Metformin Sanofi (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Sanofi India, Limited (India)

ATC Code

A10BA02 (Metformin)

Active Substance

Metformin (Rec.INN registered by WHO)

Dosage Forms

	Metformin Sanofi	Film-coated tablets, 500 mg: 30, 60, or 90 pcs.
		Film-coated tablets, 850 mg: 30, 60, or 90 pcs.
		Film-coated tablets, 1000 mg: 10, 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex.

Excipients: sodium carboxymethyl starch – 20 mg, povidone 40 – 40 mg, colloidal silicon dioxide – 7 mg, corn starch – 10 mg, magnesium stearate – 3 mg.

Film coating composition sepifilm 752 white (hypromellose – 35-45%, microcrystalline cellulose – 27-37%, macrogol stearate – 6-10%, titanium dioxide – 18-22%) – 10.648 mg, macrogol 6000 – 0.122 mg.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets white, oblong, biconvex, with a score for dividing on one side.

Excipients: sodium carboxymethyl starch – 34 mg, povidone 40 – 68 mg, colloidal silicon dioxide – 11.9 mg, corn starch – 17 mg, magnesium stearate – 5.1 mg.

Film coating composition sepifilm 752 white (hypromellose – 35-45%, microcrystalline cellulose – 27-37%, macrogol stearate – 6-10%, titanium dioxide – 18-22%) – 17.33 mg, macrogol 6000 – 0.2 mg.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets white, oblong, biconvex, with a score for dividing on both sides.

Excipients: sodium carboxymethyl starch – 40 mg, povidone 40 – 80 mg, colloidal silicon dioxide – 14 mg, corn starch – 20 mg, magnesium stearate – 6 mg.

Film coating composition sepifilm 752 white (hypromellose – 35-45%, microcrystalline cellulose – 27-37%, macrogol stearate – 6-10%, titanium dioxide – 18-22%) – 20 mg, macrogol 6000 – 0.23 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; biguanides

Pharmacological Action

Hypoglycemic drug for oral administration. Metformin is a biguanide with a hypoglycemic effect that determines the reduction of basal (fasting) and postprandial (2 hours after the start of a meal) plasma glucose concentration. Unlike sulfonylurea derivatives, Metformin does not stimulate insulin secretion by pancreatic beta-cells and does not pose a risk of hypoglycemia.

Increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. Reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. Delays the absorption of glucose in the intestine.

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

Metformin has a beneficial effect on lipid metabolism: 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.

Pediatric population

In patients aged 10-16 years who were treated with metformin for 1 year, glycemic control indicators were comparable to those in the adult population.

Pharmacokinetics

Absorption

After oral administration, Metformin is absorbed in the gastrointestinal tract. C_max is reached 2.5 hours after oral administration. The bioavailability for 500 and 850 mg doses in healthy individuals is 50-60%. The absorption of metformin when taken orally is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is nonlinear. When metformin is used at recommended doses and according to the recommended regimen, C_ss in plasma is achieved within 24-48 hours and is usually less than 1 μg/ml. C_max of metformin does not exceed 5 μg/ml, even when the drug is used at maximum doses.

Food intake reduces the extent and somewhat slows down the absorption of metformin. After oral administration of an 850 mg tablet, a decrease in C_max by 40%, a decrease in AUC by 25%, and an increase in the time to reach C_max by 35 minutes are observed.

Distribution

Metformin is rapidly distributed in tissues and practically does not bind to plasma proteins. Metformin penetrates into erythrocytes. C_max in blood is lower than C_max in plasma and is reached approximately simultaneously. Erythrocytes are probably a secondary distribution depot. The average V_d ranges from 63-276 L.

Metabolism

Metformin is excreted by the kidneys unchanged, undergoes very little metabolism, and no metabolites were detected.

Excretion

After oral administration of the drug, 20-30% of the unabsorbed substance is excreted through the intestine. The renal clearance of metformin is more than 400 ml/min, indicating the excretion of metformin by active glomerular filtration and tubular secretion. After oral administration, T_1/2 is about 6.5 hours.

In case of impaired renal function, accumulation of the drug is possible, leading to an increase in the concentration of metformin in plasma.

Special patient groups

Patients with impaired renal function. The available data obtained in patients with moderate renal failure are limited and do not allow a reliable assessment of the systemic exposure of metformin in this subgroup, as can be done in individuals with normal renal function.

Pediatric patients. After a single dose of metformin 500 mg in pediatric patients, a pharmacokinetic profile similar to that observed in healthy adults was identified. After multiple doses of metformin 500 mg twice daily for 7 days in children, C_max and AUC_0-t were reduced by approximately 33% and 40%, respectively, compared to the values of these parameters in adult patients with diabetes mellitus receiving Metformin at a dosage of 500 mg twice daily for 14 days. Since the drug dose is individually selected depending on the level of glycemia, these data have limited clinical significance.

Indications

Type 2 diabetes mellitus (especially in obese patients) when diet therapy and physical exercise are ineffective

• In adults as monotherapy or in combination with other oral hypoglycemic agents or with insulin;
• In children from 10 years of age as monotherapy and in combination with insulin.

ICD codes

Dosage Regimen

The drug is taken orally. The tablets should be taken whole during or immediately after a meal, with a small amount of liquid.

The drug Metformin Sanofi should be taken daily, without interruption. If treatment is discontinued, the patient should inform the doctor.

Adults

Monotherapy and combination therapy in combination with other oral hypoglycemic agents

Initial dose is usually 500 mg or 850 mg 2-3 times/day after or during meals. A further gradual dose increase is possible depending on blood glucose concentration.

After 10-15 days of use, the dose must be adjusted based on the results of plasma glucose concentration measurements. A slow dose increase may help improve gastrointestinal tolerance.

Maintenance dose is usually 1500-2000 mg/day. To reduce gastrointestinal side effects, the daily dose should be divided into 2-3 doses. The maximum dose is 3000 mg/day, divided into 3 doses.

Patients taking Metformin at doses of 2000-3000 mg/day can be switched from taking metformin tablets in a dosage of 500 mg to taking metformin tablets in a dosage of 1000 mg. The maximum recommended dose is 3000 mg/day, divided into 3 doses.

In case of planning a switch from taking another hypoglycemic agent: it is necessary to stop taking the other agent and start taking the drug Metformin Sanofi at the dose indicated above.

Combination with insulin

To achieve better blood glucose control, Metformin and insulin can be used as combination therapy. The initial dose of the drug Metformin Sanofi is usually 500 mg or 850 mg 2-3 times/day, while the insulin dose is selected based on blood glucose concentration indicators.

Patients with impaired renal function

Metformin can be used in patients with moderate renal impairment (CrCl 45-59 ml/min, GFR 45-59 ml/min/1.73 m² body surface area) only in the absence of other conditions that may increase the risk of lactic acidosis, and under the following dose adjustment conditions: the initial dose of the drug Metformin Sanofi is 500 mg or 850 mg once/day.

The maximum dose is 1000 mg/day, divided into 2 doses. Careful monitoring of renal function is necessary (every 3-6 months).

If CrCl<45 ml/min or GFR<45 ml/min/1.73 m² body surface area, the drug Metformin Sanofi should be immediately discontinued.

Elderly patients

Due to possible impairment of renal function, the dose of the drug Metformin Sanofi in elderly patients must be selected under regular monitoring of renal function parameters (determine serum creatinine concentration at least 2-4 times a year).

Children and adolescents

In children aged 10 years and older, the drug Metformin Sanofi can be used both as monotherapy and in combination with insulin. The initial dose is usually 500 mg or 850 mg once/day after or during a meal. After 10-15 days, the dose must be adjusted based on blood glucose concentration indicators. The maximum daily dose is 2000 mg, divided into 2-3 doses.

Adverse Reactions

When using metformin, the adverse effects listed below may occur, which are divided by system-organ classes in accordance with the MedDRA classification. Determination of the frequency of adverse effects, according to the WHO classification: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (it is not possible to determine the frequency of occurrence of the adverse effect from the available data).

From the blood and lymphatic system: frequency unknown – hemolytic anemia.

From the metabolism and nutrition: very rare – lactic acidosis, decreased absorption of vitamin B₁₂ in patients with megaloblastic anemia; frequency unknown – peripheral neuropathy in patients with vitamin B₁₂ deficiency.

From the nervous system: common – taste distortion; frequency unknown – encephalopathy.

From the gastrointestinal tract: very common – nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These adverse effects most often occur at the start of therapy and in most cases resolve on their own. To prevent their occurrence, it is recommended to take the daily dose of metformin in 2 or 3 doses during or after meals. A slow increase in the drug dose may help improve gastrointestinal tolerance.

From the skin and subcutaneous tissues: very rare – erythema, skin itching, urticaria; frequency unknown – photosensitivity.

From the liver and biliary tract: very rare – increased activity of liver transaminases or hepatitis, which disappear after drug withdrawal.

Effect on the results of laboratory and instrumental studies: frequency unknown – decrease in TSH concentration in plasma in patients with hypothyroidism, hypomagnesemia against the background of diarrhea.

Children and adolescents

Published data, post-registration use data, and results of controlled clinical trials in a limited population of children in the age group of 10-16 years who were treated with metformin for 1 year show that adverse events in children are similar in nature and severity to those in adult patients.

Contraindications

• Hypersensitivity to metformin or any excipient included in the drug;
• Diabetic ketoacidosis, diabetic precoma, coma;
• Moderate and severe renal failure or impaired renal function (CrCl<45 ml/min, GFR<45 ml/min/1.73 m² body surface area);
• Acute conditions with a risk of developing impaired renal function: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, shock;
• Acute and chronic diseases that can lead to the development of tissue hypoxia (such as acute myocardial infarction, shock, heart failure with unstable hemodynamic parameters, respiratory failure);
• Lactic acidosis (including in history);
• Extensive surgical operations and trauma (against which insulin therapy is indicated);
• Impaired liver function;
• Chronic alcoholism, acute alcohol intoxication;
• Use for less than 48 hours before and within 48 hours after radioisotope or X-ray studies with intravenous administration of iodine-containing X-ray contrast agent;
• Adherence to a hypocaloric diet (less than 1000 kcal/day);
• Pregnancy.

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 impaired renal function (CrCl 45-59 mmol/l, GFR 45-59 ml/min/1.73 m² body surface area); during breastfeeding.

Use in Pregnancy and Lactation

Uncontrolled diabetes during pregnancy is associated with an increased risk of congenital malformations and perinatal mortality. Limited data indicate that taking metformin in pregnant women does not increase the risk of fetal malformations. Animal studies have not demonstrated harmful effects on pregnancy, embryo or fetal development, labor, and postnatal development.

When planning pregnancy, as well as in case of pregnancy while taking metformin, the drug should be discontinued and insulin therapy prescribed.

It is necessary to maintain plasma glucose levels as close to normal as possible to reduce the risk of fetal malformations.

Metformin penetrates into breast milk. No side effects in newborns/infants against the background of metformin intake have been observed. However, due to limited 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 Renal Impairment

Contraindicated: moderate and severe renal failure or impaired renal function (CrCl<45 ml/min, GFR<45 ml/min/1.73 m²); — acute conditions with a risk of developing impaired renal function: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, shock.

With caution: in patients with impaired renal function (CrCl 45-59 mmol/l, GFR 45-59 ml/min/1.73 m²);

Pediatric Use

In children aged 10 years and older, the drug Metformin Sanofi can be used both as monotherapy and in combination with insulin. The initial dose is usually 500 mg or 850 mg once/day after or during a meal. After 10-15 days, the dose must be adjusted based on blood glucose concentration indicators. The maximum daily dose is 2000 mg, divided into 2-3 doses.

Geriatric Use

Due to possible impairment of renal function, the dose of the drug Metformin Sanofi in elderly patients must be selected under regular monitoring of renal function parameters (determine serum creatinine concentration at least 2-4 times a year).

Special Precautions

Lactic acidosis

Lactic acidosis is a rare but serious (high mortality in the absence of immediate treatment) metabolic complication that can occur due to the accumulation of metformin. There are reports of cases of lactic acidosis during metformin therapy in patients with diabetes mellitus and with severe renal failure or acute deterioration of renal function. Special attention should be paid to situations where renal function impairment may occur, for example, in case of dehydration (with severe diarrhea or vomiting) or at the start of antihypertensive therapy or diuretic therapy (especially “loop” diuretics), as well as at the start of NSAID therapy. In case of the occurrence of these acute conditions, therapy with the drug Metformin Sanofi should be temporarily discontinued.

Other associated risk factors should also be taken into account, such as decompensated diabetes, ketosis, prolonged fasting, excessive alcohol consumption, liver failure, and any condition associated with severe hypoxia (e.g., heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction).

The risk of developing lactic acidosis should be considered when nonspecific signs appear, such as muscle cramps, dyspeptic disorders, abdominal pain, and severe asthenia. Patients should be instructed to immediately inform their doctor about the occurrence of these symptoms, especially if the patient previously tolerated metformin therapy well. In this case, therapy with the drug Metformin Sanofi should be discontinued, at least temporarily, until the situation is clarified. The issue of resuming therapy should be decided individually, taking into account the benefit/risk ratio, as well as the state of renal function in this patient.

DiagnosisLactic acidosis is characterized by acidotic dyspnea, abdominal pain, hypothermia followed by coma. Laboratory findings include: decreased blood pH (less than 7.25), plasma lactate concentration above 5 mmol/L, and increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin administration should be discontinued and the patient hospitalized immediately.

Physicians should inform patients about the risk of developing lactic acidosis and its symptoms.

Surgical Procedures

Administration of Metformin Zentiva should be discontinued 48 hours before elective surgery under general anesthesia, spinal or epidural anesthesia. Therapy can be resumed no earlier than 48 hours after the surgery or after resuming food intake and only provided that renal function is normal.

Renal Function

Since Metformin is excreted by the kidneys, creatinine clearance should be monitored before starting therapy and then regularly

• At least once a year in patients with normal renal function;
• At least 2-4 times a year in patients with creatinine clearance at the lower limit of normal and in elderly patients.

If creatinine clearance is <45 ml/min (eGFR <45 ml/min/1.73 m² body surface area), the use of Metformin Zentiva is contraindicated.

Deterioration of renal function in elderly patients is often asymptomatic.

Special caution should be exercised in cases of possible renal impairment due to dehydration or concurrent use of antihypertensive drugs, diuretics (especially “loop” diuretics) or NSAIDs. In these cases, it is also recommended to check renal function status before starting therapy with Metformin Zentiva.

Heart Failure

Patients with heart failure have a higher risk of developing hypoxia and renal failure. In patients with stable chronic heart failure, Metformin Zentiva can be used provided that cardiac and renal function are regularly monitored.

The use of Metformin Zentiva is contraindicated in patients with acute or chronic heart failure with unstable hemodynamic parameters.

Reproductive Function

Metformin did not affect reproductive function in male or female rats when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparison.

Children and Adolescents

The diagnosis of type 2 diabetes mellitus must be confirmed before starting therapy with Metformin Zentiva.

In controlled clinical trials lasting one year, no effect of metformin on growth and puberty in children was detected. However, due to the lack of long-term data, careful monitoring of the subsequent effect of metformin on these parameters in children taking Metformin Zentiva is recommended, especially in children aged 10-12 years.

Other Precautions

• Patients should follow a diet with regular carbohydrate intake throughout the day. Overweight patients should continue to follow a low-calorie diet (but not less than 1000 kcal per day).
• Standard laboratory tests to monitor diabetes should be performed regularly.
• Metformin monotherapy does not cause hypoglycemia; nevertheless, caution is recommended when using it in combination with insulin or other hypoglycemic agents (e.g., sulfonylurea derivatives, repaglinide).
• Long-term metformin therapy is associated with a decrease in plasma vitamin B₁₂ concentration, which may cause peripheral neuropathy. Regular monitoring of plasma vitamin B₁₂ concentration is recommended.

Effect on Ability to Drive and Operate Machinery

The use of Metformin Zentiva as monotherapy does not affect the ability to drive vehicles and operate machinery.

When Metformin Zentiva is combined with other hypoglycemic agents (including sulfonylurea derivatives, insulin, meglitinides), patients should be warned about the possibility of developing hypoglycemic conditions, which impair the ability to drive vehicles and engage in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions.

Overdose

Symptoms: when used at a dose of 85 g (42.5 times the maximum daily dose), hypoglycemia was not observed. Overdose of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and requires hospital treatment. The cause of lactic acidosis may also be drug accumulation due to impaired renal function.

Early symptoms of lactic acidosis are nausea, vomiting, diarrhea, decreased body temperature, abdominal pain, muscle pain; subsequently, increased respiration, dizziness, impaired consciousness and coma may occur.

Pancreatitis may occur with metformin overdose.

Treatment: if signs of lactic acidosis appear, metformin treatment must be discontinued immediately, the patient urgently hospitalized, plasma lactate concentration determined and the diagnosis confirmed. Hemodialysis is the most effective procedure for removing lactate and metformin from the body. Symptomatic treatment is also carried out.

Drug Interactions

Contraindicated Combinations

Iodinated Contrast Media

Intravascular administration of iodinated contrast media may lead to the development of functional renal failure, thereby increasing the accumulation of metformin and the risk of lactic acidosis. In patients with eGFR >60 ml/min/1.73 m² body surface area, metformin should be discontinued before or during the radiological examination and not resumed until 48 hours after its completion, provided normal renal function is confirmed. In patients with moderate renal impairment (eGFR 45-60 ml/min/1.73 m²), metformin should be discontinued 48 hours before administration of iodinated contrast medium and resumed no earlier than 48 hours after completion of the examination and only after re-evaluation of renal function in the absence of signs of its deterioration.

Not Recommended Combinations

Alcohol

Acute alcohol intoxication increases the risk of lactic acidosis, especially in cases of fasting or insufficient nutrition, adherence to a low-calorie diet, or hepatic insufficiency. Alcohol consumption and medications containing ethanol should be avoided during treatment with the drug.

Combinations Requiring Caution

Danazol

Concomitant use of danazol is not recommended to avoid its hyperglycemic effect. If treatment with danazol is necessary and after its discontinuation, adjustment of the metformin dose under blood glucose control is required.

Chlorpromazine

Chlorpromazine in high doses (100 mg/day) increases blood glucose concentration by reducing insulin release. When treating with antipsychotics and after their discontinuation, adjustment of the metformin dose under blood glucose control is required.

Corticosteroids

Systemic and locally acting corticosteroids reduce glucose tolerance, increase blood glucose concentration, and sometimes cause ketosis. When treating with corticosteroids and after their discontinuation, adjustment of the metformin dose under blood glucose control is required.

Diuretics (especially “loop” diuretics)

Concomitant use of “loop” diuretics may lead to lactic acidosis due to possible functional renal failure. Metformin should not be prescribed to patients if creatinine clearance is below 60 ml/min.

Injectable Beta₂-Adrenergic Agonists

Beta₂-adrenergic agonists increase blood glucose concentration due to stimulation of β₂-adrenergic receptors. In this case, regular monitoring of blood glucose concentration is advisable. If necessary, insulin administration is recommended.

When using the above-mentioned drugs concomitantly, the metformin dose may need to be adjusted during treatment or after its discontinuation.

Antihypertensive drugs, except for ACE inhibitors, may alter blood glucose concentration. If necessary, the metformin dose should be adjusted.

Sulfonylurea Derivatives, Insulin and Acarbose

Hypoglycemia may develop when used concomitantly with metformin.

Salicylates

Hypoglycemia may develop when used concomitantly with metformin.

Nifedipine

Increases the absorption and C_max of metformin.

Cationic Drugs

Amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin, which are excreted by renal tubules, compete with metformin for tubular transport systems and can lead to an increase in C_max by up to 60%.

The hypoglycemic effect of metformin may be reduced by phenothiazines, glucagon, estrogens, including those in oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, slow calcium channel blockers.

Levothyroxine may reduce the hypoglycemic effect of metformin. Monitoring of blood glucose concentration is recommended, especially when starting or discontinuing thyroid hormone therapy, and the metformin dose should be adjusted if necessary.

Concomitant use of metformin with NSAIDs, MAO inhibitors, oxytetracycline, fibrate derivatives, cyclophosphamide, probenecid, chloramphenicol, sulfonamide antimicrobials may enhance the hypoglycemic effect of metformin.

Propranolol, Ibuprofen

In studies with healthy volunteers on single-dose administration of metformin and propranolol, as well as metformin and ibuprofen, no changes in their pharmacokinetic parameters were observed.

Metformin may reduce the therapeutic effect of the anticoagulant phenprocoumon. Careful monitoring of INR is recommended during concomitant use.

Storage Conditions

The drug should be stored out of the reach of children. Does not require special storage conditions.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.