Siofor® xr 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIOFOR® XR 1000 (SIOFOR® XR 1000)

Composition:

Active substance: metformin hydrochloride (metformin hydrochloride);

One prolonged-release tablet contains 1000 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 physicochemical properties: oval-shaped tablets, white to almost white, with embossing “SR 1000” on one side and smooth on the other side.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Biguanides.
ATC code A10B A02.

Pharmacological Properties

Pharmacodynamics

Metformin is a biguanide with antihyperglycemic activity. 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 hypoglycemic effects mediated through this mechanism.

Metformin acts via three pathways:

• Reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• Improves insulin sensitivity in muscle tissue, leading to enhanced peripheral glucose uptake and utilization;
• Delays intestinal absorption of glucose.

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 effect, the main action of metformin includes stabilization or slight reduction in body weight.

Independent of its glycemic effects, immediate-release metformin tablets have demonstrated a positive effect on lipid metabolism. This effect has been confirmed in controlled, medium- to long-term clinical trials using therapeutic doses: immediate-release metformin tablets reduce levels of total cholesterol, low-density lipoprotein (LDL) 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 of Risk or Delay in Onset of Type 2 Diabetes

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. Inclusion criteria included age ≥ 25 years, body mass index (BMI) ≥ 24 kg/m² (≥ 22 kg/m² for Asian Americans), impaired glucose tolerance, and fasting plasma glucose levels of 95–125 mg/dL (or ≤ 125 mg/dL for American Indians). Participants were assigned to lifestyle intervention, 2×850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

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 plasma glucose after oral glucose load 164.6±17.0 mg/dL, and BMI 34.0±6.7 kg/m². Lifestyle intervention and metformin use 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 benefited most from metformin treatment were aged 45 years or older, with BMI ≥ 35 kg/m², baseline 2-hour glucose levels of 9.6–11.0 mmol/L, baseline HbA1c ≥ 6.0%, or those with a history of gestational diabetes.

To prevent one case of type 2 diabetes over three years in the DPP patient cohort, 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.

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

Among DPPOS participants (n = 2,776), 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 placebo, 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). There were no significant differences between groups regarding the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy. However, among participants who did not develop diabetes during DPP/DPPOS, the prevalence of microvascular complications was 28% lower than in those who did develop 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 relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of Type 2 Diabetes

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

• Significant reduction in 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 or insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034;
• Significant reduction in absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years vs. diet-only 12.7 events/1000 patient-years (p = 0.017);
• Significant reduction in 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 groups (p = 0.021);
• Significant reduction in absolute risk of myocardial infarction: 11 events/1000 patient-years in the metformin hydrochloride group vs. 18 events/1000 patient-years in the diet-only group (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 one tablet of SIOFOR® XR 1000 to subjects under fasting conditions and with food, the maximum plasma concentration is 1214 ng/mL, reached on average at 5 hours (range: 4–10 hours).

The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of SIOFOR® XR 1000 are bioequivalent to a 1000 mg dose of SIOFOR® XR 500 in healthy volunteers, both under fasting conditions and after food intake.

A bioequivalent product has the following properties.

At steady state, as with immediate-release tablets, Cmax and AUC increase disproportionately relative to the orally administered dose. The AUC after a single 2000 mg oral dose of metformin hydrochloride in extended-release tablets is similar 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 extended-release metformin hydrochloride tablets is comparable to that observed with immediate-release metformin hydrochloride tablets.

After administration of 1000 mg extended-release tablets with food, AUC increased by 77% (Cmax increased by 26% and Tmax prolonged by 1 hour).

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

Distribution

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration 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 plasma metformin levels.

Special Patient Populations

Renal Impairment

Limited data are available in 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 required based on clinical efficacy and tolerability (see section "Dosage and Administration").

Preclinical Safety Data

Preclinical data revealed no specific hazard for humans based on results from traditional 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 carbohydrate metabolism despite lifestyle modifications over a period of 3 to 6 months.

Treatment with SIOFOR® XR 1000 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 when the patient is unable to implement 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 activity alone do not provide adequate glycemic control.

The medicinal product SIOFOR® XR 1000 can be used as monotherapy or in combination with other oral antidiabetic agents, or concomitantly with insulin.

Contraindications.

• Hypersensitivity to metformin or to any other component of the medicinal product;
• any type of acute metabolic acidosis (e.g., lactate acidosis, 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 (especially acute conditions or exacerbation of chronic disease): 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

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, 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 restart no sooner than 48 hours after the procedure, provided normal renal function has been confirmed (see sections "Dosage and administration" and "Special precautions").

Combinations requiring caution

Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when used concomitantly 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 1000 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 (e.g., verapamil) may reduce metformin efficacy;
• OCT1 inducers (e.g., rifampicin) may increase gastrointestinal absorption and efficacy of metformine;

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

• inhibitors of both OCT1 and OCT2 (e.g., crizotinib, olaparib) may affect metformin efficacy and renal excretion.

Therefore, particular caution is recommended when co-administering these agents with metformin, especially in patients with renal impairment, 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 cases of dehydration (severe diarrhoea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended, and medical advice should be sought.

When metformin is used, caution is advised when initiating treatment with medicinal products that may acutely impair renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol intake, hepatic insufficiency, poorly controlled diabetes, 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 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 symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin immediately and seek medical attention 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 encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) or maternally inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the disease course.

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

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, provided cardiac and renal function are regularly monitored. 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 an increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and restarted no 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 restarted no earlier than 48 hours after surgery or after resumption of oral nutrition, and only after assessment and confirmation of normal renal function.

Other precautions

Patients should adhere to a diet with balanced carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Blood glucose levels should be monitored regularly.

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. Metformin therapy should be continued as long as it is tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency 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). Fragments of tablet coating may be observed in faeces. This is a normal phenomenon 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 throughout pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational 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 that may be as high as maternal concentrations.

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

There are limited and inconclusive data on the long-term effects of metformin on offspring body weight following in utero exposure. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed in utero, although data on long-term outcomes are limited.

If clinically indicated, 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 breastfed newborns/infants. However, due to insufficient data on the safety of the medicinal product, 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 animals when administered at doses up to 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to influence the speed of reaction when driving or operating machinery.

The medicinal product SIOFOR® XR 1000 does not affect the speed of reaction when driving or operating machinery, as monotherapy with this product does not cause hypoglycaemia.

However, caution is advised 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 (values of OGTT (oral glucose tolerance test) and/or fasting plasma glucose and/or HbA1c should be within normal range). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose of SIOFOR® XR 1000 is 2 tablets (2000 mg) once daily with the evening meal.
• Regular monitoring of glycemic status (every 3–6 months) (OGTT values and/or fasting plasma glucose and/or HbA1c), as well as 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 increases physical activity, or if changes in the patient’s health status allow for lifestyle modifications.

Monotherapy or Combination Therapy with Other Oral Hypoglycemic Agents

SIOFOR® XR 1000 should be administered once daily with the evening meal. The maximum recommended dose is 2 tablets per day.

SIOFOR® XR 1000 may be used as maintenance therapy in patients already treated with metformin hydrochloride at a dose of 1000 mg or 2000 mg. When switching, the daily dose of SIOFOR® XR 1000 should be equivalent to the current daily dose of metformin hydrochloride.

Patients currently receiving metformin hydrochloride at doses exceeding 2000 mg per day should not switch to SIOFOR® XR 1000 therapy.

Patients receiving SIOFOR® XR 1000 should not exceed a daily dose of 2000 mg.

For patients initiating treatment, the usual starting dose of SIOFOR® XR is 500 mg once daily with the evening meal. After 10–15 days of treatment, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects.

If the desired glycemic level cannot be achieved with SIOFOR® XR 1000 at the maximum dose of 2000 mg administered once daily, this dose may be divided into two daily doses (once in the morning and once in the evening, with meals).

If the desired glycemic level remains unattainable, SIOFOR® coated tablets may be used at the maximum recommended dose of 3000 mg per day.

When switching from another antidiabetic agent to SIOFOR® XR 1000, the dose should be titrated, starting with SIOFOR® XR 500.

Combination Therapy with Insulin

Metformin and insulin may be used in combination to achieve better glycemic control. The usual starting dose of SIOFOR® XR is 500 mg once daily with the evening meal; insulin dosage should then be adjusted based on blood glucose measurements.

SIOFOR® XR 1000 may be used after dose titration.

Elderly Patients

Renal function may be impaired in elderly patients; therefore, the metformin dose should be selected based on assessment of renal function, 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 use in these patients (see section "Special Warnings and Precautions for Use").

Renal Impairment

eGFR should be assessed before initiating therapy with metformin-containing medicinal products 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 recommended daily dose	Additional recommendations
60–89	2000 mg	In case of impaired renal function, dose reduction should be considered.
45–59	2000 mg	Factors that may increase the risk of lactic acidosis should be evaluated prior to initiating metformin therapy (see section "Special warnings and precautions"). The initial dose should not exceed half of the maximum recommended 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.

Hypoglycemia was not observed following administration of a 85 g dose of the drug. However, in this case, lactic acidosis developed. 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 1000 must be discontinued immediately and the patient should be urgently hospitalized. Hemodialysis is the most effective intervention for removing lactate and metformin from the body.

Adverse Reactions

According to data from post-marketing and controlled clinical studies, adverse reactions in patients treated with SIOFOR® XR 1000 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 in most cases.

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

very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000).

Metabolic disorders

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

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

Nervous system disorders

Common: taste disturbances.

Gastrointestinal disorders

Very common: gastrointestinal disturbances such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse reactions most commonly 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.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of 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 and sight of children.

Packaging. 15 tablets in a blister; 2, 4 or 8 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and place of business.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

BERLIN-CHEMIE AG.

Address of the Marketing Authorization Holder.

Glienicker Weg 125, 12489 Berlin, Germany.