Sanofi Metformin, 1000 mg 60 pcs

Hypoglycemic drug for oral administration. Metformin is a biguanide with hypoglycemic effect, which determines the decrease of basal (on an empty stomach) and postprandial (2 hours after the beginning of the meal) plasma glucose concentration. Unlike sulfonylurea derivatives, metformin does not stimulate insulin secretion by pancreatic beta-cells and does not create a risk of hypoglycemia.

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

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

Metformin has a favorable effect on lipid metabolism: it reduces total cholesterol, LDL and triglycerides.

With metformin, a patient’s body weight either remains stable or decreases moderately.

Pediatric population

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

Pharmacokinetics

Intake

After oral administration, metformin is absorbed in the GI tract. Cmax is reached 2.5 h after oral administration. Bioavailability for doses of 500 and 850 mg in healthy subjects is 50-60%. Absorption of metformin when ingested is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. When metformin is used in the recommended doses and according to the recommended regimen, Css in plasma is reached 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.

Eating reduces the extent and slightly slows down the absorption of metformin. After oral administration of 850 mg tablet, there is a 40% decrease in C max, a 25% decrease in AUC and a 35 min increase in time to reach C max.

Distribution

Metformin is rapidly distributed in the tissues, with little or no binding to plasma proteins. Metformin penetrates the erythrocytes. C max in blood is lower than C max in plasma and is reached at about the same time. Erythrocytes likely represent a secondary depot of distribution. The average Vd is between 63 and 276 L.

Metabolism

Metformin is excreted unchanged by the kidneys, undergoes very little metabolism, no metabolites have been identified.

Elimination

After oral administration of the drug, 20-30% of the unabsorbed substance is excreted through the intestine. Renal clearance of metformin is more than 400 ml/min, indicating excretion of metformin by active glomerular filtration and tubular secretion. After oral administration, the T1/2 is about 6.5 h.

In impaired renal function, cumulation of the drug is possible, which leads to increased plasma concentrations of metformin.

Patient special groups

Patients with impaired renal function. The data available in patients with moderate renal impairment are sparse and do not allow a reliable assessment of the systemic effects of metformin in this subgroup, as can be done in those with normal renal function.

Patients in pediatric patients. After a single administration of metformin at a dose of 500 mg, pediatric patients showed a pharmacokinetic profile similar to that observed in healthy adults. After a repeated use of metformin in dose of 500 mg 2 times per day for 7 days in children Cmax and AUC0-t were decreased by approximately 33% and 40%, respectively, compared to the values of these parameters in adult patients with diabetes who received metformin in dosage of 500 mg 2 times per day for 14 days. Since the dose of the drug is adjusted individually depending on the level of glycemia, these data have limited clinical relevance.

Indications

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

Active ingredient

How to take, the dosage

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 Zentiva should be taken daily, without interruption. Patients should tell their physician if they stop taking it.

Adults

Monotherapy and combination therapy in combination with other oral hypoglycemic agents

The starting dose is usually 500 mg or 850 mg 2-3 times daily after or with a meal. Further gradual increase of the dose depending on the blood glucose concentration is possible.

After 10-15 days of use, the dose should be adjusted taking into account the results of plasma glucose concentration measurements. Slowly increasing the dose may improve tolerability in the gastrointestinal tract.

The 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 may be switched from 500 mg metformin tablets to 1000 mg metformin tablets. The maximum recommended dose is 3000 mg/day divided into 3 doses.

If planning to switch from another hypoglycemic drug: the other drug should be discontinued and Metformin Zentiva should be started at the dose stated above.

Combination with insulin

To achieve better blood glucose control, metformin and insulin can be used as a combination therapy. The starting dose of Metformin Zentiva is usually 500 mg or 850 mg 2-3 times daily, while the dose of insulin is adjusted based on blood glucose concentrations.

Patients with impaired renal function

Metformin can be used in patients with moderate renal function impairment (BK 45-59 ml/min, SCF 45-59 ml/min/1.73 m2 body surface area) only in the absence of other conditions that may increase the risk of lactate acidosis and under the following dose adjustment conditions: the starting dose of Metformin Zentiva is 500 mg or 850 mg once daily.

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

If CK<45 mL/min or SCFR<45 mL/min/1.73 m2 body surface area, Metformin Zentiva should be stopped immediately.

Elderly patients

Because of the possible impairment of renal function, the dose of Metformin Zentiva in elderly patients should be adjusted with regular monitoring of renal function parameters (serum creatinine concentration should be determined at least 2-4 times per year).

In children and adolescents

In children aged 10 years and older, Metformin Zentiva can be used both as monotherapy and in combination with insulin. The starting dose is usually 500 mg or 850 mg once daily after or with a meal. After 10-15 days, the dose should be adjusted on the basis of blood glucose values. The maximum daily dose is 2000 mg divided into 2-3 doses.

Interaction

Contraindicated combinations

Iodine-containing radiopaque agents

Iodine-containing radiopaque agents intravascular administration may lead to functional renal failure, thereby increasing metformin cumulation and risk of lactate acidosis. In patients with a GFR>60 ml/min/1.73 m2 body surface area, metformin should be discontinued before or during the x-ray examination and should not be restarted within 48 h after the examination, provided normal renal function is confirmed. In patients with moderate renal impairment (GFR 45-60 ml/min/1.73 m2), metformin should be stopped 48 hours before the administration of the iodine contrast agent and not resumed until 48 hours after the examination and only after reassessment of renal function with no signs of impairment.

Unrecommended combinations

Alcohol

In acute alcohol intoxication increases the risk of lactate acidosis, especially in cases of starvation or malnutrition, low-fat diet or liver failure. Alcohol and medicinal products containing ethanol should be avoided while taking the drug.

Combinations requiring caution

Danazol

The concomitant administration of danazol is not recommended to avoid the hyperglycemic effects of the latter. If treatment with danazololol is necessary and after discontinuation of the latter, correction of the metformin dose is required with monitoring of blood glucose concentrations.

Chlorpromazine

Chlorpromazine at high doses (100 mg/day) increases blood glucose concentration, reducing insulin release. When treated with neuroleptics and after discontinuation of these drugs, metformin dose adjustment is required with monitoring of blood glucose concentrations.

GCSs

Systemic and topical GCSs decrease glucose tolerance and increase blood glucose concentrations, sometimes causing ketosis. Metformin dose adjustment is required during treatment with GCS and after discontinuation of GCS under control of blood glucose concentration.

Diuretics (especially “loop diuretics”)

The simultaneous use of “loop diuretics” may lead to lactate acidosis due to possible functional renal failure. Metformin should not be administered to patients with a CK below 60 mL/min.

Beta2-adrenomimetics in the form of injection

Beta2-adrenomimetics increase blood glucose concentration due to stimulation of β2-adrenoreceptors. In this case it is advisable to carry out regular monitoring of blood glucose concentration. If necessary, administration of insulin is recommended.

In case of concomitant use of the above drugs, the dose of metformin may be adjusted during treatment or after discontinuation.

Hypotensive drugs, with the exception of ACE inhibitors, may alter blood glucose concentrations. The dose of metformin should be adjusted if necessary.

Sulfonylurea derivatives, insulin and acarbose

The simultaneous use of metformin may cause hypoglycemia.

Salicylates

Simultaneous use with metformin may cause hypoglycemia.

Nifedipine

Adds absorption and increases Cmax of metformin.

Cationic drugs

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

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

Levothyroxine may decrease the hypoglycemic effect of metformin. Monitoring of blood glucose concentrations is recommended, especially during initiation or discontinuation of thyroid hormone therapy, and the dose of metformin should be adjusted if necessary.

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

Propranolol, ibuprofen

In healthy volunteers in studies of single administration of metformin and propranolol and metformin and ibuprofen no changes in their pharmacokinetic parameters were observed.

Metformin may decrease the therapeutic effect of the anticoagulant phenprocoumon. Close monitoring of MHO is recommended when used together.

Special Instructions

Lactate acidosis

Lactate acidosis is a rare, but serious (high mortality in the absence of immediate treatment), metabolic complication that can occur due to metformin cumulation. There are reports of cases of lactate acidosis on 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 may be impaired, such as in case of dehydration (severe diarrhea or vomiting) or at the beginning of hypotensive therapy or therapy with diuretics (especially “loop” diuretics), as well as at the beginning of NSAID therapy. Therapy with Metformin Zentiva should be temporarily discontinued in case of these acute conditions.

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

The risk of lactate acidosis should be considered if nonspecific signs such as muscle cramps, dyspeptic disorders, abdominal pain and marked asthenia occur. Patients should be instructed to inform their physician immediately of the occurrence of these symptoms, especially if the patient has previously tolerated metformin therapy well. In this case, therapy with Metformin Zentiva should be discontinued, at least temporarily, until the situation is clarified. Resumption of therapy should be considered on an individual basis, taking into account the benefit/risk ratio, as well as the renal function status of the patient.

Diagnosis: lactate acidosis is characterized by acidotic dyspnea, abdominal pain, hypothermia followed by coma. Laboratory indicators include: decreased blood pH (less than 7.25), plasma lactic acid concentrations above 5 mmol/L, and elevated anion gap and lactate/pyruvate ratios. If metabolic acidosis is suspected, metformin administration should be discontinued and the patient should be hospitalized immediately.

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

Surgical surgeries

The drug Metformin Zentiva should be discontinued 48 hours before a planned surgical procedure under anesthesia, spinal or peridural anesthesia. Therapy can be resumed at least 48 hours after surgery or after restoration of food intake and only if renal function is normal.

Because metformin is excreted by the kidneys. metformin is excreted by the kidneys, the CKG should be monitored before therapy and at regular intervals thereafter:

Metformin Zentiva is contraindicated in IQ<45 ml/min (GFR<45 ml/min/1.73m2 body surface area).

Deterioration of renal function in elderly patients is often asymptomatic.

Particular caution should be exercised when renal function may be impaired in cases of dehydration or when concomitant use of hypotensive drugs, diuretics (especially loop diuretics) or NSAIDs. In these cases, it is also recommended to check renal function 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 may be used with regular monitoring of heart and renal function.

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

Reproductive function

Metformin had no effect on 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 daily dose in humans based on body surface area comparison.

Children and adolescents

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

In controlled clinical trials lasting one year, no effect of metformin on growth and puberty in children was found. However, due to the lack of long-term data, it is recommended that metformin’s subsequent effect on these parameters be closely monitored in children taking Metformin Zentiva, especially in children aged 10-12 years.

Other precautions

Contraindications

Side effects

The following side effects are possible with metformin, which are divided into systemic organ classes according to the MedDRA classification. Definition of side effect frequency according to WHO classification: very common (≥10%); common (≥1% and <10%); infrequent (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency is unknown (according to available data it is impossible to determine the frequency of side effect).

Blood and lymphatic system disorders: frequency unknown – hemolytic anemia.

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

Nervous system disorders: frequent – distortion of taste sensation; frequency unknown – encephalopathy.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These undesirable effects most often occur at the beginning of therapy and in most cases resolve on their own. To prevent their occurrence, it is recommended that the daily dose of metformin be taken in 2 or 3 doses during or after meals. Slowly increasing the dose of the drug may improve tolerability on the gastrointestinal side.

Skin and subcutaneous tissue disorders: very rare – erythema, pruritus, urticaria; frequency unknown – photosensitization.

Hepatic and biliary tract disorders: very rare – increased liver transaminase activity or hepatitis, which disappear after discontinuation of the drug.

Impact on the results of laboratory and instrumental studies: the frequency is unknown – decreased plasma concentration of TSH in patients with hypothyroidism, hypomagnesemia with diarrhea.

Children and adolescents

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

Overdose

Symptoms: when used in a dose of 85 g (42.5 times the maximum daily dose) the development of hypoglycemia has not been observed. In case of metformin overdose, lactate acidosis is possible. Lactate acidosis is an emergency condition and requires inpatient treatment. Lactate acidosis may also be caused by cumulation of the drug due to renal dysfunction.

The early symptoms of lactate acidosis are nausea, vomiting, diarrhea, decreased body temperature, abdominal pain, muscle pain; later, rapid breathing, dizziness, impaired consciousness and development of coma may occur.

In case of metformin overdose, pancreatitis may occur.

Treatment: if signs of lactate acidosis occur, metformin treatment should be stopped immediately, the patient should be hospitalized urgently, plasma lactic acid concentration should be determined and the diagnosis confirmed. The most effective procedure for excretion of lactic acid and metformin is hemodialysis. Symptomatic treatment is also carried out.

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