Siophor® xr 500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIOFOR® XR 500 (SIOFOR® XR 500)

Composition:

Active substance: metformin hydrochloride (metformin hydrochloride);

One prolonged-release tablet contains 500 mg of metformin hydrochloride;

Excipients: magnesium stearate, colloidal anhydrous silicon dioxide, sodium carmellose,
hypromellose (viscosity grade – 100,000 mPa·s, substitution type – 2208), purified water.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical characteristics: capsule-shaped tablets, white to almost white, with embossing "SR 500" on one side and smooth on the other.

Pharmacological Properties

Pharmacodynamics

Metformin is a biguanide with an antihyperglycemic effect. It reduces glucose levels in blood plasma both in the fasting state and after food intake. It does not stimulate insulin secretion and does not produce a hypoglycemic effect mediated by this mechanism.

Metformin acts via three pathways:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, leading to enhanced peripheral glucose uptake and utilization;
• delays glucose absorption in the intestine.

Metformin hydrochloride stimulates intracellular glycogen synthesis by affecting glycogen synthase. It increases the transport capacity of all known types of glucose membrane transporters (GLUT).

Pharmacodynamic effects

Clinical studies have shown that, in addition to its hypoglycemic action, the primary effect of metformin is stabilization or slight weight loss.

Independent of its effect on glycemia, immediate-release metformin tablets have demonstrated a positive effect on lipid metabolism. This effect has been confirmed in controlled medium- or long-term clinical trials using therapeutic doses: immediate-release metformin tablets reduce levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. This effect has not been observed with extended-release tablets, likely due to evening dosing. As a result, an increase in triglyceride levels may also occur.

Clinical efficacy

Reduction or delay in the onset of type 2 diabetes mellitus

The Diabetes Prevention Program (DPP) in adults was a multicenter, randomized, controlled clinical trial evaluating the effectiveness of lifestyle intervention or metformin in preventing or delaying the onset of type 2 diabetes mellitus. Inclusion criteria included age ≥ 25 years, body mass index (BMI) ≥ 24 kg/m² (≥ 22 kg/m² for Asian Americans), and impaired glucose tolerance plus fasting plasma glucose levels of 95–125 mg/dL (or ≤ 125 mg/dL for American Indians). Participants were assigned to intensive lifestyle intervention, 2×850 mg metformin plus standard lifestyle modifications, or placebo plus standard lifestyle modifications.

Mean baseline values for DPP participants (n = 3,234 over 2.8 years): age 50.6±10.7 years, fasting plasma glucose 106.5±8.3 mg/dL, 2-hour post-oral glucose load plasma glucose 164.6±17.0 mg/dL, and BMI 34.0±6.7 kg/m². Intensive lifestyle intervention and metformin reduced the risk of developing type 2 diabetes compared to placebo by 58% (95% CI 48–66%) and 31% (95% CI 17–43%), respectively.

The benefit of lifestyle intervention over metformin was greater in older patients.

Patients who derived the greatest benefit from metformin treatment were aged ≥ 45 years with BMI ≥ 35 kg/m², baseline 2-hour glucose levels of 9.6–11.0 mmol/L, baseline HbA1c ≥ 6.0%, or a history of gestational diabetes.

To prevent one case of type 2 diabetes over three years, 6.9 patients needed to be treated with lifestyle intervention and 13.9 patients with metformin. The time to reach a cumulative incidence of diabetes of 50% was delayed by approximately three years in the metformin group compared to placebo.

Diabetes Prevention Program Outcomes Study (DPPOS) – this is a long-term follow-up of the DPP, including more than 87% of the original DPP participants for continued long-term observation.

Among DPPOS participants (n = 2776), the cumulative incidence of type 2 diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the lifestyle intervention group. Overall rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and lifestyle groups, respectively. Compared to the placebo group, the risk of diabetes was reduced by 18% in the metformin group (risk ratio (RR) 0.82, 95% CI 0.72–0.93; p = 0.001) and by 27% in the lifestyle group (RR 0.73, 95% CI 0.65–0.83; p < 0.0001). Regarding the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, outcomes did not differ significantly between groups. However, among participants who did not develop diabetes during DPP/DPPOS, the prevalence of microvascular complications was 28% lower than in those who developed diabetes (RR 0.72, 95% CI 0.63–0.83; p < 0.0001). There are no comparative data on the effect of metformin on macrovascular complications in patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), and/or elevated HbA1c.

Published risk factors for type 2 diabetes include Mongoloid or Negroid ethnicity, age over 40 years, dyslipidemia, arterial hypertension, obesity or overweight, age, family history (first-degree relatives with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus

In the prospective randomized UK Prospective Diabetes Study (UKPDS), improved glycemic control was demonstrated in overweight patients with type 2 diabetes who received immediate-release metformin hydrochloride as first-line therapy after diet failed. Analysis of outcomes in overweight patients receiving metformin hydrochloride after diet failure showed:

• a significant reduction in the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/1000 patient-years) compared to the diet-only group (43.3 events/1000 patient-years), p = 0.0023, and compared to combined therapy with sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034;
• a significant reduction in the absolute risk of diabetes-related mortality: 7.5 events/1000 patient-years with metformin hydrochloride vs. 12.7 events/1000 patient-years with diet only (p = 0.017);
• a significant reduction in the absolute risk of all-cause mortality: 13.5 events/1000 patient-years in the metformin hydrochloride group vs. 20.6 events/1000 patient-years in the diet-only group (p = 0.011), and vs. 18.9 events/1000 patient-years in the combined sulfonylurea and insulin monotherapy group (p = 0.021);
• a significant reduction in the absolute risk of myocardial infarction: 11 events/1000 patient-years with metformin hydrochloride vs. 18 events/1000 patient-years with diet only (p = 0.01).

For metformin hydrochloride used as second-line therapy in combination with sulfonylurea, clinical benefit has not been demonstrated.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in individual patients, but the clinical benefit of this combination has not been formally established.

Pharmacokinetics

Absorption

After oral administration of the prolonged-release formulation SIOFOR® XR 500, metformin absorption is significantly delayed compared to immediate-release metformin tablets. The time to reach maximum concentration (Tmax) is 7 hours (Tmax for immediate-release tablets is 2.5 hours).

At steady state, as with immediate-release tablets, maximum plasma concentration (Cmax) and area under the pharmacokinetic concentration-time curve (AUC) increase disproportionately to the administered dose. The AUC after a single 2000 mg oral dose of metformin hydrochloride in prolonged-release tablets is comparable to the AUC observed after 1000 mg metformin hydrochloride in immediate-release tablets administered twice daily.

Variability in Cmax and AUC among individual patients taking prolonged-release metformin hydrochloride tablets is comparable to that observed with immediate-release metformin hydrochloride tablets.

After administration of prolonged-release tablets on an empty stomach, a 30% reduction in AUC was observed (Cmax and Tmax remained unchanged).

The absorption of metformin from prolonged-release tablets is not affected by food composition. No accumulation occurs with repeated administration of up to 2000 mg metformin hydrochloride in prolonged-release tablets.

Distribution

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum concentration in whole blood is lower than in plasma and is reached approximately at the same time. Erythrocytes likely represent a secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism

Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

Elimination

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased metformin levels in plasma.

Special patient groups

Renal impairment

Limited data are available for patients with moderate renal impairment; therefore, systemic exposure to metformin in this patient group cannot be precisely assessed compared to patients with normal renal function. Dose adjustment is therefore required based on clinical efficacy and tolerability (see section "Dosage and administration").

Preclinical safety data

Preclinical data revealed no specific hazard to humans based on results from conventional studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Clinical characteristics.

Indications.

• Reduction of risk or delay in onset of type 2 diabetes mellitus in adult patients with overweight and with IGT* and/or IFG* and/or elevated HbA1C levels, who have:
  • a high risk of developing overt (manifest) type 2 diabetes mellitus (see section "Pharmacodynamics");
  • progressive disturbances in glucose metabolism despite lifestyle modifications over a period of 3 to 6 months.

Treatment with SIOFOR® XR 500 should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Concurrently with initiation of metformin therapy, lifestyle modifications should be continued, except in cases where the patient is unable to make such changes for medical reasons.

*IGT: Impaired glucose tolerance; IFG: Impaired fasting glucose.

• Treatment of type 2 diabetes mellitus in adults, particularly in patients with overweight, when diet and physical exercise alone do not provide adequate glycemic control. The medicinal product SIOFOR® XR 500 can be used as monotherapy or in combination with other oral antidiabetic agents, or in combination with insulin.

Contraindications.

• Hypersensitivity to metformin or to any other component of the medicinal product;
• any type of acute metabolic acidosis (e.g., lactoacidosis, diabetic ketoacidosis);

− diabetic precoma;

• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);

• acute conditions associated with risk of renal function impairment: dehydration, severe infections, shock;

• diseases that may lead to tissue hypoxia (particularly acute conditions or exacerbations of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;

• hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use

Alcohol

Alcohol intoxication is associated with an increased risk of lactoacidosis, particularly in cases of fasting or adherence to a low-calorie diet, as well as in hepatic impairment.

Iodinated contrast agents

Patients should discontinue metformin before or during radiological procedures involving iodinated contrast agents and resume treatment no earlier than 48 hours after the procedure, provided normal renal function has been confirmed (see sections "Method of administration and dosage" and "Special precautions for use").

Combinations to be used with caution

Certain medicinal products, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, particularly loop diuretics, may adversely affect renal function, thereby increasing the risk of lactoacidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when using them in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics)

More frequent monitoring of blood glucose levels is required, especially at the beginning of treatment. Dose adjustment of SIOFOR® XR 500 may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (such as verapamil) may reduce metformin efficacy;
• OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

− OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal elimination of metformin, leading to increased plasma metformin concentrations;

• dual inhibitors of OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

Therefore, particular caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as plasma metformin concentrations may increase. Dose adjustment of metformin should be considered if necessary, since OCT inhibitors/inducers may influence metformin efficacy.

Special precautions for use.

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in acute renal impairment, cardiopulmonary disease, or sepsis. In acute renal impairment, metformin accumulates, increasing the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended and medical advice should be sought.

When a patient is receiving metformin, caution should be exercised when initiating medications that may acutely worsen renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic impairment, poorly controlled diabetes mellitus, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or their caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptom suggestive of lactic acidosis occurs, the patient must discontinue metformin immediately and seek medical help without delay.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate concentration (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)) and maternally inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the course of the disease.

If signs or symptoms suggestive of MELAS or MIDD occur, metformin therapy should be discontinued immediately and prompt diagnostic evaluation should be performed.

Renal impairment

eGFR should be assessed before starting treatment and regularly thereafter (see section "Dosage and administration"). Metformin is contraindicated in patients with eGFR < 30 mL/min and should be temporarily discontinued in the presence of conditions affecting renal function (see section "Contraindications").

Cardiac function

Patients with heart failure have an increased risk of hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Elderly patients

Due to limited data on therapeutic efficacy in reducing the risk of developing type 2 diabetes or delaying its onset in patients aged 75 years and older, metformin is not recommended for this age group.

Iodinated contrast agents

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and should not be restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of normal renal function (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures

Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anaesthesia, and should not be restarted earlier than 48 hours after surgery or until oral nutrition is resumed, and only after assessment and confirmation of normal renal function.

Other precautions

Patients should adhere to a diet with evenly distributed carbohydrate intake throughout the day. Obese patients should continue to follow a low-calorie diet. Regular monitoring of blood glucose levels is required.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and/or in patients with risk factors known to cause vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anaemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and not contraindicated, while appropriate corrective treatment for vitamin B12 deficiency is provided according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycaemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycaemic agents (e.g., sulfonylureas or meglitinides). The presence of tablet coating fragments in faeces is normal and has no clinical significance.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Uncontrolled hyperglycaemia during the periconception period and pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, pregnancy-induced hypertension, pre-eclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse outcomes of hyperglycaemia for both mother and child.

Metformin crosses the placenta and reaches levels in the foetus that may be as high as those in the mother.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from cohort studies based on registries and published data (meta-analyses, clinical trials, and registries) indicate no increased risk of congenital anomalies or foetal/neonatal toxicity following exposure to metformin during the periconception period and/or pregnancy.

There are limited and inconclusive data on the long-term effects of metformin on body weight in children exposed in utero. Available data suggest that metformin does not affect motor and social development in children up to 4 years of age who were exposed during pregnancy, although long-term outcome data are limited.

If clinically necessary, metformin may be considered during pregnancy and the periconception period as an adjunct or alternative to insulin.

Breastfeeding

Metformin is excreted in breast milk, but no adverse effects have been observed in newborns/infants who were breastfed. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should take into account the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility

Metformin had no effect on fertility in animal studies at doses of 600 mg/kg/day, which is almost three times the maximum recommended human daily dose based on body surface area.

Ability to drive and use machines

The medicinal product SIOFOR® XR 500 does not affect the ability to drive or operate machinery, as monotherapy with this product does not cause hypoglycaemia.

However, caution should be exercised when using metformin in combination with other hypoglycaemic agents (sulfonylureas, insulin, meglitinides) due to the risk of hypoglycaemia.

Method of Administration and Dosage

Method of Administration

Tablets should be swallowed whole with water. They should not be chewed or crushed.

Adult Patients with Normal Renal Function (eGFR ≥ 90 mL/min)

Reduction of Risk or Delayed Onset of Type 2 Diabetes Mellitus

Metformin should only be prescribed when lifestyle modifications over a period of 3–6 months have not provided adequate glycemic control.

• Treatment should be initiated with one tablet of SIOFOR® XR 500 once daily with the evening meal.
• After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements (OGTT [oral glucose tolerance test] values and/or fasting plasma glucose and/or HbA1c should be within normal limits). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose of SIOFOR® XR 500 is 4 tablets (2000 mg) once daily with the evening meal.
• Regular monitoring (every 3–6 months) of glycemic status (OGTT values and/or fasting plasma glucose and/or HbA1c) and risk factors is recommended to determine whether continuation, modification, or discontinuation of treatment is necessary.
• Re-evaluation of treatment is also required if the patient subsequently improves diet and/or physical activity or if changes in the patient’s health status allow for lifestyle modifications.

Monotherapy or Combination Therapy with Other Oral Antihyperglycemic Agents

• The recommended initial dose is 1 tablet of SIOFOR® XR 500 daily.
• After 10–15 days of treatment, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 4 tablets daily.
• The dose should be taken once daily with the evening meal, increasing by 500 mg every 10–15 days up to 2000 mg. If the desired glycemic level cannot be achieved with a once-daily dose of 2000 mg, the patient should switch to SIOFOR® XR 1000 twice daily with meals. If glycemic targets are still not met, SIOFOR® film-coated tablets may be used at the maximum recommended daily dose of 3000 mg.
• For patients previously treated with metformin, the initial dose of SIOFOR® XR 500 should be equivalent to their previous daily dose of immediate-release tablets. Patients receiving metformin doses above 2000 mg daily are not recommended to switch to SIOFOR® XR 500 therapy.
• When switching to SIOFOR® XR 500: discontinue the previous antidiabetic medication and initiate SIOFOR® XR 500 at the dose specified above.

Combination Therapy with Insulin

To achieve better glycemic control, metformin and insulin may be used together as combination therapy. The usual initial dose of SIOFOR® XR 500 is 1 tablet daily with the evening meal; insulin dosage should then be adjusted based on blood glucose monitoring.

Elderly Patients

In elderly patients, renal function may be impaired; therefore, metformin dosage must be adjusted based on renal function assessment, which should be performed regularly (see section "Special Warnings and Precautions for Use").

The benefit of reducing the risk or delaying the onset of type 2 diabetes mellitus has not been established in patients aged 75 years and older (see section "Pharmacodynamics"); therefore, metformin is not recommended for these patients (see section "Special Warnings and Precautions for Use").

Renal Impairment

eGFR should be assessed before initiating treatment with metformin-containing medications and at least annually thereafter. In patients at increased risk of worsening renal function and in elderly patients, renal function should be monitored more frequently, e.g., every 3–6 months.

eGFR (mL/min)	Maximum daily dose	Additional recommendations
60–89	2000 mg	In case of reduced kidney function, dose reduction should be considered.
45–59	2000 mg	The factors that may increase the risk of lactic acidosis should be evaluated before initiating metformin therapy (see section "Special warnings and precautions for use"). The initial dose should not exceed half of the maximum dose.
30–44	1000 mg
<30	-	Metformin is contraindicated.

Children.

The drug should not be used in children, as there are no clinical data available for this age group of patients.

Overdose.

When the drug was administered at a dose of 85 g, hypoglycemia was not observed. However, in this case, lactic acidosis developed. A significant overdose of metformin or concomitant risk factors may lead to the development of lactic acidosis. Lactic acidosis is a medical emergency. If lactic acidosis occurs, treatment with SIOFOR® XR 500 must be discontinued and the patient should be urgently hospitalized. Hemodialysis is the most effective measure for removal of lactate and metformin from the body.

Adverse reactions

According to post-marketing and controlled clinical studies, adverse reactions in patients treated with SIOFOR® XR 500 were similar in nature and severity to those observed in patients treated with SIOFOR® (immediate-release formulation).

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously.

Adverse reactions are classified by frequency of occurrence into the following categories:

very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1,000 and < 1/100), rare (> 1/10,000 and < 1/1,000), very rare (< 1/10,000).

Disorders of metabolism

Common: vitamin B12 deficiency (see section "Special precautions").

Very rare: lactic acidosis (see section "Special precautions").

From the nervous system

Common: taste disturbances.

From the gastrointestinal system

Very common: gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These adverse reactions most often occur at the beginning of treatment and usually resolve spontaneously. To minimize gastrointestinal adverse reactions, a gradual increase in the dose of the drug is recommended.

From the hepatobiliary system

Very rare: isolated reports of liver function test abnormalities or hepatitis, which completely resolve after discontinuation of metformin.

From the skin and subcutaneous tissue

Very rare: skin allergic reactions, including erythema, pruritus, urticaria.

Reporting of possible adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua or through the company's website: https://www.berlin-chemie.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 15 tablets per blister; 4 or 8 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and location of operations.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing authorization holder.

BERLIN-CHEMIE AG.

Address of the marketing authorization holder.

Glienicker Weg 125, 12489 Berlin, Germany.