Metformin-pr-mili-750

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFORMIN-PR-MILI-750 (METFORMIN-PR-MILI-750)

Composition:

active substance: metformin;

one coated tablet contains metformin hydrochloride 750 mg, equivalent to metformin 585 mg;

excipients: hypromellose K-100M, povidone K-30, colloidal anhydrous silicon dioxide, hypromellose K-15M, magnesium stearate, Opadry (OY-7300), purified water.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: white oval coated tablets, embossed with "MT" on one side and "750" on the other.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin.

Biguanides. ATC code A10BA02.

Pharmacological Properties.

Pharmacodynamics.

Metformin is a biguanide with an antihyperglycemic effect. It reduces plasma glucose levels both in the fasting state and after food intake. It does not stimulate insulin secretion and does not cause hypoglycemia mediated by this mechanism.

Metformin acts via three mechanisms:

• decreases glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, thereby enhancing peripheral glucose uptake and utilization;
• delays intestinal glucose absorption.

Pharmacodynamic effects

Clinical studies have shown that the main effect of metformin, apart from its hypoglycemic action, is stabilization or slight weight loss.

Independent of its effect on glycemia, immediate-release metformin tablets have shown a beneficial effect on lipid metabolism. This effect has been demonstrated in controlled medium- to long-term clinical trials using therapeutic doses: immediate-release metformin tablets reduce levels of total cholesterol, low-density lipoproteins, and triglycerides. This effect was not observed with prolonged-release tablets, likely due to evening administration. This may also lead to an increase in triglyceride levels.

Clinical efficacy

Reduction or delay in the 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 development of type 2 diabetes mellitus. Inclusion criteria included age ≥ 25 years, BMI [body mass index] ≥ 24 kg/m² (≥ 22 kg/m² for Asian Americans) and impaired glucose tolerance plus fasting plasma glucose levels of 95–125 mg/dL (or ≤ 125 mg/dL for American Indians). Patients were assigned to either an active lifestyle intervention, 2 × 850 mg metformin plus standard lifestyle modifications, or placebo plus standard lifestyle modifications.

Baseline characteristics of DPP participants (n = 3,234, 2.8 years) were as follows: mean age 50.6 ± 10.7 years, fasting plasma glucose 106.5 ± 8.3 mg/dL, plasma glucose 2 hours after oral glucose load 164.6 ± 17.0 mg/dL, and BMI 34.0 ± 6.7 kg/m². Active lifestyle intervention and metformin treatment significantly reduced the risk of developing diabetes compared to placebo: 58% (95% CI [confidence interval] 48–66%) and 31% (95% CI 17–43%), respectively.

The benefit of lifestyle intervention over metformin was greater in elderly patients.

Patients who derived the greatest benefit from metformin treatment were those aged 45 years or older with BMI ≥ 35 kg/m², baseline 2-hour glucose levels of 9.6–11.0 mmol/L, baseline HbA1c ≥ 6.0%, or those with a history of gestational diabetes.

To prevent one case of diabetes over three years in the DPP patient group, 6.9 patients needed to be treated in the active lifestyle group and 13.9 in the metformin group. The time to reach a cumulative diabetes incidence 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 the DPP, including more than 87% of DPP participants for extended observation.

Among DPPOS participants (n = 2,776), the 15-year cumulative incidence of diabetes was 62% in the placebo group, 56% in the metformin group, and 55% in the lifestyle intervention group. Overall rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and lifestyle groups, respectively. Compared to the placebo group, 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). 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 (hazard 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 IGT (impaired glucose tolerance) and/or IFG (impaired fasting glucose), 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, family history (first-degree relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus. A prospective randomized study (UKPDS) 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 treated with metformin hydrochloride after diet failure showed:

• 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;
• significant reduction in diabetes-related mortality: metformin hydrochloride — 7.5 events / 1000 patient-years, 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 versus 20.6 events / 1000 patient-years (p = 0.011) in the diet-only group and versus 18.9 events / 1000 patient-years (p = 0.021) in the combined sulfonylurea and insulin monotherapy groups;
• significant reduction in absolute risk of myocardial infarction: metformin hydrochloride — 11 events / 1000 patient-years, diet only — 18 events / 1000 patient-years (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 metformin in the form of extended-release tablets, 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).

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

Variability in Cmax and AUC among individuals taking extended-release metformin hydrochloride tablets is comparable to that observed with immediate-release metformin hydrochloride tablets.

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

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

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached approximately at the same time. Erythrocytes are likely the secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism. Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

Elimination. Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased plasma metformin levels.

Special patient populations: Renal impairment. Data in patients with moderate renal impairment are limited; therefore, systemic exposure to metformin in this patient group cannot be precisely assessed compared to patients with normal renal function. Dose adjustment should be based on clinical efficacy and tolerability (see section "Dosage and administration").

Clinical characteristics

Indications

• For reducing the risk or delaying the onset of type 2 diabetes mellitus in overweight adult patients 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.

Prescription of METFORMIN-PR-MILI-750 should be based on risk assessment, including appropriate measures of glycemic control and evidence of high cardiovascular risk.

Concurrently with initiating metformin therapy, lifestyle modifications should be continued, except in cases where the patient is unable to make such changes for medical reasons.

• For the treatment of type 2 diabetes mellitus in adults, particularly in patients with excess body weight, when diet and physical activity alone do not provide adequate glycemic control.

METFORMIN-PR-MILI-750 may 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;
• conditions 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 hepatic impairment.

Iodinated contrast agents. Administration of metformin should be discontinued before or during radiological procedures involving iodinated contrast media and should not be restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of normal renal function (see sections "Dosage and administration" and "Special precautions").

Combinations requiring caution

Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics—especially loop diuretics—may adversely affect renal function, thereby increasing the risk of lactic acidosis. Renal function should be closely monitored when initiating treatment with these agents or when used concomitantly 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 METFORMIN-PR-MILI-750 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:

• inhibitors of OCT1 (e.g., verapamil) may reduce the efficacy of metformin;
• 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 elimination 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 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 may be required, as OCT inhibitors/inducers may influence the efficacy of metformin.

Special precautions for use

Lactic acidosis. This is a very rare but serious metabolic complication, most commonly occurring in acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute deterioration of kidney 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 a patient is receiving metformin, 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 mellitus, ketosis, prolonged fasting, any conditions associated with hypoxia, and concomitant use of medicinal products that may cause 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 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 help without delay.

Diagnostic laboratory findings include decreased blood pH (< 7.35), increased serum lactate concentration (> 5 mmol/L), and elevated 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 (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)) 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 during metformin treatment, therapy 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 altering 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 provided cardiac and renal function are monitored. Metformine is contraindicated in patients with acute and 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 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 upon resumption of oral nutrition, and only after re-evaluation and confirmation of normal renal function.

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

Metformin may reduce serum vitamin B12 levels. The risk of vitamin B12 deficiency increases with higher metformin doses, longer treatment duration, and/or presence of patient-related factors predisposing to vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if deficiency is suspected (e.g., anemia or neuropathy). 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 well 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). Tablet coating fragments may be observed in feces. This is a normal phenomenon and has no clinical significance.

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 reach concentrations similar to those in the mother.

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 limited, unconfirmed data on the long-term effects of metformin on weight in children exposed in utero. Available evidence suggests that metformin does not affect motor and social development in children up to 4 years of age who were exposed in utero, although long-term outcome data are limited.

If clinically indicated, metformin may be used during pregnancy and in the periconception 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 safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should be made after considering the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin did not affect fertility in animal studies 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.

METFORMIN-PR-MILI-750 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 tablet of METFORMIN-PR-MILI-500 once daily, taken with the evening meal.

After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements (results 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 METFORMIN-PR-MILI-750 is 2 tablets (1500 mg) once daily, taken with the evening meal.

It is recommended to regularly monitor (every 3–6 months) glycemic status (OGTT results and/or fasting plasma glucose, and/or HbA1c), as well as risk factors, to guide decisions regarding continuation, modification, or discontinuation of therapy.

Re-evaluation of treatment is also necessary 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. METFORMIN-PR-MILI-750 is intended for patients already receiving metformin tablets (prolonged or immediate release).

The dose of METFORMIN-PR-MILI-750 should be equivalent to the daily dose of metformin tablets (prolonged or immediate release), up to a maximum of 1500 mg taken with the evening meal.

After 10–15 days, the effect of the METFORMIN-PR-MILI-750 dose should be evaluated based on blood glucose measurements.

Combination therapy with insulin. For patients already receiving combination therapy with metformin and insulin, the dose of METFORMIN-PR-MILI-750 should be equivalent to the daily dose of metformin tablets, up to a maximum of 1500 mg taken with the evening meal, while the insulin dose should be adjusted based on blood glucose monitoring results.

In elderly patients, renal function may decline; therefore, the metformin dose should be adjusted based on assessment of renal function, which should be performed regularly (see section "Special Warnings and Precautions for Use").

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

Renal impairment. eGFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of worsening renal function and in elderly patients, more frequent monitoring of renal function (e.g., every 3–6 months) is recommended.

Children. The medicinal product 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 medicinal product 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 METFORMIN-PR-MILI-750 must be discontinued and the patient should 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 metformin hydrochloride in the form of extended-release tablets were similar in nature and severity to those observed in patients treated with metformin hydrochloride immediate-release tablets.

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: vitamin B12 deficiency (see section "Special precautions").

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

From the nervous system

Common: taste disturbances.

From the gastrointestinal tract

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

From the hepatobiliary system

Very rare: liver function test abnormalities or hepatitis, which completely resolve after discontinuation of metformin.

From the skin and subcutaneous tissue

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

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. 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, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 14 tablets per blister; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. GPAX Pharmaceuticals Private Limited.

Manufacturer's address. Plot No. 646/1&2, Agrawal Industrial Estate, Somnath Temple Road, Dabhel, Daman – 396 210, India.

Marketing authorization holder. Mili Healthcare Limited.

Address of the marketing authorization holder. Second Floor Office Suite, 4 Chartfield House, Castle Street, Taunton, Somerset, England TA1 4AS, Great Britain.