Metformin-pr-milli-500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFORMIN-PR-MILI-500 (METFORMIN-PR-MILI-500)

Composition:

Active substance: metformin;

One film-coated tablet contains 500 mg of metformin hydrochloride, equivalent to 390 mg of metformin;

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 tablets, film-coated, with "MT" embossed on one side and "500" on the other.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin.

Biguanides. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic activity. It reduces glucose levels in blood plasma both in 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 pathways:

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

Metformin hydrochloride stimulates intracellular glycogen synthesis by affecting glycogen synthase. It increases the transport capacity of all known types of membrane glucose transporters.

Pharmacodynamic effects

Clinical studies have shown that, in addition to its hypoglycemic effect, the main action of metformin is stabilization or slight reduction in body weight.

Independent of its effect on glycemia, immediate-release metformin tablets have a positive effect on lipid metabolism. This effect has been demonstrated in controlled medium- to long-term clinical studies 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. As a result, an increase in triglyceride levels may also be observed.

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 implementing an active lifestyle or using metformin to prevent or delay the development of type 2 diabetes. 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). Participants were assigned to either an active lifestyle intervention, 2 × 850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

Baseline characteristics of participants in the DPP (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, 2-hour plasma glucose after oral glucose load 164.6 ± 17.0 mg/dL, and BMI 34.0 ± 6.7 kg/m². Implementing an active lifestyle and using metformin 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 advantage of lifestyle changes over metformin use was greater in elderly patients.

Patients who benefited most from metformin treatment were those aged 45 years and 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 type 2 diabetes over three years in the DPP cohort, 6.9 patients needed to be treated with an active lifestyle and 13.9 with metformin. 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 the DPP, including more than 87% of 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 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 active 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 active lifestyle group (HR 0.73, 95% CI 0.65–0.83; p < 0.0001). Regarding the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, outcomes 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 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 sources include: Asian or African ancestry, 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 trial (UKPDS) established the benefit of intensive glucose control in patients with type 2 diabetes and overweight who received immediate-release metformin hydrochloride as first-line therapy after diet alone proved ineffective. Analysis of outcomes in overweight patients treated with 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 groups (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, 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 compared to 20.6 events / 1000 patient-years (p = 0.011) in the diet-only group and 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, a benefit in clinical outcomes 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, 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 AUC increase disproportionately to the administered internal 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 taken 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 on an empty stomach, 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 concentration in blood is lower than in plasma and is reached at approximately 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, thus prolonging the elimination half-life and leading to increased metformin levels in plasma.

Special patient populations: Renal impairment. Data in patients with moderate renal impairment are limited; therefore, it is not possible to accurately assess systemic exposure to metformin in this patient group 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 adult patients with overweight and 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 the medicinal product METFORMIN-PR-MILI-500 should be based on a risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Lifestyle modifications should be continued alongside initiation of metformin therapy, except in cases where the patient is unable to implement 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-500 can be used as monotherapy or in combination with other oral antidiabetic agents, or concomitantly 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 a risk of renal function impairment, such as: dehydration, severe infections, shock;
• conditions that may lead to tissue hypoxia (especially acute illnesses or exacerbations of chronic disease): decompensated heart failure, respiratory insufficiency, recent myocardial infarction, shock;
• hepatic insufficiency, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction

Combinations not recommended for use

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 insufficiency.

Iodinated contrast media. Administration of metformin should be discontinued before or during contrast imaging procedures 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 that should be used with 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 negatively affect renal function, thereby increasing the risk of lactic acidosis. Renal function should be carefully monitored at the initiation of treatment with these medicinal products or when used in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics)

Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of the medicinal product METFORMIN-PR-MILI-500 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 (such as verapamil) may reduce metformin efficacy;
• inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• inhibitors of OCT2 (such as 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 (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 may be required, as OCT inhibitors/inducers may influence metformin efficacy.

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 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), temporary discontinuation of metformin is recommended, and medical advice should be sought.

When metformin is administered, caution is advised 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, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as 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 and seek immediate medical attention.

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 encephalomyopathy, 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 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 an increased risk of hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure provided cardiac and renal function are monitored. 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 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 assessment and confirmation of normal renal function.

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

Metformin may decrease serum vitamin B12 levels. The risk of vitamin B12 deficiency increases with higher metformin doses, longer duration of treatment, 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 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 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 exposure 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 in the periconception period and/or during pregnancy.

There are some unconfirmed data regarding the long-term effect 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 in utero, although data on long-term outcomes are limited.

If clinically indicated, metformin may be used during pregnancy and in the preconception period either as an adjunct to or as an alternative to insulin.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have 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, 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-500 does not affect reaction speed when driving or operating machinery, as monotherapy with this drug 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 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 is 4 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 risk factors, is recommended to guide decisions on 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. 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 2000 mg.

If adequate glycemic control cannot be achieved with METFORMIN-PR-MILI-500 at a dose of 2000 mg taken once daily, the patient should switch to a dose of 1000 mg twice daily with meals.

If glycemic targets are not met, metformin hydrochloride in immediate-release tablets may be used at the maximum recommended dose of 3000 mg daily.

For patients already treated with metformin, the initial dose of METFORMIN-PR-MILI-500, prolonged-release tablets, should be equivalent to the daily dose of immediate-release tablets. Patients receiving metformin doses exceeding 2000 mg daily should not be switched to therapy with METFORMIN-PR-MILI-500.

When switching to METFORMIN-PR-MILI-500, prolonged-release tablets, concomitant oral antidiabetic medications must be discontinued.

Combination therapy with insulin. To achieve better blood glucose control, metformin and insulin may be used together as combination therapy. The usual initial dose of METFORMIN-PR-MILI-500 is 1 tablet once daily with the evening meal, and the insulin dose should be adjusted based on blood glucose monitoring.

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

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 for these patients (see section "Special Instructions").

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

Children. The drug should not be administered to 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 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-500 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 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/low levels (see section "Special precautions").

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

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Packaging. 14 tablets in a 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 Authorisation Holder. Mili Healthcare Limited.

Address of the Marketing Authorisation Holder. Second Floor Office Suite, 4 Chartfield House, Castle Street, Taunton, Somerset, England TA1 4AS, Great Britain.