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 insulins. Biguanides. ATC code A10BA02.

Pharmacological Properties

Pharmacodynamics

Metformin is a biguanide with antihyperglycemic effects. It reduces glucose levels in blood plasma both in the fasting state and after meals. It does not stimulate insulin secretion and does not cause hypoglycemia via this mechanism.

Metformin acts through 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 glucose absorption in the intestine.

Pharmacodynamic Effects

Clinical studies have shown that the main non-glycemic effect of metformin is stabilization or modest reduction in body weight.

Independent of its effects on glycemia, immediate-release metformin tablets have demonstrated a beneficial 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. Consequently, an increase in triglyceride levels may occur.

Clinical Efficacy

Reduction or Delay in the 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 intensive lifestyle intervention, 2 × 850 mg metformin, standard lifestyle modifications, or placebo with standard lifestyle modifications.

Mean baseline values for DPP participants (n = 3,234 over 2.8 years) were: age 50.6 ± 10.7 years, fasting plasma glucose 106.5 ± 8.3 mg/dL, 2-hour post-glucose load plasma glucose 164.6 ± 17.0 mg/dL, and BMI 34.0 ± 6.7 kg/m². Intensive lifestyle intervention and metformin significantly reduced the risk of developing type 2 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, 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 the development of type 2 diabetes over 3 years, 6.9 participants needed to be treated in the lifestyle intervention group and 13.9 in the metformin group. The time to reach a cumulative incidence of 50% for type 2 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 the DPP, including more than 87% of the original DPP participants for continued 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 incidence rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and lifestyle intervention groups, respectively. Compared to placebo, the risk of diabetes was reduced by 18% in the metformin group (hazard ratio [HR] 0.82, 95% CI 0.72–0.93; p = 0.001) and by 27% in the lifestyle intervention group (HR 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 (HR 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 include Mongoloid or Negroid ethnicity, 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

The prospective randomized UK Prospective Diabetes Study (UKPDS) demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes who received immediate-release metformin hydrochloride as first-line therapy after diet failed. Analysis of study results 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: metformin hydrochloride – 7.5 events/1000 patient-years, diet-only – 12.7 events/1000 patient-years, 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 versus 20.6 events/1000 patient-years in the diet-only group (p = 0.011), and versus 18.9 events/1000 patient-years in the combined sulfonylurea and insulin monotherapy groups (p = 0.021);
• A significant reduction in the absolute risk of myocardial infarction: 11 events/1000 patient-years with metformin hydrochloride versus 18 events/1000 patient-years with diet-only (p = 0.01).

For metformin hydrochloride used as second-line therapy in combination with sulfonylurea, no advantage in clinical outcomes has 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, absorption of metformin from extended-release tablets is significantly slower 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).

After a single oral dose of one 1000 mg extended-release metformin tablet administered with or without food, the maximum plasma concentration is 1214 ng/mL, reached on average at 5 hours (range: 4–10 hours).

The bioequivalent product has the following characteristics.

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

Variability in Cmax and AUC among individual patients is comparable between extended-release and immediate-release metformin hydrochloride tablets.

After administration of extended-release tablets under fasting conditions, a 30% reduction in AUC was observed (Cmax and Tmax remained unchanged).

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

Absorption of metformin from extended-release tablets is not affected by the composition of food. No accumulation occurs with repeated dosing up to 2000 mg metformin hydrochloride as 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 at approximately 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 both glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance of metformin 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").

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.

The use of medicinal product Diaformin® SR should be based on risk assessment, including appropriate measures of 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 overweight patients, when diet and exercise alone do not provide adequate glycemic control. The medicinal product Diaformin® SR may 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 drug;
• 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 exacerbations 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 the presence of hepatic impairment.

Iodinated contrast agents. Patients should discontinue metformin before or during the procedure and resume 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 non-steroidal 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 negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these agents 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. The dose of Diaformin® SR should be adjusted 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:

• 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;

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

Therefore, caution is recommended when co-administering these drugs 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 affect 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 worsen 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, potentially progressing to coma. If any symptom suggestive of lactic acidosis occurs, 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), 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) and 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 metformin use, metformin therapy should be discontinued immediately and prompt diagnostic evaluation initiated.

Renal impairment

eGFR should be assessed before initiating 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 type 2 diabetes or delaying its onset in patients aged 75 years and older, metformin is not recommended in 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. Patients should discontinue metformin before or during the procedure and resume no earlier than 48 hours after the procedure, provided normal renal function is confirmed (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 feeding, provided normal renal function is confirmed.

Other precautions

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

Metformin commonly reduces serum vitamin B12 levels, potentially leading to deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and in patients with risk factors known to cause vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if deficiency is suspected (e.g., in patients with megaloblastic anaemia or newly developed neuropathy), and current clinical guidelines for testing and treating vitamin B12 deficiency should be followed. 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, with appropriate corrective treatment for vitamin B12 deficiency 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., sulphonylureas or meglitinides). Tablet shell fragments 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 diabetes during pregnancy (gestational or pre-existing) increases the 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 related to hyperglycaemia for both mother and child.

Metformin crosses the placenta and reaches levels similar to those in the mother.

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) indicates no increased risk of congenital anomalies or foetal/neonatal toxicity following exposure to metformin during the periconceptional period and/or pregnancy.

Limited and inconclusive evidence exists regarding the long-term effects of metformin on the weight of 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.

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

Breastfeeding

Metformin is excreted in breast milk, but adverse effects 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 effects for the infant.

Fertility

Metformin did not affect fertility in animals when administered at a dose 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 Diaformin® SR does not affect reaction speed when driving or operating machinery, as monotherapy with this drug does not cause hypoglycaemia.

However, caution is advised when using metformin in combination with other hypoglycaemic agents (sulphonylureas, insulin, meglitinides) due to the risk of hypoglycaemia.

Method of Administration and Dosage

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 1 tablet of Diaformin® SR 500 mg 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 limits). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose is 2000 mg once daily, taken with the evening meal.

Regular monitoring of glycemic status (every 3–6 months) — including 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 therapy is necessary.

Repeated assessment 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 Hypoglycemic Agents

The recommended initial dose is 500 mg once 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 2000 mg per day.

Diaformin® SR should be administered once daily with the evening meal, increasing by 500 mg every 10–15 days up to 2000 mg.

If the desired glycemic control cannot be achieved with Diaformin® SR 2000 mg once daily, the patient should switch to Diaformin® SR 1000 mg twice daily with meals.

If adequate glycemic control is still not achieved, Diaformin® may be used at the maximum recommended dose of 3000 mg per day.

Patients taking Diaformin® SR should not exceed a dosage of 2000 mg per day.

When switching from another antidiabetic agent to Diaformin® SR, treatment should be initiated with Diaformin® SR 500 mg (the other 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 currently receiving more than 2000 mg of metformin per day should not be switched to Diaformin® SR therapy.

Diaformin® SR 750 mg and Diaformin® SR 1000 mg are intended for patients who have previously used metformin (either extended-release or immediate-release formulations).

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

Combination Therapy with Insulin

Metformin and insulin may be used together in combination therapy to achieve better glycemic control. The usual starting dose of Diaformin® SR is 500 mg once daily with the evening meal, while the insulin dose should be titrated according to blood glucose measurements.

For patients already receiving combined therapy with metformin and insulin, the dose of Diaformin® SR 750 mg or Diaformin® SR 1000 mg should be equivalent to the previous daily dose of metformin, up to a maximum of 1500 mg or 2000 mg, respectively, taken with the evening meal, while insulin dosing should be adjusted based on blood glucose monitoring.

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").

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"), and therefore metformin is not recommended for use in these patients (see section "Special Precautions").

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 progressive renal impairment and in elderly patients, renal function should be monitored more frequently, for example every 3–6 months.

Children.

The drug is not to 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 the drug at a dose of 85 g. However, in this case, lactic acidosis did develop. 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.

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").

With long-term use of the drug, vitamin B12 absorption may be reduced, leading to decreased serum levels. This possible cause of vitamin B12 deficiency should be considered if a patient presents with megaloblastic anemia.

Nervous system disorders

Common: taste disturbances.

Gastrointestinal disorders

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use the drug 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 in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.