Diformin® sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAFORMIN® SR (DIAFORMIN SR)

Composition:

Active substance: metformin;

1 tablet contains metformin hydrochloride (calculated as 100% dry substance) – 1000 mg;

1 tablet contains metformin hydrochloride (calculated as 100% dry substance) – 750 mg;

1 tablet contains metformin hydrochloride (calculated as 100% dry substance) – 500 mg;

Excipients: hypromellose, sodium carmellose, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

1000 mg tablets – white or almost white, oval-shaped, biconvex tablets with a score line;

750 mg tablets – white or almost white, oblong-shaped, biconvex tablets with a score line;

500 mg tablets – white or almost white, round-shaped, biconvex tablets.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic activity. It reduces glucose levels in blood plasma both in fasting state and after meals. It does not stimulate insulin secretion and does not cause hypoglycemia. Metformin reduces fasting hyperinsulinemia and, when used in combination with insulin, decreases insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• reduces glucose production in the liver;
• enhances peripheral glucose uptake and utilization, partly by increasing insulin action;
  • alters glucose metabolism in the intestine: glucose absorption into the bloodstream increases, while absorption from food decreases. Additional intestinal mechanisms include increased release of glucagon-like peptide-1 (GLP-1) and reduced reabsorption of bile acids. Metformin alters the gut microbiome;
  • may improve lipid profile in patients with hyperlipidemia.

In clinical trials, patients' body weight remained stable or slightly decreased during metformin treatment.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK) and enhances the transport capacity of all types of glucose membrane transporters (GLUT).

Clinical efficacy

Reduction of risk or delay in onset of type 2 diabetes mellitus

The Diabetes Prevention Program (DPP) in adults was a multicenter, randomized, controlled clinical trial evaluating the effectiveness of an active 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), impaired glucose tolerance, and fasting plasma glucose level of 95–125 mg/dL (or ≤ 125 mg/dL for American Indians). Participants were assigned to an active lifestyle intervention, 2 × 850 mg metformin, standard lifestyle changes, or placebo plus standard lifestyle changes.

Mean baseline characteristics of 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. Both lifestyle intervention and metformin significantly reduced the risk of developing diabetes compared to placebo: 58% (95% confidence interval (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 diabetes onset over 3 years, 6.9 participants from the DPP needed to be treated in the active lifestyle group and 13.9 in the metformin group. The time to reach 50% cumulative incidence of diabetes was delayed by approximately 3 years in the metformin group compared to placebo.

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

Among DPPOS participants (n = 2,776), cumulative incidence of diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the active lifestyle group. Overall incidence rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and active 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 active lifestyle group (RR 0.73, 95% CI 0.65–0.83; p < 0.0001). For the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, results 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.

Known risk factors for type 2 diabetes from published literature: Mongoloid or Negroid race, age over 40 years, dyslipidemia, arterial hypertension, obesity or overweight, family history (first-degree relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus

The prospective randomized UK Prospective Diabetes Study (UKPDS) demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes treated with 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 (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 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 on outcomes has not been demonstrated.

In type 1 diabetes, metformin hydrochloride combined with 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 extended-release metformin, absorption of metformin is significantly slower compared to immediate-release metformin tablets. Time to reach maximum concentration (Tmax) is 7 hours (Tmax for immediate-release tablets is 2.5 hours).

After oral administration of one 1000 mg extended-release metformin tablet to subjects fed or fasting, maximum plasma concentration is 1214 ng/mL, reached on average at 5 hours (range: 4 to 10 hours).

Maximum concentration (Cmax) and area under the concentration-time curve (AUC) of 1000 mg extended-release metformin are bioequivalent to a 1000 mg dose of extended-release metformin 500 mg in healthy volunteers, both under fed and fasting conditions.

The bioequivalent product has the following properties.

At steady state, as with immediate-release tablets, Cmax and AUC increase disproportionately to the orally administered dose. AUC after single oral administration of 2000 mg metformin hydrochloride as extended-release tablets is similar to the AUC observed after administration of 1000 mg metformin hydrochloride as immediate-release tablets twice daily.

Variability in Cmax and AUC among individual patients with extended-release metformin hydrochloride tablets compared to variability 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 from extended-release tablets is not affected by food composition. No accumulation occurs with repeated administration up to 2000 mg metformin hydrochloride as extended-release tablets.

Distribution

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum concentration in blood is lower than maximum concentration in plasma and is reached approximately at the same time. Erythrocytes likely represent a secondary distribution compartment. 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, elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance of metformin decreases proportionally to creatinine clearance, thus prolonging elimination half-life and leading to increased plasma metformin levels.

Special patient groups.

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").

Clinical characteristics.

Indications.

• Reduction of risk or delay in the 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.

The use of medicinal product Diaformin® SR should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Concomitant with initiation of metformin therapy, lifestyle modifications should be continued, except in cases where 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 achieve adequate glycemic control. The medicinal product Diaformin® SR can be used as monotherapy or in combination with other oral antidiabetic agents, or together with insulin.

Contraindications.

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

− diabetic precoma;

• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• acute conditions associated with risk of renal function impairment, such as 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 types of interactions.

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 contrast imaging procedures and restart no earlier than 48 hours after the procedure, provided normal renal function has been confirmed (see sections "Special precautions for use" and "Dosage and administration").

Combinations requiring caution

Some 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, especially loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating these medicinal products or when using them in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Diaformin® SR may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT). Metformin is a substrate for both transporters—OCT1 and OCT2.

Concomitant use of metformin with:

• inhibitors of OCT1 (e.g., verapamil) may reduce metformin efficacy;
• inducers of OCT1 (e.g., rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

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

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

Therefore, extreme caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as plasma concentrations of metformin 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 attention 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 consumption, 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, potentially progressing to coma. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate levels (> 5 mmol/L), and increased anion gap and 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) or mitochondrial 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 after initiating metformin, treatment with metformin should be immediately discontinued and 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 altering renal function (see section "Contraindications").

Cardiac function

Patients with heart failure have an increased risk of developing 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 in this population.

Iodinated contrast agents

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Patients should discontinue metformin before or during the procedure and resume no earlier than 48 hours after the procedure, provided renal function test results are normal (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Surgical procedures

Metformin should be discontinued during surgical procedures involving general, spinal, or epidural anaesthesia and restarted no earlier than 48 hours after surgery or upon resumption of oral nutrition, provided renal function test results are normal.

Other precautions

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

Metformin commonly reduces serum vitamin B12 levels, potentially leading to deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and 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. Periodic monitoring of vitamin B12 levels is recommended in patients with risk factors for deficiency. Metformin therapy should be continued as long as it is well tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.

Metformin monotherapy 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 in the preconception period and during 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 related to hyperglycaemia for both mother and child.

Metformin crosses the placenta and reaches levels that may be as high as maternal concentrations.

A large amount of data from pregnant women (over 1000 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 in the periconceptional period and/or during pregnancy.

There are some unconfirmed data on the long-term effect of metformin on body weight in children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed during pregnancy, although data on long-term outcomes are limited.

Metformin may be considered during pregnancy and in the periconceptional period, if clinically necessary, as an adjunct or alternative to insulin.

Lactation

Metformin is excreted in breast milk, but adverse reactions have not been observed in breastfed newborns/infants. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse reactions for the infant.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Diaformin® SR does not affect reaction speed 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 dosing.

Adult patients with normal renal function (eGFR ≥ 90 mL/min)

Reduction of risk or delay in 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 1 tablet of Diaformin® SR 500 mg once daily with a meal in the evening.

After 10–15 days of ongoing 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). Slow dose escalation may improve gastrointestinal tolerability. The maximum recommended dose is 2000 mg once daily, taken with a meal in the evening.

Regular monitoring (every 3–6 months) of glycemic status (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 therapy 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

The recommended initial dose is 500 mg per day.

After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg per day.

The medicinal product Diaformin® SR should be administered once daily with an evening meal, increasing by 500 mg every 10–15 days up to 2000 mg. The dose should be adjusted based on blood glucose measurements.

If the desired glycemic level cannot be achieved with Diaformin® SR 2000 mg once daily, the patient should switch to Diaformin® SR 1000 mg twice daily (once in the morning and once in the evening, with meals).

If glycemic targets are not met, the medicinal product Diaformin® may be used at the maximum recommended dose of 3000 mg per day.

Patients taking Diaformin® SR should not exceed a daily dose of 2000 mg.

When switching from another antidiabetic agent to Diaformin® SR, treatment should be initiated with Diaformin® SR 500 mg (the previous oral antidiabetic agent must be discontinued).

For patients already treated with metformin, the initial dose of Diaformin® SR extended-release tablets should be equivalent to the daily dose of immediate-release metformin tablets. Patients receiving metformin doses exceeding 2000 mg per day are not recommended to switch to Diaformin® SR therapy.

The medicinal products Diaformin® SR 750 mg and Diaformin® SR 1000 mg are intended for patients who have previously used metformin (either prolonged or immediate release).

The dose of Diaformin® SR 750 mg or Diaformin® SR 1000 mg should be equivalent to the daily dose of metformin (prolonged or immediate release), up to a maximum of 1500 mg or 2000 mg, respectively, taken with an evening meal.

Combination therapy with insulin

To achieve better glycemic control, metformin and insulin may be used in combination therapy. The usual initial dose of Diaformin® SR is 500 mg once daily with an evening meal, while the insulin dose should be titrated according to blood glucose measurements. Diaformin® SR 1000 mg prolonged-release tablets may be used after dose titration.

In elderly patients, renal function may be impaired; therefore, the metformin dose should be adjusted based on renal function assessment, which should be performed regularly (see section "Special precautions for use").

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

Renal impairment

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

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

Children.

The drug is not recommended for use in children, as there are no clinical data available for this age group of patients.

Overdose.

Hypoglycemia was not observed following administration of the drug at a dose of 85 g. 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 Diaformin® SR must be discontinued immediately and the patient should be urgently hospitalized. Hemodialysis is the most effective intervention 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 prolonged-release metformin hydrochloride were similar in nature and severity to those observed in patients treated with immediate-release metformin.

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

Metabolic disorders

Common: vitamin B12 deficiency.

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

Long-term use of the drug may reduce vitamin B12 absorption, resulting in decreased serum levels. This possible cause of vitamin B12 deficiency should be considered if a patient develops megaloblastic anemia.

Nervous system disorders

Common: taste disturbances.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These adverse reactions most frequently occur at the beginning of treatment and usually resolve spontaneously in most cases. To minimize gastrointestinal adverse effects, 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 rash, erythema, pruritus, urticaria.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. 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 the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3 or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.