Glucovans tablets p/o 500mg/5mg №15×2

Name Glyukovans tabl p / film.ob. 500mg/5mg in bl. in pack. №15х2 ManufacturerAcino Pharma AG Switzerland Plant manufacturerMerk Sante s.a.s. (Merck Sante sas) Center de Production Semoy, 2 rue du Pressoir Vert, 45400 Semoy, France Center de Production Semoy, 2 rue du Pressoir Vert, 45400 Semoy, France Country of originFrance Main active ingredient Metformin + glibenclamide Release formFilm-coated tablets Prescription drug doctor Pharmacological actionGlucovance® is a fixed combination of two oral hypoglycemic agents of different pharmacological groups: metformin and glibenclamide. Pharmacodynamics Metformin belongs to the group of biguanides and reduces the content of both basal and postprandial glucose in blood plasma. It does not stimulate insulin secretion and therefore does not cause hypoglycemia. The action of metformin may be due to 3 mechanisms: (1) a decrease in glucose production by the liver due to inhibition of gluconeogenesis and glycogenolysis; (2) increased sensitivity of peripheral receptors to insulin, uptake and utilization of glucose by muscle cells; (3) delaying the absorption of glucose in the gastrointestinal tract. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters. In humans, regardless of the effect on the level of glycemia, metformin has a beneficial effect on lipid metabolism. This has been demonstrated at therapeutic doses in controlled, medium- or long-term clinical studies: Metformin lowered total cholesterol, low-density lipoprotein (LDL) and triglycerides. In the course of clinical studies conducted to date, such a beneficial effect on lipid metabolism has not been shown when taking a combination of metformin and glibenclamide. Glibenclamide belongs to the group of second generation sulfonylurea derivatives with an average half-life: it leads to a decrease in glucose levels as a result of stimulation of insulin secretion by the pancreas. This effect depends on the presence of functioning ?-cells in the islets of Langerhans. Of great importance is the stimulation of insulin secretion by glibenclamide as a result of food intake. The use of glibenclamide in diabetics leads to an increase in the postprandial insulin-stimulating response. The increased postprandial response in the form of insulin and C-peptide secretion becomes permanent after at least 6 months of treatment. Metformin and glibenclamide have different mechanisms of action, but complement each other’s hypoglycemic activity. Glibenclamide stimulates insulin production by the pancreas, while metformin reduces cellular resistance to insulin by acting on peripheral (skeletal muscle) and hepatic insulin sensitivity. The results obtained in controlled double-blind clinical trials compared with reference drugs in the treatment of patients with type II diabetes mellitus, inadequately controlled by monotherapy with metformin or glibenclamide in combination with diet and exercise, demonstrated that the combined use had an additional effect on glucose regulation . Pediatric Patients In a 26-week, actively controlled, double-blind clinical trial that included 167 children aged 9 to 16 years with type II diabetes mellitus inadequately controlled by diet and exercise, with or without oral medication, the fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not more effective than metformin hydrochloride or glibenclamide alone in reducing HbAlc from baseline. Therefore, Glucovance should not be used in children. Combination Pharmacokinetics The combination of metformin and glibenclamide in a single dosage form has the same bioavailability as when taking tablets containing metformin or glibenclamide separately. Food intake does not affect the bioavailability of metformin in combination with glibenclamide. It also does not affect the bioavailability of glibenclamide, but the rate of absorption of glibenclamide during meals increases. Associated with Metformin Absorption: After ingestion of metformin tablets, the maximum plasma concentration (Cmax) is reached after about 2.5 hours (tmax). The absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After oral administration, approximately 20-30% is excreted through the gastrointestinal tract unchanged. When administered orally, metformin absorption is saturable and incomplete. It is believed that the pharmacokinetics of metformin absorption is not linear. When taking the usual doses of metformin and the usual dosing regimen, a stable level of plasma concentration is reached after 24-48 hours and is generally less than 1 g / ml. In controlled clinical studies, the maximum level of metformin in blood plasma (Cmax) did not exceed 5 μg / ml, even when taking maximum doses. Distribution: Practically does not bind to plasma proteins. Metformin breaks down in erythrocytes. The peak concentration in the blood is lower than in plasma, and occurs at about the same time. Red blood cells during distribution mainly act as a secondary compartment. The mean volume of distribution ranges from 63 to 276 liters. Biotransformation: Metformin is excreted in the urine unchanged. No metabolites have been found in the human body. Excretion: Renal clearance of metformin is >400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the terminal elimination half-life is approximately 6.5 hours. With impaired renal function, renal clearance decreases, as well as creatinine clearance, while the half-life increases, which leads to an increase in the concentration of metformin in blood plasma. Glibenclamide Associated Absorption: Glibenclamide is very well absorbed (>95%) from oral administration. Peak plasma concentration is reached within 4 hours. Distribution: Glibenclamide is highly bound to plasma albumin (99%), which may lead to some drug interactions. Biotransformation: Glibenclamide is completely metabolized in the liver with the formation of two metabolites. Liver failure reduces the metabolism of glibenclamide and, accordingly, slows down its excretion. Withdrawal: Glibenclamide is excreted as metabolites through the biliary tract (60%) and in the urine (40%), excretion is completed within 45-72 hours. The terminal elimination half-life is 4-11 hours. Biliary excretion of metabolites increases in case of renal insufficiency, in accordance with the severity of renal impairment until creatinine clearance reaches 30 ml / min. Thus, the elimination of glibenclamide is independent of the presence of renal insufficiency as long as the creatinine clearance remains above 30 ml/min. Pediatric patients There were no differences in the pharmacokinetics of glibenclamide and metformin between children and healthy adults of the corresponding weight and gender. Indications for use Adult type II diabetes mellitus to replace previous two-drug therapy (metformin and a sulfonylurea derivative) in patients with stable and well-controlled glycemic levels. Use during pregnancy and lactation Pregnancy There are no preclinical and clinical data on the use of the combination of metformin and glibenclamide during pregnancy. Diabetes risk Uncontrolled diabetes (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. Diabetes should be controlled as much as possible throughout the gestation period in order to reduce the risk of congenital anomalies. The risk associated with the use of metformin In animal studies, no negative effects on the course of pregnancy and childbirth, embryonic and fetal development, postnatal development have been identified. Limited data on the use of metformin during pregnancy do not indicate an increased risk of congenital anomalies. Risk associated with the use of glibenclamide Animal studies have not shown a teratogenic effect. Due to the lack of teratogenicity in animals, the development of fetal malformations when used in humans is not expected, since substances known to cause malformations in humans have been found to have teratogenic activity in two species of animals to date. . In clinical practice, there are currently no data that could be used in assessing the potential risk of developing malformations or fetotoxicity in connection with the use of glibenclamide during pregnancy. Treatment Adequate control of blood glucose levels allows pregnancy in this category of patients to proceed normally. Glucovans® should not be used to treat diabetes during pregnancy. It is important that insulin be used during pregnancy to achieve adequate blood glucose control. It is recommended to transfer the patient from taking oral hypoglycemic drugs to taking insulin during pregnancy planning or during the pregnancy itself. It is recommended to monitor the level of glucose in the blood of newborns. Breastfeeding Metformin is excreted in breast milk. When using metformin, no adverse reactions were observed in newborns / infants who were breastfed or in mothers. However, due to the lack of data on the penetration of glibenclamide into human milk and due to the risk of neonatal hypoglycemia, the use of this drug during breastfeeding is contraindicated. Fertility Reproductive function in female and male rats was not affected by metformin at a dose of 600 mg/kg/day, which is approximately three times the maximum recommended daily dose based on body surface area. The reproductive function of female and male rats was not affected by oral administration of glibenclamide at doses of 100 and 300 mg/kg/day. Precautions Lactic acidosis Lactic acidosis is an extremely rare but serious (high mortality in the absence of emergency treatment) complication that can occur due to the accumulation of metformin. Cases of lactic acidosis in patients treated with metformin occurred mainly in patients with diabetes mellitus with severe renal insufficiency. The incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, alcoholism, liver failure, and any condition associated with severe hypoxia. Diagnosis: The risk of developing lactic acidosis should be taken into account when non-specific signs appear, such as muscle cramps, accompanied by dyspeptic disorders, abdominal pain and severe weakness. This condition may be accompanied by acidotic dyspnea, abdominal pain, hypothermia, and coma. Diagnostic laboratory parameters are: low blood pH, plasma lactate concentration above 5 mmol/l, increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, this drug should be discontinued and the patient should be hospitalized immediately (see section “Overdose”). Hypoglycemia Since Glucovance® contains a sulfonylurea derivative, its use is accompanied by the risk of hypoglycemia in the patient. Gradual dose titration after the start of treatment may prevent the occurrence of hypoglycemia. This treatment can only be prescribed to a patient who adheres to a regular meal regimen (including breakfast). It is important that carbohydrate intake is regular, as the risk of developing hypoglycemia increases with late meals, insufficient or unbalanced carbohydrate intake. The development of hypoglycemia is most likely with a low-calorie diet, after intense or prolonged physical activity, when drinking alcohol, or when taking a combination of hypoglycemic agents. Diagnosis: Other symptoms of hypoglycemia in patients with diabetes mellitus may be headache, hunger, nausea, vomiting, severe fatigue, sleep disorders, agitation, aggression, impaired concentration and psychomotor reactions, depression, confusion, speech impairment, visual impairment, trembling , paralysis and paresthesia, dizziness, delirium, convulsions, drowsiness, unconsciousness, shallow breathing and bradycardia. As a result of compensatory reactions caused by hypoglycemia, sweating, fear, tachycardia, hypertension, palpitations, angina pectoris and arrhythmia may occur. The latter symptoms may be absent if hypoglycemia develops slowly, in the case of autonomic neuropathy, or while taking β-blockers, clonidine, reserpine, guanethidine, or sympathomimetics. Treatment of hypoglycemia: Moderate symptoms of hypoglycemia without loss of consciousness or neurological symptoms should be corrected by immediate intake of sugar. Changes in dosage selection and/or food intake should be made. Severe hypoglycemic reactions accompanied by coma, seizures, or other neurological manifestations are also possible and require immediate intravenous administration of glucose as soon as the diagnosis is made or if it is suspected, before immediate hospitalization of the patient. Careful patient selection, dose selection, and proper patient instructions are important to reduce the risk of hypoglycemia. If the patient has recurring episodes of hypoglycemia that are either severe or associated with unawareness of the symptoms, treatment with other hypoglycemic agents should be considered. Factors contributing to the development of hypoglycemia: concomitant use of alcohol, especially during fasting, refusal or (especially for older patients) inability of the patient to interact with the doctor and follow the recommendations outlined in the instructions for use, poor nutrition, irregular meals, skipping meals, fasting or changes in diet, imbalance between physical activity and carbohydrate intake, renal failure, severe liver failure, overdose of Glucovance®, individual endocrine disorders: thyroid, pituitary and adrenal insufficiency, simultaneous administration of certain drugs (see section “Interaction with other medicinal products). Renal and hepatic insufficiency: Pharmacokinetics and / or pharmacodynamics may change in patients with hepatic insufficiency or severe renal insufficiency. The hypoglycemia that occurs in such patients can be prolonged, in which case appropriate treatment should be initiated. Elderly patients: Age 65 years or older is considered a risk factor for the development of hypoglycemia in patients treated with sulfonylurea derivatives. Diagnosis of hypoglycemia in elderly patients is difficult. The initial and maintenance dose of glibenclamide should be carefully selected to reduce the risk of hypoglycemia (see section “Method of application and dosage”). Information for the Patient: Information about the risk of hypoglycemia, its symptoms and treatment, as well as its pre-existing conditions, should be explained to the patient and his or her family. You should also take into account the risk of developing lactic acidosis with the appearance of non-specific signs such as muscle cramps, accompanied by dyspeptic disorders, abdominal pain and severe weakness, acidotic dyspnea, hypothermia and coma. In particular, the patient should be informed of the importance of following a diet, following a program of regular exercise, and regularly measuring glycemic levels. Instability of blood glucose In case of surgery or other cause of diabetes decompensation, it is recommended to consider a temporary transition to insulin therapy. Symptoms of hyperglycemia are frequent urination, severe thirst, dry skin. Renal function Since metformin is excreted by the kidneys, before starting treatment, and regularly thereafter, it is necessary to determine creatinine clearance and / or serum creatinine using the Cockcroft-Gault formula: at least once a year in patients with normal renal function, from 2 to 4 times a year in elderly patients, as well as in patients with creatinine clearance at the lower limit of normal. Decreased renal function in elderly patients is common and asymptomatic. Particular caution is advised in cases where renal function may be impaired, such as in elderly patients, or if antihypertensive therapy, diuretics or non-steroidal anti-inflammatory drugs (NSAIDs) are started. Use of iodine-containing radiopaque agents Intravascular administration of iodine-containing radiopaque agents during radiological examinations can lead to renal failure. This can lead to accumulation of metformin and lead to the development of lactic acidosis. Depending on the state of kidney function, 48 hours before the examination or at the time of the examination, Glucovance® should be discontinued. Treatment is recommended to be resumed no earlier than 48 hours later, and only after kidney function has been assessed and found to be normal (see section “Interaction with other drugs”). Co-administration of glibenclamide with other medicinal products Co-administration of glibenclamide with alcohol, phenylbutazone and danazol is not recommended (see section “Interaction with other medicinal products”). Surgical interventions Because Glucovance® contains metformin hydrochloride, the drug should be discontinued 48 hours before a planned surgical intervention with general, spinal or epidural anesthesia and should not be resumed earlier than 48 hours after the intervention or oral nutrition and only after kidney function has been assessed and found to be normal. Other Precautions All patients should continue to follow a diet with a regular distribution of carbohydrate intake throughout the day. Overweight patients should follow a hypocaloric diet. Regular physical activity is essential while taking Glucovance®. Routine laboratory tests to control diabetes (glycemia, HbAlc) should be performed regularly. Treatment of patients with G6PD deficiency with sulfonylurea derivatives can lead to hemolytic anemia. Since glibenclamide belongs to the class of sulfonylurea derivatives, caution should be exercised when taking Glucovans® in patients with G6PD deficiency, and an alternative treatment option with non-sulfonylurea drugs may also be considered. Glucovance® contains lactose, therefore its use is not recommended in patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome. Interaction with other drugs: Contraindicated combinations Associated with the use of glibenclamide Miconazole (systemic use, oral gel): Increased hypoglycemic effect with the possible development of hypoglycemia and even coma (see section “Contraindications”). Combinations that are not recommended Associated with the use of sulfonylurea derivatives Alcohol: An antabuse reaction (alcohol intolerance) is very rarely observed with the simultaneous use of alcohol and glibenclamide. Strengthening the hypoglycemic effect (by inhibiting compensatory reactions), which may contribute to the development of hypoglycemic coma (see section “Precautions”). During the period of treatment with Glucovance®, alcohol and medicines containing alcohol should be avoided. Phenylbutazone (systemic use): Increases the hypoglycemic effect of sulfonylurea derivatives (replacing sulfonylurea derivatives at protein binding sites and / or reducing their elimination). It is preferable to use other anti-inflammatory drugs that show less interactions, or to warn the patient about the need for self-monitoring of glycemic levels; if necessary, the dose should be adjusted when the anti-inflammatory agent is used together and after its termination. Associated with the use of all hypoglycemic agents Danazol: If concomitant use is necessary, the patient should be warned about the implementation of mandatory self-monitoring of blood glucose levels. With the simultaneous use of danazol and after its termination, if possible, the dose of the hypoglycemic agent should be adjusted. Associated with the use of metformin Alcohol: The risk of developing lactic acidosis is increased in acute alcohol intoxication, especially in case of fasting (see Precautions section), or poor nutrition, or liver failure. During the period of treatment with Glucovance®, alcohol and medicines containing alcohol should be avoided. Combinations requiring caution Associated with the use of all hypoglycemic agents Chlorpromazine: In high doses (100 mg chlorpromazine per day) causes an increase in blood glucose levels (decrease in insulin release). Precautions: the patient should be warned about the need for self-monitoring of blood glucose. If possible, the dose of the hypoglycemic agent should be adjusted during the simultaneous use of an antipsychotic and after stopping its use. Corticosteroids (glucocorticosteroids) and tetracosactide (systemic and topical): An increase in blood glucose, sometimes accompanied by ketosis (corticosteroids cause a decrease in glucose tolerance). Precautions: the patient should be warned about the need for self-monitoring of blood glucose. If possible, the dose of the hypoglycemic agent should be adjusted during concomitant use of corticosteroids and after discontinuation of their use. α2-adrenergic agonists: Increased blood glucose concentration due to stimulation of α2-adrenergic receptors. Precautions: it is necessary to warn the patient and establish control of blood glucose levels, transfer to insulin therapy is possible. Angiotensin-converting enzyme (ACE) inhibitors (eg captopril, enalapril): The use of ACE inhibitors helps to lower blood glucose levels. If necessary, the dose of Glucovance® should be adjusted during concomitant use with ACE inhibitors and after discontinuation of their use. Metformin Associated Diuretics: Lactic acidosis associated with metformin in the presence of diuretic-induced functional renal failure, especially loop diuretics. Iodine-containing radiocontrast agents: Intravascular administration of iodine-containing contrast agents can lead to the development of renal failure. This can cause the accumulation of metformin and the development of lactic acidosis. Treatment with Glucovance should be discontinued, depending on renal function, 48 hours before or at the time of the study and not resumed earlier than 48 hours after, provided that during the study, renal function was found to be normal. Organic Cation Transporters (OCTs): Metformin is a substrate for two types of transporters, OCT1 and OCT2. Co-administration of metformin with: OCT1 substrates/inhibitors (such as verapamil) may reduce the effectiveness of metformin; OCT1 inducers (such as rifampicin) may increase its absorption in the gastrointestinal tract and thereby increase its effectiveness. OCT2 substrates/inhibitors (such as cimetidine, dolutegravir, crizotinib, olaparib, daclatasvir, vandetanib) may decrease renal excretion of metformin and thus lead to an increase in plasma metformin concentrations. Therefore, caution is advised when coadministering these medicinal products with metformin, and consideration should be given to dose adjustments, especially in patients with renal insufficiency. Glibenclamide-associated ?-blockers: All ?-blockers mask some of the symptoms of hypoglycemia: palpitations and tachycardia; most non-selective ?-blockers increase the incidence and severity of hypoglycemia. The patient should be warned about the need for self-monitoring of blood glucose, especially at the beginning of treatment. Fluconazole: Increased half-life of sulfonylurea with possible manifestations of hypoglycemia. The patient should be warned about the need for self-monitoring of blood glucose; dose adjustment of hypoglycemic drugs may be required during concomitant treatment with fluconazole and after discontinuation of its use. Bosentan: Bosentan reduces the concentration of glibenclamide in the blood, thereby increasing the risk of reducing the hypoglycemic effect of glibenclamide. In patients receiving glibenclamide and bosentan at the same time, an increase in the level of liver enzymes was noted. It is necessary to warn the patient, establish constant monitoring of the level of glycemia and liver enzymes in the blood, and, if necessary, also adjust the dose of hypoglycemic drugs. Means that promote the excretion of bile acids: When used together, the concentration of glibenclamide in plasma decreases, which can lead to a decrease in the hypoglycemic effect. This effect was not observed when taking glibenclamide for a certain period of time before taking another drug. Glucovans® is recommended to be taken at least 4 hours before taking a bile acid eliminator. Other interactions: combinations to be considered: Associated with the use of glibenclamide Desmopressin: Decreased antidiuretic effect. Contraindications hypersensitivity to metformin, glibenclamide or other sulfonylurea derivatives and sulfonamides, as well as to excipients (see section “Composition”); type I diabetes mellitus (insulin-dependent diabetes), diabetic precoma; metabolic acidosis of any type (lactic acidosis, diabetic ketoacidosis); renal failure or impaired renal function (creatinine clearance less than 60 ml / min); acute conditions that can lead to a change in kidney function: dehydration, severe infection, shock; acute or chronic diseases that are accompanied by tissue hypoxia: heart or respiratory failure, recent myocardial infarction, shock; liver failure, chronic alcoholism, acute alcohol intoxication; porphyria; breastfeeding period; concomitant use of miconazole (see section “Interaction with other drugs”). Composition 1 film-coated tablet contains: Dosage 500 mg/5 mg: Active ingredients: metformin hydrochloride – 500 mg, glibenclamide – 5 mg. Auxiliary components: Core: croscarmellose sodium – 14.0 mg, povidone K 30 – 20.0 mg, microcrystalline cellulose – 54.0 mg, magnesium stearate – 7.0 mg. Shell: Opadry 31-F-22700 yellow – 12.0 mg: lactose monohydrate – 36.0%, hypromellose 15 cP – 28.0%, titanium dioxide – 20.42%, macrogol – 10.00%, dye quinoline yellow – 3.00%, yellow iron oxide – 2.50%, red iron oxide – 0.08%; purified water – qs Dosage and administration Dose selection Glucovance® is intended for oral administration. For use in adult patients only. General information: The dose of the drug is determined by the doctor individually for each patient, depending on the individual metabolic response (glycemia level, HbAlc). Initiation of treatment: The initial dose of the combination should not exceed the daily dose of glibenclamide or metformin previously used; the dose of the drug is gradually increased depending on the level of glycemia. Dose titration: Depending on the level of glycemia, every 2 or more weeks after the start of treatment, the dose of the drug is adjusted by increasing the number of tablets taken by 1 tablet. Gradually increasing the dose may promote gastrointestinal tolerance and prevent the development of hypoglycemia. Maximum recommended daily dose: The maximum recommended daily dose is 4 tablets of Glucovance® 500 mg/5 mg or 6 tablets of Glucovance® 500 mg/2.5 mg. Combination with insulin therapy There are no clinical data on the use of this medicinal product in combination with insulin therapy. Elderly patients Patients aged 65 years and older: The initial and maintenance dose of glibenclamide should be carefully selected to reduce the risk of hypoglycemia. Treatment should be initiated at the lowest available dose and increased gradually if necessary. Increasing the dose in such patients to the maximum possible is not recommended in order to avoid the risk of hypoglycemia. It is necessary to conduct a regular assessment of kidney function (see section “Precautions”). Pediatric patients: Glucovance® is not recommended for use in children (see Pharmacodynamics section). Dosing regimen The dosage regimen depends on the individual prescription: For dosages of 500 mg / 2.5 mg and 500 mg / 5 mg: Once a day, in the morning during breakfast, when prescribing 1 tablet per day. Twice a day, morning and evening, at the appointment of 2 or 4 tablets per day. For a dosage of 500 mg/2.5 mg: Three times a day, morning, afternoon and evening, when prescribed 3, 5 or 6 tablets per day. For a dosage of 500 mg/5 mg: Three times a day, morning, afternoon and evening, at the appointment of 3 tablets per day. The tablets should be taken with meals. The dosage regimen should be selected in accordance with individual preferences for food intake. However, each meal should be accompanied by a high carbohydrate meal to prevent hypoglycemia. When co-administered with drugs that promote the excretion of bile acids, Glucovance® is recommended to be taken at least 4 hours before taking these drugs in order to minimize the risk of reduced absorption (see section “Interaction with other drugs”). Overdose In case of overdose, hypoglycemia may develop due to the presence of a sulfonylurea derivative (see section “Precautions”). Long-term overdose or the presence of associated risk factors may provoke the development of lactic acidosis due to the presence of metformin in the composition (see section “Precautions”). Lactic acidosis is a medical emergency; treatment of lactic acidosis should be carried out in the clinic. The most effective treatment for removing lactate and metformin is hemodialysis. Plasma clearance of glibenclamide may be increased in patients with liver disease. Since glibenclamide actively binds to blood proteins, it is not eliminated during dialysis. Side effects At the beginning of treatment, the most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain and loss of appetite, which in most cases disappear on their own. In order to avoid the development of these adverse reactions, it is recommended to take the daily dose of Glucovance® in 2 or 3 doses during the day and gradually increase the dose. At the beginning of treatment, transient visual impairment may occur due to a decrease in blood glucose. During treatment with Glucovance®, the following adverse reactions may occur. The frequency of adverse reactions is regarded as follows: very often: ?1/10; often: ?1/100, <1/10; infrequently: ?1/1000, <1/100; rarely: ?1/10000, <1/1000; very rarely: <1/10000. Blood and lymphatic system disorders: These adverse reactions disappear after discontinuation of the drug. Rare: leukopenia, thrombocytopenia. Very rare: agranulocytosis, hemolytic anemia, bone marrow aplasia and pancytopenia. Metabolic and nutritional disorders: Hypoglycemia (see Precautions section). Uncommon: attacks of hepatic porphyria and cutaneous porphyria. Very rare: lactic acidosis (see Precautions section); a decrease in the absorption of vitamin B12, accompanied by a decrease in its concentration in the blood serum with prolonged use of metformin (if megaloblastic anemia is detected, the possibility of such an etiology must be taken into account); disulfiram-like reaction when drinking alcohol. Nervous system disorders: Often: taste disturbance. Visual disturbances At the beginning of treatment, transient visual impairment may occur due to a decrease in blood glucose. Gastrointestinal disorders: Very common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These symptoms are more common at the beginning of treatment and in most cases go away on their own. To prevent the development of these symptoms, it is recommended to take the drug in 2 or 3 doses; slowly increasing the dose of the drug also improves its tolerability. Skin and subcutaneous tissue disorders: Cross-reactivity to sulfonamides and their derivatives may occur. Rare: skin reactions such as pruritus, urticaria, maculopapular rash. Very rare: cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, urticaria up to the development of shock. Liver and biliary tract disorders: Very rare: abnormal liver function tests or hepatitis requiring discontinuation of treatment. Influence on the results of laboratory and instrumental studies: Infrequently: a moderate or moderate increase in serum urea and creatinine concentrations. Very rare: hyponatremia. Reporting Suspected Adverse Reactions It is important to report suspected adverse reactions after drug registration. This will allow continuous monitoring of the benefit-risk ratio of the medicinal product. If an adverse reaction occurs that is indicated in this package leaflet or not mentioned in it, patients are advised to contact their doctor. Medical professionals are encouraged to report any suspected adverse drug reactions to the Republican Unitary Enterprise "Center for Expertise and Testing in Health Care" (see section "Send information about adverse reactions to the address"). Storage conditions At temperatures not higher than