Vildagliptin + Metformin (Vildagliptinum + Metforminum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Hypoglycemic synthetic and other agents

Included in the formulation
  • Galvus Met
    pills inwards 
    Novartis Pharma AG     Switzerland
    • АТХ:

    A.10.B.D.08   Metformin and vildagliptin

    A.10.B.D   Combination of biguanides and sulfonylurea derivatives

    Pharmacodynamics:

    Combined oral hypoglycemic drug. The composition of the drug includes two hypoglycemic agents with different mechanisms of action: vildagliptin, belonging to the class of inhibitors of dipeptidyl peptidase-4, and metformin (in the form of hydrochloride), a representative of the biguanide class. CombInactivation of these components allows more effective control of the concentration of glucose in the blood in patients with type 2 diabetes mellitus within 24 hours.

    Vildagliptin

    Vildagliptin is a representative of the class of stimulants of the islet apparatus of the pancreas, selectively inhibits the enzyme dipeptidyl peptidase-4, which destroys the glucagon-like peptide of type 1 and the glucose-dependent insulinotropic polypeptide.

    Fast and complete inhibition of activity dipeptidyl peptidase-4 causes an increase in both basal and food-stimulated secretion glucagon-like peptide type 1 and a glucose-dependent insulinotropic polypeptide from the intestine to the systemic circulation throughout the day.

    Increasing concentration glucagon-like peptide type 1 and glucose-dependent insulinotropic polypeptide, vildagliptin causes an increase in the sensitivity of β-cells of the pancreas to glucose, which leads to an improvement in the glucose-dependent secretion of insulin. The degree of improvement in the function of β-cells depends on the degree of their initial damage; so, in individuals without diabetes mellitus (with a normal concentration of glucose in the blood plasma), vildagliptin does not stimulate the secretion of insulin and does not reduce the concentration of glucose.

    Increasing the concentration of endogenous glucagon-like peptide type 1 , vildagliptin increases the sensitivity of α-cells to glucose, which leads to an improvement in glucose-dependent regulation of glucagon secretion. Reducing the increased concentration of glucagon during meals, in turn, causes a decrease in insulin resistance.

    Increase in the ratio of insulin / glucagon to the background of hyperglycemia, due to increased concentration glucagon-like peptide type 1 and glucose-dependent insulinotropic polypeptide, causes a decrease in the production of glucose by the liver both during and after a meal, which leads to a decrease in the concentration of glucose in the blood plasma.

    In addition, against the background of the use of vildagliptin there was a decrease in the concentration of lipids in blood plasma after ingestion, but this effect is not related to its effect on glucagon-like peptide of type 1 or a glucose-dependent insulinotropic polypeptide and improvement of the function of islet cells of the pancreas.

    It is known that an increase in the concentration glucagon-like peptide type 1 can lead to a slowdown of gastric emptying, however, against the background of the use of vildagliptin, this effect is not observed.

    When using vildagliptin, a significant long-term decrease in the concentration of glycated hemoglobin (HbA) was observed in 5759 patients with type 2 diabetes for 52 weeks as monotherapy or in combination with metformin, sulfonylurea derivatives, thiazolidinedione, or insulin1c) and fasting blood glucose.

    Metformin

    Metformin improves glucose tolerance in patients with type 2 diabetes, reducing the concentration of glucose in the plasma both before and after meals. Metformin reduces the production of glucose by the liver, reduces the absorption of glucose in the intestine and reduces insulin resistance by enhancing the capture and utilization of glucose by peripheral tissues. In contrast to the sulfonylurea derivatives, metformin does not cause hypoglycemia in either patients with type 2 diabetes, nor in healthy individuals (except in special cases). The drug therapy does not lead to the development of hyperinsulinemia. When metformin is used, the secretion of insulin does not change, while the concentration of insulin in the blood plasma on an empty stomach and during the day can decrease.

    Metformin induces intracellular synthesis of glycogen, acting on glycogen synthase, and enhances the transport of glucose by some gluculin-transport membrane proteins (GLUT-1 and GLUT-4).

    When using metformin, a favorable effect on the metabolism of lipoproteins is noted: a decrease in the concentration of total cholesterol, cholesterol low density lipoprotein and triglycerides, not related to the effect of the drug on the concentration of glucose in the plasma.

    Vildagliptin + metformin

    When combined therapy with vildagliptin and metformin at daily doses of 1500-3000 mg of metformin and 50 mg of vildagliptin 2 times a day for 1 year, a statistically significant persistent decrease in blood glucose concentration was observed (determined by a decrease in HbA1c) and an increase in the proportion of patients who have a decrease in HbA1c was at least 0.6-0.7% (compared to the group of patients who continued to receive only metformin).

    In patients who received a combination of vildagliptin and metformin, there was no statistically significant change in body weight compared with the baseline. 24 weeks after the start of treatment in the groups of patients receiving vildagliptin in combination with metformin, there was a decrease in systolic and diastolic blood pressure in patients with arterial hypertension.

    When a combination of vildagliptin and metformin was used as an initial therapy for patients with type 2 diabetes mellitus, a dose-dependent decrease in HbA1c and body weight in comparison with the monotherapy of these drugs. The incidence of hypoglycemia was minimal in both treatment groups.

    When using vildagliptin (50 mg twice a day) together / without metformin in combination with insulin (mean dose 41 units) in patients in the clinical study, the HbA1c statistically significantly decreased - by 0.72% (the initial indicator - an average of 8.8%). The incidence of hypoglycemia in the treated group was comparable to the incidence of hypoglycemia in the placebo group.

    With the use of vildagliptin (50 mg 2 times a day) together with metformin (≥ 1500 mg) in combination with glimepiride (≥4 mg per day) in patients in the clinical study, the HbA1c statistically significantly decreased - by 0.76% (from the average level - 8.8%).

    Pharmacokinetics:

    In studies, bioequivalence is shown for AUC and Cmax of the drug at three different dosages (50 mg / 500 mg, 50 mg / 850 mg and 50 mg / 1000 mg) and vildagliptin and metformin taken at appropriate doses as separate tablets.

    Food does not affect the extent and rate of absorption of vildagliptin in the formulation. The values ​​of Cmax and AUC metformin in the composition of the drug with simultaneous intake with food decreased by 26% and 7%, respectively. In addition, against the background of food intake, metformin absorption was slowed, which led to an increase in Tmax (from 2 to 4 hours). A similar change in Cmax and AUC on the background of food intake was noted in the case of metformin separately, but in the latter case, the changes were less significant.

    The effect of food on the pharmacokinetics of vildagliptin and metformin in the formulation did not differ from that with both drugs alone.

    Indications:

    Diabetes mellitus type 2 (in combination with diet and exercise):

    - with insufficient effectiveness of monotherapy with vildagliptin or metformin;

    - in patients who previously received combination therapy with vildagliptin and metformin in the form of monopreparations;

    - in combination with sulfonylurea derivatives (triple combination therapy) in patients previously treated with sulfonylureas and metformin without adequate glycemic control;

    - as part of triple combination therapy with insulin in patients who had previously received insulin therapy at a stable dose and metformin without achieving adequate glycemic control;

    - as an initial therapy in patients with type 2 diabetes mellitus with insufficient effectiveness of diet therapy, physical exercises and the need to improve the control of glycemia.

    ICD-10

    IV.E10-E14.E11   Non-insulin-dependent diabetes mellitus

    Contraindications:

    - renal failure or renal dysfunction: at a serum creatinine level ≥ 1.5 mg% (> 135 μmol / l) for men and ≥ 1.4 mg% (> 110 μmol / L) for women;

    - acute conditions that occur with the risk of developing renal dysfunction: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxia conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);

    - acute and chronic heart failure, acute myocardial infarction, acute cardiovascular failure (shock);

    - respiratory insufficiency;

    - violations of the liver function;

    - Acute or chronic metabolic acidosis (including diabetic ketoacidosis in combination with or without coma). Diabetic ketoacidosis should be corrected by insulin therapy;

    - laktatsidoz (including in the anamnesis);

    - the drug is not prescribed for 2 days before surgical operations, radioisotope, X-ray studies with the introduction of contrast agents and within 2 days after their conduct;

    - Pregnancy;

    - lactation period;

    - Type 1 diabetes mellitus;

    - chronic alcoholism, acute alcohol poisoning;

    - compliance with the hypocaloric diet (less than 1000 kcal per day);

    - Children's age till 18 years (efficiency and safety of application is not established);

    - Hypersensitivity to vildagliptin or metformin or any other components of the drug.

    Since patients with impaired hepatic function in some cases had lactic acidosis, possibly one of the side effects of metformin, should not be used in patients with liver diseases or liver biochemical indices.

    Carefully:

    FROM caution It is recommended that preparations containing metformin, in patients older than 60 years, as well as in the performance of heavy physical work in connection with the increased risk of lactic acidosis.

    Pregnancy and lactation:

    In experimental studies with the appointment of vildagliptin at doses 200 times higher than recommended, the drug did not cause impairment of fertility and early development of the embryo and did not have a teratogenic effect on the fetus. When appointing vildagliptin in combination with metformin in a ratio of 1:10, there was also no teratogenic effect on the fetus.

    Since there are no sufficient data on the use of the drug in pregnant women, the use of the drug in pregnancy is contraindicated.

    In cases of impaired glucose metabolism, the risk of developing congenital anomalies, as well as the incidence of neonatal morbidity and mortality, is increasing in pregnant women. To normalize blood glucose levels during pregnancy, monotherapy with insulin is recommended.

    Since it is not known whether vildagliptin or metformin with human breast milk, the use of the drug in the period of breastfeeding is contraindicated.

    Dosing and Administration:

    The drug is used inside. Dosage regimen should be selected individually, depending on the effectiveness and tolerability. When using the drug, do not exceed the recommended maximum daily dose of vildagliptin (100 mg).

    The recommended initial dose of the drug should be selected, taking into account already used in the patient's regimens for treatment with vildagliptin and / or metformin. To reduce the severity of side effects from the digestive system, characteristic of metformin, taken with food.

    The initial dose of the drug with ineffectiveness of monotherapy with vildagliptin: treatment with the drug can begin with a single pill dosage of 50 mg / 500 mg 2 times a day, and after assessing the therapeutic effect of the dose can be gradually increased.

    The initial dose of the drug with ineffective monotherapy with metformin: depending on the dose of metformin already taken, treatment with the drug can begin with a single tablet with a dosage of 50 mg / 500 mg, 50 mg / 850 mg or 50 mg / 1000 mg 2 times a day.

    The initial dose of the drug in patients who previously received combination therapy with vildagliptin and metformin in the form of individual tablets: depending on the doses of vildagliptin or metformin already taken, the drug should be started with the tablet as close as possible to the existing treatment of 50 mg / 500 mg, 50 mg / 850 mg or 50 mg / 1000 mg, and titrated by the effect.

    The initial dose of the drug as an initial therapy in patients with type 2 diabetes mellitus with insufficient effectiveness of diet and exercise: as a starting therapy should be administered in an initial dose of 50 mg / 500 mg 1 time per day and after evaluating the therapeutic effect, titrate the dose gradually to 50 mg / 100 mg 2 times a day.

    Combination therapy with the preparation together with derivatives of sulfonylureas or insulin: the dose of the drug is calculated from a dose of vildagliptin 50 mg 2 times a day (100 mg per day) and metformin in a dose equal to that previously taken as a mono drug.

    The use of the drug is contraindicated in patients with renal insufficiency or with impaired renal function, with a serum creatinine concentration ≥ 1.5 mg% (> 135 μmol / L) for men and ≥ 1.4 mg% (> 110 μmol / L) for women.

    Metformin is excreted by the kidneys. Since y patients older than 65 years there is often a decrease in renal function, this drug is prescribed at the lowest dose that ensures the normalization of glucose concentration, only after determining the creatinine clearance to confirm normal kidney function. When using the drug in patients older than 65 years, it is necessary to regularly monitor the kidney function.

    Because the safety and efficacy of the drug children and adolescents under 18 years of age has not been studied, the use of the drug is contraindicated in this category of patients.

    Side effects:

    The data presented refer to the use of vildagliptin and metformin as a monotherapy and in combination.

    Determination of the incidence of adverse reactions: very often (≥ 1/10); often (≥ 1/100, <1/10); sometimes (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), including individual cases.

    Undesirable reactions, possibly associated with the use of combination therapy with vildagliptin and metformin (the incidence of which in the group vildagliptin + metformin differed from that on the background of the use of placebo and metformin by more than 2%) are presented below.

    From the nervous system: often - headache, dizziness, tremor.

    When vildagliptin was used in combination with metformin in various doses, hypoglycemia was noted in 0.9% of cases (for comparison in the placebo group in combination with metformin - in 0.4%).

    Frequency of adverse reactions from the digestive system against combined therapy, vildagliptin / metformin was 12.9%. In the use of metformin, such adverse events were noted in 18.1% of patients.

    In the groups of patients who received metformin in combination with vildagliptin, violations of the gastrointestinal tract were noted with a frequency of 10-15%, and in the group of patients who received metformin in combination with placebo, with a frequency of 18%.

    Long-term clinical trials of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin as monotherapy.

    The study of the use of a combination of vildagliptin and metformin as a starting therapy for type 2 diabetes did not reveal risks and additional safety data.

    When using vildagliptin together with insulin

    In controlled clinical trials with vildagliptin at a dose of 50 mg 2 times a day in combination with insulin in combination with or without metformin, the frequency of discontinuation of therapy due to adverse reactions was 0.3% in the vildagliptin group, with no placebo in the placebo group.

    The incidence of hypoglycemia was comparable in both groups (14% in the vildagliptin group and 16.4% in the placebo group). In the vildagliptin group, severe hypoglycemia was noted in 2 patients, in the placebo group in 6 patients.

    At the time of completion of the study, the drug had no effect on the average body weight (body weight was increased by 0.6 kg compared to the initial group in the vildagliptin group, and there was no change in the placebo group). Adverse events in patients who received vildagliptin in a dose of 50 mg 2 times a day in combination with insulin (with or without metformin) are presented below.

    From the nervous system: often - headache, chills.

    From the digestive system: often - nausea, gastroesophageal reflux; infrequent - diarrhea, flatulence.

    From the side of metabolism: often - hypoglycemia.

    When using vildagliptin in combination with sulfonylureas

    There were no cases of drug withdrawal associated with unwanted reactions in the combination therapy group of vildagliptin, metformin and glimepiride. In the group of combined placebo, metformin and glimepiride, the incidence of adverse reactions was 0.6%.

    Hypoglycemia was noted frequently in both groups (5.1% in the combination therapy group of vildagliptin, metformin and glimepiride and 1.9% in the placebo, metformin and glimepiride combination therapy group). In the vildagliptin group, 1 episode of severe hypoglycemia was noted.

    At the time of completion of the study, no significant effect on body weight was detected (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

    Undesirable reactions in patients who received vildagliptin 50 mg 2 times a day in combination with metformin and sulfonylureas are presented below.

    From the nervous system: often - dizziness, tremor.

    From the side of metabolism: often - hypoglycemia.

    From the skin and subcutaneous tissues: often hyperhidrosis.

    Common reactions: often fatigue.

    When using vildagliptin as a monotherapy

    From the nervous system: often - dizziness, headache.

    From the digestive system: often - constipation.

    From the skin and subcutaneous tissues: sometimes - a skin rash.

    From the musculoskeletal system: often - arthralgia.

    Common reactions: sometimes - peripheral edema.

    When combined therapy with vildagliptin and metformin was used, there was no clinically significant increase in the frequency of the above undesirable reactions observed with the use of vildagliptin.

    Against the background of monotherapy with vildagliptin or metformin, the incidence of hypoglycemia was 0.4%.

    Monotherapy with vildagliptin and combined treatment vildagliptin + metformin did not affect the patient's body weight.

    Long-term clinical trials of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin as monotherapy.

    Postmarketing research: during post-marketing studies, the following adverse reactions were identified: rarely - hepatitis(reversible upon discontinuation of therapy); frequency unknown - hives, pancreatitis, localized skin peeling, blisters.

    Changes in laboratory indicators: when using vildagliptin in a dose of 50 mg 1 time per day or 100 mg per day (in 1 or 2 doses) for 1 year, the frequency of increase in ALT and AST activity more than 3 times compared with the upper limit of the norm was 0.3% and 0.9%, respectively (0.3% in placebo group). Increased activity alanine aminotransferase and aspartate aminotransferase, as a rule, was asymptomatic, did not increase and was not accompanied by cholestasis or jaundice.

    When using metformin as a monotherapy

    From the side of metabolism: very rarely - reduced absorption of vitamin B12, lactic acidosis. Because the decrease in absorption of vitamin B12 and a decrease in its serum concentration against the background of metformin was observed very rarely in patients who received the drug for a long time, this undesirable phenomenon is not of clinical significance. Consider the possibility of reducing the absorption of vitamin B12 only in patients with megaloblastic anemia.

    From the digestive system: very often - nausea, vomiting, diarrhea, abdominal pain, loss of appetite; often a metallic taste in the mouth.

    From the liver and biliary tract: very rarely - violations of biochemical parameters of liver function. Individual cases of biochemical abnormalities of liver or hepatitis, which were observed against metformin, were resolved after the withdrawal of metformin.

    From the skin and subcutaneous tissue: very rarely - skin reactions (in particular erythema, pruritus, urticaria).

    Overdose:

    Vildagliptin

    Symptoms: well tolerated when administered at a dose of up to 200 mg per day. When using the drug at a dose of 400 mg per day, pain in the muscles can be observed, rarely - lungs and transient paresthesias, fever, edema and transient increase in lipase concentration (2 times higher than the upper limit of the norm). With an increase in the dose of vildagliptin up to 600 mg per day, edema of the limbs accompanied by paresthesia and an increase in the concentration of creatine kinase, aspartate aminotransferase, C-reactive protein and myoglobin. All symptoms of overdose and changes in laboratory parameters disappear after discontinuation of the drug.

    Treatment: the removal of the drug from the body by dialysis is unlikely.However, the main hydrolysis metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.

    Metformin

    Symptoms: Several cases of metformin overdose were noted, including as a result of ingestion of the drug in excess of 50 g. Metformin overdose in about 10% of cases showed hypoglycemia (however, its association with the drug is not established). In 32% of cases lactoacidosis was noted. The early symptoms of lactic acidosis are nausea, vomiting, diarrhea, lower body temperature, abdominal pain, muscle pain, there may be more rapid breathing, dizziness, impaired consciousness and coma development.

    Treatment: symptomatic, based on the state of the patient and clinical manifestations. It is excreted from the blood with the help of hemodialysis (with a clearance of up to 170 ml / min) without the development of hemodynamic disorders. Thus, hemodialysis can be used to remove metformin from the blood during an overdose of the drug.

    Interaction:

    Vildagliptin + Metformin

    With the simultaneous use of vildagliptin (100 mg once a day) and metformin (1000 mg once a day) there were no clinically significant pharmacokinetic interactions between them.Neither during clinical trials nor during extensive clinical use of the drug in patients receiving other concomitant drugs and substances, there were no unforeseen interactions.

    Vildagliptin

    Vildagliptin has a low potential for drug interaction. Because the vildagliptin is not a substrate of cytochrome P450 enzymes, nor does it inhibit or induce these enzymes, its interaction with drugs that are substrates, inhibitors or P450 inducers is unlikely. With simultaneous application vildagliptin does not affect the metabolic rate of drugs that are substrates of the enzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5.

    Clinically significant interaction of vildagliptin with the drugs most often used in the treatment of type 2 diabetes mellitus (glibenclamide, pioglitazone, metformin) or having a narrow therapeutic range (amlodipine, digoxin, ramipril, simvastatin, valsartan, warfarin), not installed.

    Metformin

    Furosemide increases Cmax and AUC metformin, but does not affect its renal clearance. Metformin reduces Cmax and AUC furosemide and also does not affect its renal clearance.

    Nifedipine increases absorption, Cmax and AUC metformin, in addition, it increases the excretion of it with urine. Metformin practically does not affect the pharmacokinetic parameters of nifedipine.

    Glibenclamide does not affect the pharmacokinetic / pharmacodynamic parameters of metformin. Metformin, as a whole, reduces Cmax and AUC of glibenclamide, however, the magnitude of the effect varies greatly. For this reason, the clinical significance of this interaction remains unclear.

    Organic cations, for example amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin and others, excreted by the kidneys through tubular secretion, can theoretically interact with metformin, as they compete for common kidney tubule transport systems. So, cimetidine increases both the concentration of metformin in plasma / blood, and its AUC - by 60 and 40%, respectively. Metformin does not affect the pharmacokinetic parameters of cimetidine. Care should be taken when using the drug together with drugs that affect kidney function or the distribution of metformin in the body.

    Other drugs. Some drugs can cause hyperglycemia and contribute to a decrease in the effectiveness of hypoglycemic agents. Such drugs include thiazides and other diuretics, glucocorticosteroids, phenothiazines, thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, a nicotinic acid, sympathomimetics, calcium antagonists and isoniazid. In the appointment of such concomitant medications, or, on the contrary, in the event of their withdrawal, it is recommended to carefully monitor the effectiveness of metformin (its hypoglycemic effect) and, if necessary, adjust the dose of the drug. It is not recommended simultaneous reception of danazol in order to avoid hyperglycemic action of the latter. If necessary, treatment with danazol and after stopping the latter requires a dose adjustment of metformin under the control of glucose concentration.

    Chlorpromazine: when taken in high doses (100 mg once a day) increases glycemia, reducing the release of insulin. When treating with neuroleptics and after stopping the intake of the latter, correction of the dose of the drug under the control of glucose concentration is required.

    Iodine-containing radiopaque agents: Radiological study using iodine-containing radiocontrast agents can cause the development of lactic acidosis in patients with diabetes mellitus on the background of functional renal failure.

    Injection β2-sympathomimetics: increase glycemia due to stimulation of β2receptors. In this case, it is necessary to control glycemia. If necessary, the appointment of insulin is recommended.

    With the simultaneous use of metformin with derivatives of sulfonylurea, insulin, acarbose, salicylates, hypoglycemic action may be increased.

    Since the use of metformin in patients with acute alcohol intoxication increases the risk of developing lactic acidosis (especially when fasting, exhaustion or liver failure), drug treatment should refrain from drinking alcohol and drugs containing ethyl alcohol.

    Special instructions:

    In patients receiving insulin, the drug can not replace insulin.

    Vildagliptin

    Dysfunction of the liver. Since the use of vildagliptin increases the activity of aminotransferases (as a rule,without clinical manifestations) was noted somewhat more often than in the control group, before prescribing the drug, and also regularly during the treatment with the drug it is recommended to determine the biochemical parameters of liver function. If the patient has an increased activity of aminotransferases, this result should be confirmed by a second study, and then regularly performed biochemical indices of liver function until they are normalized. If the activity is exceeded alanine aminotransferase or aspartate aminotransferase in 3 or more times above the upper limit of the norm is confirmed by repeated examination, it is recommended to cancel the drug.

    Metformin

    Lactic acidosis is a very rare but severe metabolic complication arising from the accumulation of metformin in the body. Lactic acidosis in patients with metformin was observed mainly in patients with diabetes mellitus with renal insufficiency of high severity. The risk of developing lactic acidosis is increased in patients with diabetes mellitus, which is difficult to treat, with ketoacidosis, prolonged starvation, long-term alcohol abuse, liver failure and diseases that cause hypoxia.

    With the development of lactic acidosis, shortness of breath, abdominal pain and hypothermia, followed by a coma. The following laboratory indicators are of diagnostic value: a decrease in blood pH, a serum lactate concentration above 5 nmol / L, and an increased anion interval and an increased lactate / pyruvate ratio. When suspected of metabolic acidosis, the drug should be discontinued and the patient immediately hospitalized.

    Control of kidney function. Because the metformin is largely excreted by the kidneys, the risk of its accumulation and the development of lactic acidosis is higher the more the renal function is impaired. When using the drug should regularly assess the renal function, especially in the following conditions that contribute to its disruption: the initial phase of treatment with antihypertensive drugs, hypoglycemic agents or non-steroidal anti-inflammatory drugs. As a rule, the kidney function should be evaluated before starting treatment with the drug, and then at least 1 time per year for patients with normal renal function and at least 2-4 times a year for patients with serum creatinine above the upper limit of the norm.In patients with a high risk of impaired renal function, it should be monitored more than 2-4 times a year. If there are signs of impaired renal function, the drug should be discontinued.

    Use of iodine-containing radiopaque agents for intravascular injection. When carrying out X-ray studies that require intravascular injection of iodine-containing radiocontrast agents, the drug should be temporarily discontinued (48 hours before and 48 hours after the test), because intravascular injection of iodine-containing radiopaque agents can lead to a sharp deterioration in kidney function and increase the risk of developing lactic acidosis. Resume the drug can only be done after a reassessment of kidney function.

    Hypoxia. In acute cardiovascular insufficiency (shock), acute heart failure, acute myocardial infarction and other conditions for which hypoxia is characteristic, lactoacidosis and prerenal acute renal failure may develop. If the above conditions occur, the drug should be immediately discontinued.

    Surgical interventions. For the duration of surgical interventions (except for small surgeries, not related to the restriction of food and liquid intake), the drug should be discontinued. You can resume taking the drug after the patient starts eating on his own and shows that the kidney function is not broken.

    Alcohol consumption. It is established that alcohol enhances the effect of metformin on the metabolism of lactate. Patients should be warned about the inadmissibility of alcohol abuse during the use of the drug.

    The content of vitamin B12. Determined that metformin about 7% of cases cause an asymptomatic decrease in serum vitamin B12. Such a decrease in very rare cases leads to the development of anemia. Therefore, after the withdrawal of metformin and / or replacement therapy with vitamin B12 serum concentration of vitamin B12 quickly normalizes. Patients receiving the drug are advised to conduct a general blood test at least once a year and, if any violations are found, determine their cause and take appropriate measures. Apparently, in some patients (for example, in patients with insufficient intake or disordersabsorption of vitamin B12 or calcium), there is a predisposition to a decrease in serum vitamin B12. In such cases, it may be recommended to determine the serum concentration of vitamin B12 at least 1 time in 2-3 years.

    Deterioration of the condition of patients with type 2 diabetes mellitus who had previously responded to therapy. If a patient with type 2 diabetes who previously responded to therapy showed signs of worsening (laboratory changes or clinical manifestations), and the symptoms are not clearly expressed, tests should be performed immediately to detect ketoacidosis and / or lactic acidosis. If acidosis is confirmed in one form or another, immediately discontinue the drug and take appropriate measures.

    Hypoglycemia. Typically, patients receiving only this drug, hypoglycemia is not observed, but it can occur against a low calorie diet (when the intense physical load is not compensated by the caloric content of food) or against the background of alcohol consumption. Hypoglycemia is most likely in elderly, debilitated or depleted patients, as well as against hypopituitarism,adrenal insufficiency or alcohol intoxication. In elderly patients and those receiving β-blockers, the diagnosis of hypoglycemia may be difficult.

    Decreased effectiveness of hypoglycemic agents. Under stress (including fever, trauma, infection, surgical intervention), which has arisen in a patient receiving hypoglycemic drugs according to a stable scheme, there may be a sharp decrease in the effectiveness of the latter for a while. In this case, it may be necessary to cancel the drug and prescribe insulin. You can resume treatment with the drug after the end of the acute period.

    Influence on the ability to drive vehicles and work with machinery. The effect of the drug on the ability to drive vehicles and work with mechanisms has not been studied. With the development of dizziness against the background of the drug should be refrained from driving and working with mechanisms.

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