developing osteoporosis.

Sequential therapy (2 years of letrozole followed by 3 years of tamoxifen) may also be considered in the adjuvant setting, depending on the patient's safety profile (see sections "Posology and method of administration" and "Undesirable effects").

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

Tendinitis and tendon rupture

Tendinitis and tendon rupture may occur (rarely). Affected patients should be carefully evaluated and appropriate measures (e.g., immobilization) taken regarding the affected tendon (see section "Undesirable effects").

Laboratory test abnormalities

No dose-dependent effects of letrozole on any hematological or biochemical parameters have been observed. A moderate decrease in lymphocyte count of uncertain clinical significance has been observed in some patients treated with 2.5 mg of letrozole. This lymphocyte decrease was transient in approximately half of the affected patients. Thrombocytopenia has been reported in two patients treated with letrozole; a causal relationship with letrozole has not been established.

Other precautions

Concomitant use of letrozole with tamoxifen, other estrogen antagonists, or estrogen-containing medicinal products should be avoided, as these agents may counteract the pharmacological effect of letrozole (see section "Interaction with other medicinal products and other forms of interaction").

The product contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding

Perimenopausal women or women of reproductive potential

Letrozole should be used only in women with clearly established postmenopausal status. Spontaneous abortions and congenital anomalies in newborns have been reported in mothers who received letrozole. Due to reports of ovarian function recovery in women during letrozole treatment despite a clearly defined postmenopausal status at the start of therapy, the physician should discuss appropriate contraceptive measures with the patient, if necessary.

Pregnancy

Based on human experience with letrozole and isolated cases of congenital malformations (labial fusion, intermediate-type external genitalia), letrozole may cause congenital developmental abnormalities when used during pregnancy. Animal studies have shown reproductive toxicity of the drug.

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.

Letrozole is contraindicated during breastfeeding.

Fertility

The pharmacological action of letrozole involves reduction of estrogen production by inhibition of aromatase. In premenopausal women, suppression of estrogen synthesis leads to increased gonadotropin levels (LH, FSH). In turn, elevated FSH levels stimulate follicular growth and may induce ovulation.

Ability to affect reaction speed when driving vehicles or operating machinery

The effect of letrozole on the ability to drive vehicles or operate machinery is negligible. However, since general weakness and dizziness, and in individual cases somnolence, may occur during treatment with Letrozole Astra, caution is recommended when driving vehicles or operating complex machinery.

Method of Administration and Dosage

Adults, including elderly patients. The recommended dose of Letrozole Astra is 2.5 mg once daily. In adjuvant and extended adjuvant therapy, treatment with letrozole should continue for 5 years or until disease recurrence. For patients with metastatic disease, letrozole therapy should be continued until signs of disease progression become evident. In the adjuvant setting, sequential treatment strategies should also be considered (letrozole for 2 years followed by tamoxifen for 3 years).

In the neoadjuvant setting, treatment with Letrozole Astra should be continued for 4–8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, therapy with the drug should be discontinued and planned surgical intervention initiated and/or further treatment options discussed with the patient.

Dose adjustment is not required for elderly patients.

Children. The drug is not indicated for use in children. The safety and efficacy of letrozole in pediatric patients have not been established. Available data are limited; therefore, dosage recommendations cannot be provided.

Patients with hepatic and/or renal impairment. Dose adjustment is not required for patients with mild to moderate hepatic impairment (Child–Pugh class A and B) or renal impairment (with creatinine clearance ≥10 mL/min). Data in patients with severe renal impairment (creatinine clearance <10 mL/min) or severe hepatic dysfunction are insufficient. Patients with severe hepatic impairment (Child–Pugh class C) require close monitoring.

Method of Administration

Letrozole Astra 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 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

The drug is not indicated for use in children, as the efficacy and safety of the drug 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 letrozole overdose. Treatment should be symptomatic and supportive.

Adverse Reactions

Adverse reactions were observed in nearly 1/3 of patients treated with letrozole for metastatic and neoadjuvant settings, and in almost 80% of patients receiving adjuvant or extended adjuvant therapy. Letrozole is generally well tolerated. Most adverse reactions are mild to moderate in severity and are often related to estrogen deficiency. The most commonly reported adverse reactions include hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important adverse reactions that may occur during letrozole treatment include musculoskeletal events such as osteoporosis and/or bone fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many of these adverse effects may be consequences of the pharmacological estrogen deficiency (e.g., hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment. Frequency categories for these adverse reactions are described below.

Adverse reactions are listed by frequency, with the most common listed first.

The frequency of letrozole adverse reactions was primarily determined from data obtained in clinical trials. The frequency of various adverse reactions was classified as follows: 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).

Infections and infestations: uncommon – urinary tract infections.

Benign, malignant and unspecified neoplasms, including cysts and polyps: uncommon – tumour pain¹.

Blood and lymphatic system disorders: uncommon – leukopenia.

Immune system disorders: frequency not known – anaphylactic reactions.

Metabolism and nutrition disorders: very common – hypercholesterolemia; common – anorexia, increased appetite.

Psychiatric disorders: common – depression; uncommon – anxiety (including nervousness), irritability.

Nervous system disorders: common – headache, dizziness; uncommon – somnolence, insomnia, memory impairment, dysesthesia (including paresthesia, hypesthesia), taste disturbance, stroke, carpal tunnel syndrome.

Eye disorders: uncommon – cataract, eye irritation, blurred vision.

Cardiac and vascular disorders: very common – hot flushes; common – palpitations¹, hypertension; uncommon – tachycardia, myocardial ischaemia (including onset or worsening of angina, angina requiring surgical intervention, myocardial infarction, and myocardial ischaemia); uncommon – thrombophlebitis (including superficial and deep vein thrombophlebitis); rare – pulmonary embolism, arterial thrombosis, cerebrovascular infarction.

Respiratory system disorders: uncommon – dyspnoea, cough.

Gastrointestinal disorders: common – nausea, vomiting, dyspepsia¹, constipation, diarrhoea, abdominal pain; uncommon – stomatitis¹, dry mouth.

Hepatobiliary disorders: uncommon – increased liver enzymes, hyperbilirubinaemia, jaundice; frequency not known – hepatitis.

Skin and subcutaneous tissue disorders: very common – increased sweating; common – alopecia, rash (including erythematous, maculopapular, psoriasiform, and vesicular), dry skin; uncommon – pruritus, urticaria; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema.

Musculoskeletal and connective tissue disorders: very common – arthralgia; common – myalgia, bone pain¹, osteoporosis, bone fractures, arthritis; uncommon – tendonitis; rare – tendon rupture; frequency not known – trigger finger syndrome.

Renal and urinary disorders: uncommon – urinary frequency.

Reproductive system and breast disorders: common – vaginal bleeding; uncommon – vaginal discharge or dryness, breast pain.

General disorders and administration site conditions: very common – fatigue (including asthenia and malaise); common – peripheral oedema, chest pain; uncommon – increased temperature, dry mucous membranes, thirst, anasarca.

Investigations: common – weight increased; uncommon – weight decreased.

¹ Only during treatment of metastatic disease.

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

Table 1

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

Unwanted side effects	Letrozole, frequency of events		Tamoxifen, frequency of events
	N = 2448		N = 2447
	During treatment (median 5 years)	At any time after randomization (median 8 years)	During treatment (median 5 years)	At any time after randomization (median 8 years)
Bone fracture	10.2 %	14.7 %	7.2 %	11.4 %
Osteoporosis	5.1 %	5.1 %	2.7 %	2.7 %
Thromboembolic events	2.1 %	3.2 %	3.6 %	4.6 %
Myocardial infarction	1.0 %	1.7 %	0.5 %	1.1 %
Endometrial hyperplasia/ endometrial cancer	0.2 %	0.4 %	2.3 %	2.9 %

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 2

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

Adverse reactions	Letrozole monotherapy	Letrozole- >tamoxifen	Tamoxifen – >letrozole
	N = 1535	N = 1527	N = 1541
	5 years	2 years – >3 years	2 years – >3 years
Bone fractures	10.0%	7.7%*	9.7%
Endometrial proliferative disorders	0.7%	3.4%**	1.7%**
Hypercholesterolemia	52.5%	44.2%*	40.8%*
Hot flushes	37.6%	41.7%**	43.9%**
Vaginal bleeding	6.3%	9.6%**	12.7%**

*Significantly lower than in the monotherapy group with the drug.

**Significantly higher than in the monotherapy group with the drug.

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

Description of selected adverse reactions

Cardiac adverse reactions

In the adjuvant treatment setting, in addition to the data presented in Table 1, the following adverse events were reported during treatment with letrozole and tamoxifen, respectively (with a median duration of treatment of 60 months plus 30 days): angina pectoris requiring surgical intervention (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); arterial hypertension (5.6% vs. 5.7%); cerebrovascular disorders / transient ischemic attack (2.1% vs. 1.9%).

In the extended adjuvant 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 intervention (0.8% vs. 0.6%); newly diagnosed angina or worsening of angina symptoms (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke / transient ischemic attack* (1.5% vs. 0.8%).

The frequency of adverse reactions marked with * was statistically significantly different between the two treatment groups.

Musculoskeletal adverse reactions

Safety data for the musculoskeletal system obtained in the adjuvant treatment setting are presented in Table 1.

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). The median duration of treatment was 5 years for letrozole compared to 3 years for placebo.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets per blister; 3 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

ASTRAFARM LLC.

Manufacturer's address and location of its business operations

6, Kyivska Street, Vyshneve, Bucha District, Kyiv Oblast, 08132, Ukraine.