Metaphora®-sr

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METAFORA®-SR (METAFORA-SR)

Composition:

Active substance: metformin hydrochloride;

1 tablet contains metformin hydrochloride 500 mg;

Excipients: sodium carmellose, hypromellose, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties: round, biconvex tablets, white or almost white in color.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Biguanides.

ATC code A10B A02.

Pharmacological Properties

Pharmacodynamics

Metformin is a biguanide with an antihyperglycemic effect: it reduces glucose levels both fasting and postprandial. It does not stimulate insulin secretion and does not cause hypoglycemia. Metformin reduces fasting hyperinsulinemia, and when used in combination with insulin, it reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• Decreases glucose production in the liver;
• Enhances peripheral glucose uptake and utilization, partly by improving insulin action;
  • Alters glucose metabolism in the intestine: increases glucose uptake into the bloodstream, while reducing glucose absorption from food. 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 moderately 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).

Clinic 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 lifestyle intervention or metformin administration in preventing or delaying the development of type 2 diabetes mellitus. Inclusion criteria included age ≥25 years, BMI ≥24 kg/m² (≥22 kg/m² for Asian Americans), impaired glucose tolerance plus fasting plasma glucose levels of 95–125 mg/dL (or ≤125 mg/dL for American Indians). Patients 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) were as follows: 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. Intensive lifestyle intervention and metformin significantly reduced the risk of developing diabetes compared to placebo: 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, 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 diabetes over 3 years among DPP participants, 6.9 individuals needed to be treated in the lifestyle group and 13.9 in the metformin group. The time to reach a cumulative diabetes incidence of 50% 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 intensive 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 (hazard ratio (HR) 0.82, 95% CI 0.72–0.93; p=0.001) and by 27% in the lifestyle group (HR 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 (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, 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.

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 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 and 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 group (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 alone (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 in combination 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 Metaphora®-SR, a prolonged-release formulation, metformin absorption is significantly delayed compared to immediate-release metformin tablets. Time to maximum concentration (Tmax) is 7 hours (Tmax for immediate-release tablets is 2.5 hours).

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

Variability in Cmax and AUC among individuals is comparable between prolonged-release and immediate-release metformin hydrochloride tablets.

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

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

Distribution

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum concentration in blood is lower than 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 excretion via glomerular filtration and tubular secretion. After oral administration, 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 groups

Renal impairment

Limited data are available in patients with moderate renal impairment; therefore, systemic exposure to metformin in this patient group compared to those with normal renal function cannot be precisely determined. 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 impaired glucose tolerance (IGT)* and/or impaired fasting glucose (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 Metaphora®-SR should be based on risk assessment, including appropriate measures of glycemic control and evidence of high cardiovascular risk.

Concomitant with the initiation of metformin, 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 overweight patients, when diet and physical exercise alone do not provide adequate glycemic control. The medicinal product 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., 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, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (particularly acute conditions or exacerbations of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• hepatic insufficiency, 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 insufficiency.

Iodinated contrast agents. Patients should discontinue metformin before or during radiological procedures involving iodinated contrast agents and should not resume treatment earlier than 48 hours after the procedure, and only after normal renal function has been confirmed (see sections "Special precautions for use" and "Method of administration and dosage").

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 adversely 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 glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of the medicinal product 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 metformin;
• OCT2 inhibitors (e.g., cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformin, leading to increased plasma metformin concentrations;
• inhibitors of both OCT1 and OCT2 (e.g., 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 when 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 worsening of renal function, cardiopulmonary disease, or sepsis. Acute worsening of renal function leads to accumulation of metformin, increasing the risk of lactic acidosis.

In case of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), it is recommended to temporarily discontinue metformin and seek medical attention.

When metformin is used, caution should be exercised when initiating treatment with agents that may acutely worsen renal function (e.g., antihypertensive drugs, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, 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 interactions").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia with possible progression 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), increased 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) 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 and symptoms suggestive of MELAS or MIDD occur after starting metformin, treatment with metformin should be discontinued immediately and a 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 a higher risk of developing hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section "Contraindications").

Elderly patients

Due to limited data on therapeutic efficacy for 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 restarted no earlier than 48 hours after the procedure, provided normal renal function is confirmed (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interactions").

Surgical procedures

Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and restarted no earlier than 48 hours after surgery or upon resumption of oral intake, 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. 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 presence of patient-related risk factors known to cause vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia 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, with appropriate corrective treatment for vitamin B12 deficiency provided according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides).

The presence of tablet coating fragments in feces may occur. This is a normal phenomenon and has no clinical significance.

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

Use during pregnancy or breastfeeding

Pregnancy. Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational hypertension, preeclampsia, 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 hyperglycemia for both mother and child.

Metformin crosses the placenta in amounts that may be as high as maternal concentrations.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from cohort studies based on registries, published meta-analyses, and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure during 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 in utero, although data on long-term outcomes are limited.

If clinically necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an 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 data on the safety of the drug, 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 to the infant.

Fertility. Metformin had no effect on fertility in animals when administered at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to affect reaction speed when driving or operating machinery

Metaphora®-SR does not affect reaction speed when driving or operating machinery, as monotherapy with this drug does not cause hypoglycemia.

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

Dosage and Administration

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 Metafora®-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 (OGTT (oral glucose tolerance test) values and/or fasting plasma glucose and/or HbA1c should be within normal range). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose is 4 tablets (2000 mg) once daily with the evening meal.
• Regular monitoring of glycemic status (OGTT values and/or fasting plasma glucose and/or HbA1c) every 3–6 months, 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 adopts improved dietary habits 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 1 tablet daily.

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 4 tablets daily.

The dose should be taken once daily with the evening meal, increasing by 500 mg every 10–15 days up to a maximum of 2000 mg.

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

If the desired glycemic control is not achieved, Metafora® film-coated tablets may be used at the maximum recommended dose of 3000 mg daily.

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

When switching to Metafora®-SR 500 mg extended-release tablets, concomitant oral antidiabetic drugs must be discontinued.

Combination therapy with insulin

To achieve better glycemic control, metformin and insulin may be used in combination therapy. The usual initial dose of Metafora®-SR is 1 tablet daily with the evening meal, and the insulin dose should be adjusted based on blood glucose measurements.

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 Warnings and 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"); therefore, metformin is not recommended in these patients (see section "Special Warnings and 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.

Children

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

Overdose

No hypoglycemia was 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 Metaphora®-SR should be discontinued immediately and the patient must 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 Metaphora®-SR were similar in nature and severity to those observed in patients treated with Metaphora® (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 effects 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 and nutrition

Common: decreased levels/vitamin B12 deficiency (see section "Special precautions for use").

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

Central 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 effects most commonly occur at the beginning of treatment and usually resolve spontaneously. To minimize gastrointestinal adverse effects, a gradual increase in the dose of the drug is recommended.

Hepatobiliary disorders

Very rare: isolated reports of liver function test abnormalities 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 medicine authorization is important. It allows continuous 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. 2 years.

Storage conditions

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

Keep out of reach and sight of children.

Packaging

10 tablets per blister; 3 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity

38 Kopilivska Street, Kyiv, 04073, Ukraine.