Glucophage XR extended-release tablets 1000 mg No. 30

Instructions for Glucophage XR extended-release tablets 1000 mg No. 30

Composition

active ingredient: metformin;

1 film-coated tablet contains metformin hydrochloride 1000 mg;

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

Dosage form

Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 1000 mg: oval-shaped tablets with a biconvex surface, white in color, film-coated, with a score on both sides and engraving "1000" on one side.

Pharmacotherapeutic group

Oral hypoglycemic agents, except insulins. ATC code A10B A02.

Pharmacological properties

Pharmacodynamics

Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after a meal. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.

Metformin works in three ways:

leads to a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization; delays glucose absorption in the intestine.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).

Pharmacodynamic effects.

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

Independently of its effect on glycaemia, metformin immediate-release tablets have a positive effect on lipid metabolism. This effect has been demonstrated at therapeutic doses in controlled medium- or long-term clinical trials: metformin immediate-release tablets reduce total cholesterol, low-density lipoproteins and triglycerides. A similar effect was not observed with the prolonged-release tablets, probably due to the evening administration of the drug. This may also lead to an increase in triglycerides.

Clinical efficacy.

Reducing the risk or delaying the onset of type 2 diabetes.

The Diabetes Prevention Program (DPP) in Adults was a multicenter, randomized, controlled clinical trial that evaluated the effectiveness of an active lifestyle or metformin in preventing or delaying the development of type 2 diabetes. Inclusion criteria were age ≥25 years, BMI ≥24 kg/m2 (≥22 kg/m2 for Asian Americans), and impaired glucose tolerance plus a fasting glucose level of 95–125 mg/dL (or ≤125 mg/dL for American Indians). Patients were assigned to an active lifestyle, 2×850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

The mean baseline values for DPP participants (n=3,234 for 2.8 years) were as follows: age 50.6±10.7 years, fasting plasma glucose 106.5±8.3 mg/dL, plasma glucose 2 hours after oral glucose 164.6±17.0 mg/dL, and BMI 34.0±6.7 kg/m2. Implementing an active lifestyle together with metformin significantly reduced the risk of developing diabetes compared with placebo by 58% (95% CI 48-66%) and 31% (95% CI 17-43%), respectively.

The benefit of implementing lifestyle changes over metformin was greater in older patients.

Patients who benefited most from metformin treatment were those aged 45 years or older with a BMI ≥ 35 kg/m2, a baseline 2-hour glucose level of 9.6-11.0 mmol/L, a baseline HbA1C ≥ 6.0%, or patients with gestational diabetes.

For the prevention of one development of diabetes over three years in the DPP group, 6.9 patients were in the active lifestyle group and 13.9 in the metformin group. The point of reaching the cumulative incidence of diabetes of 50% was delayed by approximately three years in the metformin group compared with placebo.

Among DPPOS participants (n = 2776), 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. The 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 with placebo, the risk of diabetes was reduced by 18% in the metformin group (hazard ratio (HR) 0.82, 95% CI 0.72-0.93; p=0.001) and by 27% (HR 0.73, 95% CI 0.65-0.83; p<0.0001) in the active lifestyle group. For the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, the results did not differ significantly between groups, but for 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 PTH and/or PGN and/or elevated HbA1c.

Published risk factors for type 2 diabetes include: Mongoloid or Negroid ancestry, age over 40 years, dyslipidemia, hypertension, obesity or overweight, age, family history (1st degree relative with diabetes mellitus, history of gestational diabetes mellitus, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes.

A prospective randomised (UKPDS) trial demonstrated the benefit of intensive blood glucose control in overweight patients with type 2 diabetes treated with immediate-release metformin hydrochloride as first-line therapy after diet failure. Analysis of the outcomes of overweight patients treated with metformin hydrochloride after diet failure showed:

a significant reduction in the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/1000 patient-years) compared with the diet group (43.3 events/1000 patient-years), p=0.0023, and compared with the sulfonylurea combination therapy and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034. a significant reduction in the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017; significant reduction in the absolute risk of all-cause mortality: in the metformin hydrochloride group 13.5 cases/1000 patient-years compared to 20.6 cases/1000 patient-years (p=0.011), in the diet group, and compared to the combination therapy with sulfonylurea and insulin monotherapy group; 18.9 cases/1000 patient-years (p=0.021); significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 cases/1000 patient-years, diet alone – 18 cases/1000 patient-years (p=0.01)

For metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea, no advantage in terms of clinical outcomes has been shown.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Pharmacokinetics

Absorption.

After oral administration of 1 tablet of Glucophage XR 1000 mg to patients after meals and fasting, the maximum plasma concentration is 1214 ng/ml and is reached on average in 5 hours (from 4 to 10 hours).

The maximum concentration (Cmax) and area under the AUC curve of Glucophage XR 1000 mg are bioequivalent to a 1000 mg dose of Glucophage XR 500 mg in healthy volunteers both after food and in the fasted state.

A bioequivalent drug has the following properties.

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

The fluctuations in Cmax and AUC in individual subjects when taking metformin hydrochloride extended-release tablets are comparable to those observed when taking metformin hydrochloride immediate-release tablets.

Following administration of the 1000 mg prolonged-release tablets after food, a 77% increase in AUC was observed (Cmax increased by 26% and Tmax was prolonged to 1 hour).

The absorption of metformin hydrochloride from prolonged-release tablets is not affected by food intake. No accumulation is observed after multiple doses of up to 2000 mg of metformin hydrochloride prolonged-release tablets.

Distribution.

Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes. The maximum concentration in the blood is lower than the maximum concentration in plasma and is reached after approximately the same time. Erythrocytes most likely represent a second distribution chamber. The mean volume of distribution (Vd) ranges from 63 to 276 liters.

Metabolism.

Metformin is excreted unchanged in the urine. Metabolites have not been identified in humans.

Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After an oral dose, the elimination half-life is approximately 6.5 hours. In cases of renal impairment, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.

Special patient groups.

Kidney failure.

Limited data are available in patients with moderate renal impairment, so it is not possible to accurately estimate the systemic exposure of metformin in this patient group compared to patients with normal renal function. Therefore, dose adjustment is necessary according to clinical efficacy/tolerability (see section 4.2).

Indication

Reducing the risk or delaying the onset of type 2 diabetes in overweight adult patients with PTH* and/or PGH* and/or elevated HbA1C who have:

high risk of developing overt (manifest) type 2 diabetes mellitus (see section "Pharmacodynamics"); progressive disorders of carbohydrate metabolism, despite modification of an active lifestyle for 3 to 6 months.

Treatment with Glucophage XR should be based on a risk assessment, including appropriate glycemic control measures and evidence of high cardiovascular risk.

Lifestyle changes should be continued while starting metformin, except in cases where the patient is unable to make such changes for medical reasons.

* IGT: Impaired glucose tolerance; FPG: Impaired fasting glycemia.

Treatment of type 2 diabetes mellitus in adults, especially in overweight patients, when diet and exercise alone do not provide adequate glycaemic control.

Glucophage XR can be used as monotherapy or in combination with other oral antidiabetic agents, or in combination with insulin.

Contraindication

Hypersensitivity to metformin or any other component of the drug; any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis); diabetic precoma; severe renal failure (glomerular filtration rate (GFR) < 30 ml/min); acute conditions with a risk of developing renal dysfunction, such as: dehydration, severe infectious diseases, shock; diseases that may lead to the development of tissue hypoxia (especially acute diseases or exacerbation of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock; liver failure, acute alcohol poisoning, alcoholism.

Interaction with other medicinal products and other types of interactions

Combinations that are not recommended for use.

Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or low-calorie dieting, and in liver failure.

Iodinated radiocontrast agents: Patients should discontinue metformin prior to or at the time of the procedure and not resume treatment until 48 hours after the procedure and only after renal function has been re-evaluated and found to be normal (see sections 4.2 and 4.4).

Combinations to be used with caution. Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) II inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics, may adversely affect renal function, which may increase the risk of lactic acidosis. When initiating treatment with the above medicinal products or when they are used in combination with metformin, renal function should be closely monitored.

Drugs that have a hyperglycemic effect (glucocorticosteroids of systemic and local action, sympathomimetics).

Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of Glucophage XR should be adjusted 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 the efficacy of metformin; OCT1 inducers (such as rifampicin) may increase the gastrointestinal absorption and efficacy of metformin; OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with subsequent increase in metformin plasma concentrations; inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.

Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.

Application features

Lactic acidosis.

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.

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

If a patient is receiving metformin, caution should be exercised when initiating treatment with drugs that may acutely impair renal function (e.g. antihypertensives, diuretics and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of drugs that may lead to lactic acidosis (see sections 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia, which may progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical attention immediately.

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

Kidney failure.

GFR should be assessed before treatment is initiated and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with a GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Cardiac function.

Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section 4.3).

Elderly patients.

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

Iodine-containing radiopaque agents.

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Patients should discontinue metformin prior to or at the time of the examination and not resume treatment until 48 hours after the examination and only after renal function has been re-evaluated and found to be normal (see sections 4.2 and 4.5).

Surgical interventions.

Metformin should be discontinued during surgery performed under general, spinal or epidural anesthesia and should not be resumed until 48 hours after surgery or resumption of oral nutrition and only after renal function has been assessed and found to be normal.

Other precautions.

Patients should follow a diet with a balanced intake of carbohydrates throughout the day. Overweight patients should continue to follow a low-calorie diet. Laboratory blood glucose levels should be monitored regularly.

Metformin monotherapy does not cause hypoglycemia, but caution should be exercised when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides). Tablet shell fragments may be present in the feces. This is normal and has no clinical significance.

Ability to influence reaction speed when driving vehicles or other mechanisms

Glucophage XR does not affect the speed of reactions when driving or working with other mechanisms, since monotherapy with the drug does not cause hypoglycemia.

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

Use during pregnancy or breastfeeding

Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. There are limited data from the use of metformin in pregnant women, which do not indicate an increased risk of congenital anomalies. Preclinical studies have not revealed any adverse effects on pregnancy, embryonal or foetal development, labour and postnatal development. It is recommended that metformin not be used to treat impaired glycaemic control or diabetes if pregnancy is planned or if pregnancy occurs. For the treatment of diabetes, insulin is recommended to maintain blood glucose levels as close to normal as possible to reduce the risk of foetal malformations.

Breast-feeding.

Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. A decision on whether to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of adverse effects to the child.

Fertility.

Metformin did not affect animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area.

Method of administration and doses

Adult patients with normal renal function (GFR ≥ 90 mL/min).

Reducing the risk or delaying the onset of type 2 diabetes.

Metformin should only be prescribed when lifestyle changes within 3–6 months do not provide adequate glycemic control.

Treatment should begin with one tablet of Glucophage XR 500 mg once a day with the evening meal.

After 10-15 days of treatment, the dose should be adjusted according to the results of blood glucose measurements (OGTT (oral glucose tolerance test) and/or fasting plasma glucose and/or HbA1c should be normal). A slow increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of Glucophage XR 1000 mg is 2 tablets (2000 mg) taken with an evening meal.

It is recommended to regularly monitor (every 3–6 months) glycemic status (OGTT (oral glucose tolerance test) values and/or fasting plasma glucose and/or HbA1c), as well as risk factors to decide whether to continue, change or discontinue treatment.

Treatment should also be re-evaluated if the patient subsequently implements improved nutrition and/or exercise or if changes in the patient's health status allow for lifestyle changes.

Monotherapy or combination therapy compatible with other oral hypoglycemic agents.

Glucophage XR 1000 mg should be taken once daily with the evening meal. The maximum recommended dose is 2 tablets per day.

Glucophage XR 1000 mg should be used as maintenance therapy for patients already treated with metformin hydrochloride 1000 mg or 2000 mg. When switching, the daily dose of Glucophage XR should be equivalent to the current daily dose of metformin hydrochloride.

Patients treated with metformin hydrochloride at a dosage of more than 2000 mg per day are not recommended to switch to Glucophage XR therapy.

Patients treated with Glucophage XR should not exceed a dosage of 2000 mg per day.

For patients starting treatment, the usual starting dose of Glucophage XR is 500 mg once daily with the evening meal. After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements. Slow dose increases may help reduce gastrointestinal side effects.

If the desired glycemic level cannot be achieved with the maximum dose of 2000 mg of Glucophage XR taken once daily, this dose can be divided into 2 doses per day (once in the morning and once in the evening, during meals).

If the required glycemia level remains unattained, Glucophage film-coated tablets can be used at the maximum recommended dose of 3000 mg per day.

When switching from another antidiabetic drug to Glucophage XR 1000 mg, titrate the dose and start with Glucophage XR 500 mg.

Combination therapy with insulin.

To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose of Glucophage XR is 500 mg once daily with the evening meal, then the insulin dose should be adjusted according to blood glucose measurements.

Glucophage XR, extended-release tablets, 1000 mg can be used after titration of the drug dose.

In elderly patients.

The benefit of reducing the risk of developing type 2 diabetes or delaying its onset has not been established in patients aged 75 years and older (see section 5.1), therefore metformin is not recommended for use in such patients (see section 4.2).

Kidney failure.

GFR should be assessed before starting treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal failure and in elderly patients, renal function should be monitored more frequently, e.g. every 3-6 months.

Children

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

Overdose

When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can cause the occurrence of lactic acidosis. Lactic acidosis is an emergency. In the event of lactic acidosis, treatment with Glucophage XR should be discontinued and the patient urgently hospitalized. The most effective measure for removing lactate and metformin from the body is hemodialysis.

Adverse reactions

According to post-marketing and controlled clinical studies, adverse reactions in patients using Glucophage XR were similar in nature and severity to those in patients using Glucophage (immediate-release).

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms resolve on their own in most cases.

Adverse effects are classified according to the 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.

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

With prolonged use of the drug, absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood serum. It is recommended to consider this possible cause of hypovitaminosis B12 if the patient has megaloblastic anemia.

From the nervous system.

Common: taste disturbance.

From the digestive tract.

Very common: digestive system disorders such as: nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and in most cases disappear spontaneously. To prevent the occurrence of side effects from the digestive tract, a slow increase in the dose of the drug is recommended.

On the part of the hepatobiliary system.

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

On the skin and subcutaneous tissue.

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

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 ° C. Keep out of the reach of children!

Packaging

10 tablets in a blister, 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Merck Santé, France. Merck Healthcare KGaA, Germany.

Location of the manufacturer and its business address

2 rue du Pressoir Vert, 45400 Semois, France. Frankfurter Strasse 250, 64293 Darmstadt, Germany.