Glucophage^® (Tablets) Instructions for Use

ATC Code

A10BA02 (Metformin)

Active Substance

Metformin

Clinical-Pharmacological Group

Hypoglycemic drug of the biguanide group for oral administration

Pharmacotherapeutic Group

Oral hypoglycemic agent of the biguanide group

Pharmacological Action

Metformin reduces hyperglycemia without leading to the development of hypoglycemia. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals. It increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. It reduces the production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis. It delays the absorption of glucose in the intestine.

Metformin stimulates glycogen synthesis by acting on glycogen synthase. It increases the transport capacity of all types of membrane glucose transporters.

In addition, it has a beneficial effect on lipid metabolism: it reduces the content of total cholesterol, LDL and triglycerides. Against the background of metformin intake, the patient’s body weight either remains stable or moderately decreases. Clinical studies have also shown the effectiveness of metformin for the prevention of diabetes in patients with prediabetes with additional risk factors for the development of overt type 2 diabetes, in whom lifestyle changes have not achieved adequate glycemic control.

Pharmacokinetics

Absorption

After oral administration of the drug in the form of a 500 mg prolonged-release tablet, the absorption of metformin is slowed compared to a tablet with immediate release of metformin. The T_max of metformin is 7 hours. At the same time, the T_max for a tablet with immediate release is 2.5 hours.

The mean T_max of metformin (1193 ng/ml) in blood plasma is 5 hours (in the range of 4-12 hours) after oral administration of 1500 mg of metformin in the prolonged-release dosage form of 750 mg.

The mean T_max of metformin (1214 ng/ml) in blood plasma after food intake is 5 hours (in the range of 4-10 hours) after a single oral dose of 1000 mg of metformin in the prolonged-release dosage form.

At steady state, identical to the steady state of metformin in the immediate-release dosage form, C_max and AUC increase not proportionally to the dose taken. After a single oral dose of 2000 mg of metformin in the prolonged-release dosage form, the AUC is similar to that observed after taking 1000 mg of metformin in immediate-release tablets twice a day.

The intra-individual variability of C_max and AUC after taking metformin in the prolonged-release dosage form is similar to that observed after taking the immediate-release dosage form.

The absorption of metformin from the prolonged-release dosage form does not change depending on food intake.

No accumulation is observed with repeated administration of up to 2000 mg of metformin in the prolonged-release dosage form.

Distribution

Binding to plasma proteins is negligible. C_max in blood is lower than C_max in plasma and is reached in approximately the same time. The mean V_d ranges from 63-276 L.

Metabolism

No metabolites have been detected in humans.

Excretion

Metformin is excreted unchanged by the kidneys. After oral administration, T_1/2 is about 6.5 hours. The renal clearance of metformin is >400 ml/min, indicating that Metformin is excreted by glomerular filtration and tubular secretion.

In case of impaired renal function, the clearance of metformin decreases in proportion to the CrCl, and T_1/2 increases, which can lead to an increase in the plasma concentration of metformin.

Indications

Type 2 diabetes mellitus in adults, especially in patients with obesity, when diet therapy and physical exercise are ineffective:

• As monotherapy;
• In combination with other oral hypoglycemic drugs, or in combination with insulin.

Monotherapy for prediabetes in cases where lifestyle changes have not achieved adequate glycemic control.

ICD codes

Dosage Regimen

Tablets

For oral administration once a day with the evening meal.

The dose is selected by the doctor individually for each patient based on the results of blood glucose measurements.

Monotherapy and combination therapy in combination with other hypoglycemic agents for type 2 diabetes mellitus

• For patients already receiving treatment with metformin, the initial dose should be equivalent to the daily dose of metformin in the immediate-release dosage form.
• For patients not taking Metformin, it is recommended to start taking metformin preparations with prolonged release in dosages of 500 mg or 750 mg once a day with the evening meal.
• Metformin 1000 mg in the prolonged-release dosage form is used as maintenance therapy for patients taking Metformin in the immediate-release dosage form at a dose of 1000 mg or 2000 mg. Metformin 1000 mg in the prolonged-release dosage form should be taken once a day with the evening meal.
• Every 10-15 days, it is recommended to adjust the dose depending on the plasma glucose level. A slow increase in dose helps to reduce gastrointestinal side effects.
• Patients taking Metformin in the immediate-release dosage form at a dose exceeding 2000 mg are not recommended to switch to Metformin in the prolonged-release dosage form.
• When switching from another hypoglycemic agent, the dose selection is carried out, starting with the use of metformin preparations with prolonged release in dosages of 500 mg or 750 mg, with a possible subsequent transition to the drug Metformin 1000 mg in the prolonged-release dosage form.
• The maximum daily dose of metformin in the prolonged-release dosage form is 2000-2250 mg.

Combination with insulin

To achieve better blood glucose control, Metformin and insulin can be used as combination therapy. The usual initial dose of metformin in the prolonged-release dosage form is 500 mg or 750 mg once a day with the evening meal, while the insulin dose is selected based on blood glucose measurement results. Subsequently, a transition to Metformin in the prolonged-release dosage form of 1000 mg is possible.

Daily dose

The maximum recommended dose of metformin in the prolonged-release dosage form is 2000-2250 mg. If adequate glycemic control is not achieved when taking the maximum recommended dose once a day with the evening meal, then the maximum dose can be divided into two doses: with breakfast and with the evening meal.

If adequate glycemic control is not achieved when taking 2000 mg of metformin in the prolonged-release dosage form, a transition to Metformin with immediate release of the active substance with a maximum daily dose of 3000 mg is possible.

Monotherapy for prediabetes

The usual dose is 1000-1500 mg once a day during or after a meal. Regular glycemic control is recommended to assess the need for further use of the drug.

Patients with renal insufficiency

Metformin can be used in patients with moderate renal insufficiency (CrCl 30-59 ml/min) only in the absence of conditions/risk factors that may increase the risk of lactic acidosis. Renal function (CrCl) should be assessed before starting therapy with metformin, and then at least once a year. In patients with an increased risk of progression of renal insufficiency and in elderly patients, renal function should be monitored more frequently (every 3-6 months).

If the CrCl is below 30 ml/min, the drug should be discontinued immediately.

Elderly patients

Due to possible decreased renal function, the dose is adjusted based on the assessment of renal function, which must be performed regularly, at least 2 times a year.

Duration of treatment course

Metformin in the prolonged-release dosage form should be taken daily, without interruption. In case of treatment discontinuation, the patient should inform the doctor.

Missed dose

In case of a missed dose, the patient should take the next dose at the usual time. A double dose of metformin in the prolonged-release dosage form should not be taken.

Adverse Reactions

The frequency of adverse effects of the drug is assessed as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000).

Metabolism and nutrition disorders very rare – lactic acidosis. With long-term use of metformin, a decrease in the absorption of vitamin B₁₂ may be observed. If megaloblastic anemia is detected, the possibility of such etiology should be considered.

Nervous system disorders common – taste disturbance (metallic taste in the mouth).

Gastrointestinal disorders very common – nausea, vomiting, diarrhea, abdominal pain and loss of appetite. They most often occur during the initial period of treatment and in most cases resolve spontaneously. To prevent symptoms, it is recommended to take Metformin during or after a meal. A slow increase in dose may improve gastrointestinal tolerance.

Hepatobiliary disorders very rare – impaired liver function tests and hepatitis; after discontinuation of metformin, these adverse events completely disappear.

Skin and subcutaneous tissue disorders very rare – skin reactions such as erythema (redness of the skin), itching, urticaria.

If any of the side effects listed in the instructions worsen, or any other side effects not listed in the instructions are noticed, the patient must inform the doctor.

Contraindications

• Hypersensitivity to metformin or to any excipient;
• Diabetic ketoacidosis, diabetic precoma, coma;
• Renal failure or impaired renal function (CrCl less than 30 ml/min);
• Acute conditions with a risk of impaired renal function: dehydration (in chronic or severe diarrhea, repeated episodes of vomiting), severe infectious diseases (e.g., respiratory and urinary tract infections), shock;
• Clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
• Major surgical operations and injuries, when insulin therapy is indicated;
• Hepatic failure, impaired liver function;
• Chronic alcoholism, acute alcohol intoxication;
• Lactic acidosis (including in history);
• Use for at least 48 hours before and for 48 hours after radioisotope or X-ray studies with the introduction of an iodine-containing contrast agent (e.g., intravenous urography, angiography);
• Adherence to a hypocaloric diet (less than 1000 kcal/day);
• Pregnancy;
• Children under 18 years of age due to the lack of data on efficacy and safety of use in this age group.

With caution the drug should be used:

• In patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis in them;
• In patients with renal insufficiency (CrCl 30-59 ml/min);
• During breastfeeding.

Use in Pregnancy and Lactation

Decompensated diabetes mellitus during pregnancy is associated with an increased risk of congenital malformations and perinatal mortality.

A limited amount of data indicates that the use of metformin in pregnant women does not increase the risk of congenital malformations in children.

When planning pregnancy, as well as in case of pregnancy while taking metformin for prediabetes and type 2 diabetes, the drug should be discontinued, and in case of type 2 diabetes, insulin therapy should be prescribed. It is necessary to maintain blood glucose levels as close to normal as possible to reduce the risk of fetal malformations.

Metformin passes into breast milk. No adverse reactions were observed in newborns during breastfeeding while taking metformin. However, due to the limited amount of data, the use of the drug during breastfeeding is not recommended. The decision to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of side effects in the child.

Use in Hepatic Impairment

Contraindicated in hepatic failure, impaired liver function.

Use in Renal Impairment

Contraindicated in renal failure or impaired renal function (CrCl less than 30 ml/min).

With caution, the drug should be used in patients with renal insufficiency (CrCl 30-59 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age due to the lack of data on use.

Geriatric Use

With caution, the drug should be used in patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis in them.

Special Precautions

Lactic acidosis

Lactic acidosis is a very rare but serious complication (high mortality in the absence of emergency treatment) that can occur due to the accumulation of metformin. Cases of lactic acidosis while taking metformin occurred mainly in diabetic patients with severe renal failure.

Other associated risk factors should be considered, such as decompensated diabetes, ketosis, prolonged fasting, alcoholism, severe infectious disease, hepatic failure, any condition associated with severe hypoxia, and the simultaneous use of drugs that can cause the development of lactic acidosis. This can help reduce the incidence of lactic acidosis.

The risk of developing lactic acidosis should be considered when nonspecific signs appear, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and severe asthenia.

Lactic acidosis is characterized by severe malaise with general weakness, acidotic dyspnea, vomiting, abdominal pain, muscle cramps and hypothermia followed by coma. Diagnostic laboratory indicators are a decrease in blood pH (less than 7.35), plasma lactate concentration above 5 mmol/L, increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected, it is necessary to stop taking the drug and immediately consult a doctor.

Surgical operations

The use of metformin should be discontinued 48 hours before planned surgical operations and can be continued no earlier than 48 hours after, provided that renal function was found to be normal during the examination.

Renal function

Since Metformin is excreted by the kidneys, before starting treatment and regularly thereafter, it is necessary to determine CrCl: at least once a year in patients with normal renal function, every 3-6 months in patients with CrCl 45-59 ml/min and every 3 months in patients with CrCl 30-44 ml/min.

If CrCl is less than 30 ml/min, the use of the drug is contraindicated.

Particular caution should be exercised in case of possible impairment of renal function in elderly patients, in dehydration (chronic or severe diarrhea, repeated episodes of vomiting), with simultaneous use of antihypertensive drugs, diuretics or NSAIDs.

Heart failure

Patients with heart failure have a higher risk of developing hypoxia and renal failure. Patients with chronic heart failure should regularly monitor cardiac function and renal function while taking metformin.

The use of metformin in acute heart failure and chronic heart failure with unstable hemodynamic parameters is contraindicated.

Other precautions

• Patients are advised to continue following a diet with even carbohydrate intake throughout the day. Patients with excess body weight are advised to continue following a hypocaloric diet (but not less than 1000 kcal/day). Patients should also regularly exercise.
• Patients should inform the doctor about any ongoing treatment and any infectious diseases, such as colds, respiratory infections or urinary tract infections.
• It is recommended to regularly perform standard laboratory tests to monitor diabetes.
• Metformin in monotherapy does not cause hypoglycemia, however, caution is recommended when using it in combination with insulin or other oral hypoglycemic agents (for example, sulfonylurea derivatives or repaglinide and others). Symptoms of hypoglycemia are weakness, headache, dizziness, increased sweating, palpitations, visual impairment or impaired concentration.
• The patient should be warned that the inactive components of the prolonged-release dosage form of metformin may be excreted unchanged through the intestines, which does not affect the therapeutic activity of the drug.

Effect on the Ability to Drive Vehicles and Machinery

Monotherapy with metformin in the extended-release dosage form does not cause hypoglycemia and therefore does not affect the ability to drive vehicles and machinery.

Nevertheless, the development of hypoglycemia is possible when metformin is used in combination with other hypoglycemic drugs (sulfonylurea derivatives, insulin, repaglinide, and others). If symptoms of hypoglycemia appear, you should not drive vehicles or operate machinery.

Drug Interactions

Contraindicated Combinations

Iodinated X-ray contrast agents: against the background of functional renal insufficiency in patients with diabetes, radiological examination using iodinated X-ray contrast agents can cause the development of lactic acidosis. Treatment with metformin in the extended-release dosage form should be discontinued, depending on renal function, 48 hours before or for the duration of the X-ray examination using iodinated X-ray contrast agents and should not be resumed earlier than 48 hours after, provided that renal function was found to be normal during the examination.

Not Recommended Combinations

Alcohol. Acute alcohol intoxication increases the risk of lactic acidosis, especially in cases of

• Malnutrition, adherence to a low-calorie diet;
• Hepatic insufficiency.

Alcohol consumption and the use of medicines containing ethanol should be avoided during drug administration.

Combinations Requiring Caution

Medicinal products with indirect hyperglycemic action (e.g., systemic and topical corticosteroids and tetracosactide), beta₂-adrenergic agonists, danazol, chlorpromazine when taken in high doses (100 mg/day) and diuretics may require more frequent monitoring of blood glucose concentration, especially at the beginning of treatment. If necessary, the dose of metformin in the extended-release dosage form may be adjusted during treatment and after its discontinuation, based on the glycemic level.

Diuretics simultaneous administration of "loop" diuretics may lead to the development of lactic acidosis due to possible functional renal failure.

When metformin in the extended-release dosage form is used concomitantly with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemia may develop.

Nifedipine increases the absorption and C_max of metformin.

Cationic medicinal products (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin), which are secreted in the renal tubules, compete with metformin for tubular transport systems and may lead to an increase in its C_max.

Colesevelam when used concomitantly with metformin in the extended-release tablet form increases the plasma concentration of metformin (increase in AUC without a significant increase in C_max).

Organic Cation Transporters (OCT)

Metformin is a substrate of both transporters – OCT1 and OCT2. Concomitant use of metformin with

• OCT1 inhibitors (verapamil) may reduce the efficacy of metformin;
• OCT1 inducers (rifampicin) may increase the absorption of metformin in the gastrointestinal tract and its efficacy;
• OCT2 inhibitors (cimetidine, dolutegravir, ranolazine, trimethoprim, crizotinib, olaparib, daclatasvir, vandetanib) may reduce the renal elimination of metformin and thus lead to an increase in the plasma concentration of metformin.

In this regard, caution is recommended, especially in patients with renal insufficiency, when these drugs are taken simultaneously with metformin, as an increase in the plasma concentration of metformin is possible. If necessary, a dose adjustment of metformin may be considered, as OCT inhibitors/inducers may alter the efficacy of metformin.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.