Metaphora® - sr

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

Composition:

Active substance: metformin;

1 tablet contains 1000 mg of metformin hydrochloride;

Excipients: sodium carmellose, hypromellose, magnesium stearate.

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties: oval-shaped, biconvex tablets, white or almost white.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Antidiabetic drugs. Oral hypoglycemic agents, excluding insulins. Biguanides.

ATC code A10B A02.

Pharmacological Properties.

Pharmacodynamics.

Metformin hydrochloride 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 in combination with insulin, reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

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

In clinical trials, during metformin treatment, patient body weight remained stable or moderately decreased.

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 lifestyle intervention or metformin administration in preventing or delaying the development 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 plus fasting plasma glucose level of 95–125 mg/dL (or ≤125 mg/dL for American Indians). Participants were assigned to intensive lifestyle intervention, 2×850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

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 one case of type 2 diabetes over 3 years, 6.9 patients needed to be treated in the intensive lifestyle group and 13.9 in the metformin group. 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 extended observation.

Among DPPOS participants (n=2776), the 15-year cumulative incidence of diabetes was 62% in the placebo group, 56% in the metformin group, and 55% in the intensive lifestyle 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). For the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, outcomes did not differ significantly between groups, but 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 (risk ratio 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 ≥40 years, dyslipidemia, 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 mellitus.

The prospective randomized UKPDS study demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes receiving 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 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 alone (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 a single 1000 mg tablet to patients with or without food, the maximum plasma concentration is 1214 ng/mL, reached on average at 5 hours (range 4–10 hours).

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

Variability in Cmax and AUC among individuals after administration of metformin hydrochloride extended-release tablets is comparable to that observed with immediate-release tablets. After administration of a 1000 mg extended-release tablet 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 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 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.

Excretion.

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, thus prolonging the elimination half-life and leading to increased plasma metformin levels.

Special patient populations.

Renal impairment.

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

Clinical characteristics.

Indications.

• Reduction of risk or delay of 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 Metaphora®-SR should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

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

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

• Treatment of type 2 diabetes mellitus in adults, particularly in patients with overweight, when diet and physical activity 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., 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 acute 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. Metformin should be discontinued before or during radiological procedures involving iodinated contrast agents and should not be restarted until at least 48 hours after the procedure, and only after re-evaluation and confirmation of normal renal function (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, 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 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 (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 excretion of metformin, leading to increased plasma concentrations of metformin;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

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

When metformin is being administered, caution is advised when initiating treatment with agents that may acutely impair renal function (e.g., antihypertensive drugs, 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 their 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 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 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 and symptoms suggestive of MELAS or MIDD occur after initiating metformin therapy, treatment with metformin should be discontinued immediately 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 that alter 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, provided regular monitoring of cardiac and renal function is performed. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Elderly patients.

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

Iodinated contrast agents.

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and 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").

Surgery.

Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and restarted no earlier than 48 hours after surgery or resumption of oral nutrition, and only after assessment and confirmation of normal renal function.

Other precautions.

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

Metformin may reduce serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and/or in the presence of patient-related risk factors known to cause vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g., anemia or neuropathy). Patients with risk factors for vitamin B12 deficiency may require 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.

Metformin monotherapy 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). Undissolved tablet shell fragments may appear in feces. 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 hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, pregnancy-induced 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 concentrations that may be as high as maternal levels.

Extensive data from pregnant women (over 1000 pregnancy outcomes) from registry-based cohort studies and published meta-analyses and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure during the periconception 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 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 take into account the benefits of breastfeeding and the potential risk of adverse effects for the infant.

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

Ability to influence reaction speed when driving or operating machinery.

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

However, caution is advised 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 one prolonged-release tablet of metformin hydrochloride 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 range). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose of Metaphora®-SR 1000 mg is 2 tablets (2000 mg) once daily with the evening meal.
• Regular monitoring of glycemic status (OGTT values (oral glucose tolerance test) and/or fasting plasma glucose, and/or HbA1c) every 3–6 months, as well as assessment of 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 adopts improved dietary habits and/or increased physical activity, or if changes in the patient’s health status allow for lifestyle modifications.

Monotherapy or combination therapy with other oral antihyperglycemic agents.

Metaphora®-SR 1000 mg should be administered once daily with the evening meal. The maximum recommended dose is 2 tablets per day.

Metaphora®-SR 1000 mg should be used as maintenance therapy in patients who have previously been treated with metformin hydrochloride at a dose of 1000 mg or 2000 mg. When switching, the total daily dose 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 be switched to Metaphora®-SR therapy.

Patients receiving Metaphora®-SR should not exceed a total daily dose of 2000 mg.

For patients initiating treatment, the usual starting dose of metformin hydrochloride 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 control cannot be achieved with metformin hydrochloride at the maximum dose of 2000 mg taken once daily, this dose may be divided into two daily doses (once in the morning and once in the evening, with meals).

If adequate glycemic control remains unachieved, Metaphora®, film-coated tablets, may be used at the maximum recommended dose of 3000 mg per day.

When switching to Metaphora®-SR prolonged-release tablets, concomitant oral antidiabetic medication must be discontinued.

Combination therapy with insulin.

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

Metaphora®-SR prolonged-release tablets 1000 mg may be used following dose titration.

In elderly patients.

Renal function may be impaired; therefore, the metformin dose should be adjusted based on assessment of renal function, 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"); therefore, metformin is not recommended in these patients (see section "Special precautions").

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, for example 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.

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 the drug must be discontinued and the patient should be urgently hospitalized. Hemodialysis is the most effective measure 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 prolonged-release metformin hydrochloride were similar in nature and severity to those observed in patients treated with immediate-release metformin hydrochloride.

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 (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

Metabolic disorders.

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

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

From the nervous system.

Common: taste disturbances.

From the gastrointestinal tract.

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

From the hepatobiliary system.

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

From the skin and subcutaneous tissue.

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

Reporting suspected adverse reactions.

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through 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 in a blister; 3 blisters in a carton.

10 tablets in a blister; 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.