Glucophage xr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLUCOPHAGE XR (GLUCOPHAGE® XR)

Composition:

Active substance: metformin;

One coated tablet contains: metformin hydrochloride 500 mg;

Excipients: sodium carmellose, hypromellose 100,000 cP, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with "500" engraved on one side.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

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 in combination with insulin, reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• reduces glucose production in the liver;
• enhances peripheral glucose uptake and utilization, partly by increasing insulin action;
  • alters glucose metabolism in the intestine: increases uptake into the bloodstream and reduces 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, patient 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).

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 an active lifestyle intervention or metformin in preventing or delaying the onset 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 an active 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. Active lifestyle intervention and metformin treatment 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 derived the greatest benefit from metformin treatment were 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 diabetes over three years among DPP participants, 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 incidence of diabetes of 50% was delayed by approximately three 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), the cumulative incidence of diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the active lifestyle group. Overall 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, 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 (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 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 relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus.

A prospective randomized (UKPDS) study demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes receiving metformin hydrochloride immediate-release as first-line therapy after diet failure. 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 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 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 compared to 20.6 events/1000 patient-years in the diet-only group (p=0.011), and compared to the combined sulfonylurea and insulin monotherapy group: 18.9 events/1000 patient-years (p=0.021);
• significant reduction in absolute risk of myocardial infarction: metformin hydrochloride 11 events/1000 patient-years vs. diet-only 18 events/1000 patient-years (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 combined with insulin has been used in individual patients, but the clinical benefit of this combination has not been formally established.

Pharmacokinetics.

Absorption.

After oral administration of the prolonged-release formulation Glucophage XR, metformin absorption is significantly delayed 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 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 after administration of prolonged-release tablets is comparable to that observed with immediate-release tablets.

After administration of prolonged-release tablets in the fasting state, a 30% reduction 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 administration up to 2000 mg metformin hydrochloride as prolonged-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.

Elimination.

Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated by both glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance 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 cannot be precisely assessed compared to patients with normal renal function. Dose adjustment is required based on clinical efficacy and tolerability (see section "Dosage and administration").

Clinical characteristics.

Indications.

• Reduction of risk or delay in the 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 Glucophage XR should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Concurrently with initiation of metformin, lifestyle modifications should be continued, except in cases where 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. Glucophage XR 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., lactoacidosis, diabetic ketoacidosis);

− diabetic precoma;

• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• acute conditions associated with risk of developing renal 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 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, especially in cases of fasting or low-calorie diet, as well as in hepatic impairment.

Iodinated contrast agents.

Patients should discontinue metformin before or during the examination and resume no earlier than 48 hours after the procedure, provided normal renal function test results are obtained (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Combinations requiring caution.

Some medicinal products, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, particularly loop diuretics, may negatively affect renal function, which could increase the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when using them in combination with metformin.

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

Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Glucophage XR 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 administration 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 metformin concentrations;

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

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 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 patients are receiving metformin, 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, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis.

Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, possibly progressing to coma. If any symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin immediately and seek medical attention without delay.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate levels (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Renal impairment.

eGFR should be assessed before initiating treatment and regularly thereafter (see section "Posology and method of 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 developing hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Elderly patients.

Due to limited data on therapeutic efficacy in reducing the risk of 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 induce contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Patients should discontinue metformin before or during the procedure and resume no earlier than 48 hours after the procedure, provided normal renal function is confirmed (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interactions").

Surgical procedures.

Metformin should be discontinued during surgical procedures involving general, spinal, or epidural anesthesia and restarted no earlier than 48 hours after surgery or upon resumption of oral nutrition, provided normal renal function is confirmed.

Other precautions.

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

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 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 administered according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycemia; however, caution is advised when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides). Tablet shell fragments may be observed in feces. This is a normal phenomenon and has no clinical significance.

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

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycemia during the preconception period and 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 associated with hyperglycemia for both mother and child.

Metformin crosses the placenta in concentrations similar to those in the mother.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from registry-based cohort studies, published meta-analyses, and clinical trials indicate no increased risk of congenital malformations or fetal/neonatal toxicity due to metformin exposure during the periconception period and/or during pregnancy.

There are some unconfirmed data regarding the long-term effects of metformin on the weight of children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed 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 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 animals 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 rate when driving or operating machinery.

Glucophage XR does not affect reaction speed when driving or operating machinery, as monotherapy with this medicinal product 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.

Method of Administration and Dosage.

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 Glucophage XR 500 mg once daily during 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 during the evening meal.

Regular monitoring of glycemic status (OGTT values (oral glucose tolerance test) and/or fasting plasma glucose and/or HbA1c) as well as risk factors every 3–6 months is recommended to make decisions regarding the need for 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 per day.

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 per day.

The drug should be administered once daily during the evening meal, increasing by 500 mg every 10–15 days up to 2000 mg.

If adequate glycemic control cannot be achieved with Glucophage XR 2000 mg administered once daily, the patient should switch to Glucophage XR 1000 mg twice daily during meals.

If target glycemic levels are not achieved, Glucophage film-coated tablets may be used at the maximum recommended dose of 3000 mg per day.

For patients previously treated with metformin, the initial dose of Glucophage XR extended-release tablets should be equivalent to the daily dose of immediate-release tablets. Patients receiving metformin doses exceeding 2000 mg per day are not recommended to switch to therapy with Glucophage XR.

When switching to Glucophage XR extended-release tablets 500 mg, concomitant oral antidiabetic drugs should be discontinued.

Combination therapy with insulin.

Metformin and insulin may be used together as combination therapy to achieve better blood glucose control. The usual initial dose of Glucophage XR is 1 tablet once daily during the evening meal, while the insulin dose should be adjusted based on blood glucose measurements.

In elderly patients, renal function may be impaired; therefore, the dose of metformin 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 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 progressive renal impairment and in elderly patients, renal function should be monitored more frequently, for example every 3–6 months.

eGFR (mL/min)	Maximum daily dosage	Additional recommendations
60-89	2000 mg	In case of impaired renal function, dose reduction should be considered.
45-59	2000 mg	The factors that may increase the risk of lactic acidosis should be evaluated before initiating metformin therapy (see section "Special warnings and precautions for use"). The initial dose should not exceed half of the maximum dose.
30-44	1000 mg
<30	-	Metformin is contraindicated.

Children.

Do not use the drug in children, as there are no clinical data available for this age group of patients.

Overdose.

When the drug was administered at a dose of 85 g, hypoglycemia was not observed. 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 Glucophage XR 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 Glucophage XR were similar in nature and severity to those observed in patients treated with Glucophage (immediate-release formulation).

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhoea, 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 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Disorders of metabolism.

Common: vitamin B12 deficiency/low levels (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, diarrhoea, abdominal pain, and loss of appetite. These adverse effects most commonly occur at the beginning of treatment and spontaneously resolve in most cases. To prevent gastrointestinal adverse effects, a gradual increase in the dose of the medication is recommended.

From the hepatobiliary system.

Very rare: isolated reports of 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 rash, erythema, pruritus, urticaria.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should 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.

4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

15 tablets per blister. 2 or 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Merck Sante, France.

Manufacturer's address and place of business.

2 rue du Pressoir Vert, 45400 Semoy, France.