Metformin + Sitagliptin
1 tablet contains: active substance: citagliptina phosphate monohydrate 64.25 mg (equivalent to 50 mg of sitagliptin free base) and metformin hydrochloride 1000 mg.Vspomogatelnye substances: microcrystalline cellulose, polyvinylpyrrolidone (povidone), sodium stearyl fumarate, sodium lauryl sulfate, water ochischennaya.Sostav shells: Opadry II Red 85 F15464 (polyvinyl alcohol, titanium dioxide (E 171), macrogol / polyethylene glycol 3350, talc, ferric oxide red (E 172), ferric oxide black (E 172)).
Metformin + Sitagliptin is a combination of two active ingredients (DV) with a complementary (complementary) mechanism of action - Sitagliptin, a DPP-4 inhibitor, and Metformin, a member of the biguanide class. It is used to improve glycemic control in patients with type 2 diabetes. Sitagliptin, when taken orally, is an active, highly selective inhibitor of DPP-4, intended for the treatment of type 2 diabetes. Pharmacological effects of the class of drugs - DPP-4 inhibitors are mediated by activation of incretin. Inhibiting DPP-4, sitagliptin increases the concentration of two known active hormones of the incretin family: GLP-1 and HIP. Incretins are part of the internal physiological system for regulating glucose homeostasis. At normal or elevated blood glucose concentrations, GLP-1 and HIP contribute to an increase in insulin synthesis and secretion by pancreatic beta cells. GLP-1 also suppresses glucagon secretion by pancreatic alpha cells, reducing, thus, the synthesis of glucose in the liver. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate insulin release and at low concentrations of blood glucose, which is fraught with the development of sulfonyl-induced hypoglycemia not only in patients with type 2 diabetes, but also in healthy individuals. Being a highly selective and effective inhibitor of the enzyme DPP-4, sitagliptin at therapeutic concentrations does not inhibit the activity of the related enzymes DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological action from analogues of GLP-1, insulin, sulfonylurea derivatives or meglitinides,biguanides, peroxisome-activated proliferator-activated gamma receptor gamma receptors (PPARγ), alpha-glucosidase inhibitors and amylin analogues Its pharmacological mechanisms of action differ from those of other classes of oral hypoglycemic agents. Methtformin reduces glucose synthesis in the liver, absorbs glucose in the intestine, and increases insulin sensitivity by enhancing peripheral uptake and glucose utilization. Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia in patients with type 2 diabetes mellitus or in healthy people (with the exception of certain circumstances, see “Restrictions on the Use”, Metformin) and does not cause hyperinsulinemia. During treatment with metformin, insulin secretion does not change, and the fasting insulin concentration and daily plasma insulin concentration may decrease. Oral administration of a single dose of sitagliptin in patients with type 2 diabetes leads to suppression of the activity of DPP-4 enzyme for 24 hours, which is accompanied by two to three times an increase in the concentration of circulating active GLP-1 and HIP, an increase in the plasma concentration of insulin and C-peptide, a decrease in the concentration of glucagon and plasma concentration of fasting glucose, and a decrease in the amplitude of fluctuations in glycemia after glucose or nutritional load. Receiving sitagliptin at a daily dose of 100 mg for 4–6 months significantly improved the function of pancreatic beta cells in patients with type 2 diabetes mellitus, as evidenced by the corresponding changes in markers such as HOMA— β (assessment of homeostasis in the model-β), the ratio of proinsulin / insulin, evaluation of the reaction of beta cells of the pancreas according to the panel of repeated tests for food tolerance. According to clinical data from phase II and phase III, the efficacy of glycemic control of sitagliptin in the 50 mg regimen 2 times a day was comparable to that of the 100 mg regimen once a day. In a randomized, placebo-controlled double-blind with double imitation of a 4-period cross-sectional study in healthy volunteers studied the effect of sitagliptin in combination with metformin, or only sitagliptin, or only metformin, or placebo on changes in plasma concentrations of active and total GLP-1 and glucose after a meal .The weighted average concentration of active GLP-1 after 4 h after a meal increased about 2 times after taking only sitagliptin or only metformin compared with placebo. The combined use of sitagliptin and metformin provided a summation of the effect with a 4-fold increase in the concentration of active GLP-1 compared to the dynamics in the placebo group. Only receiving sitagliptin was accompanied by an increase in the concentration of only active GLP-1 due to inhibition of DPP-4, while metformin was accompanied by a symmetric increase in the concentration of total and active GLP-1. The data obtained reflected the different mechanisms underlying the increase in the concentration of active GLP-1 after taking these two drugs. The results of the study also demonstrated that it was sitagliptin, and not metformin, that provided an increase in the concentration of active GLP-1. In studies of healthy volunteers, sitagliptin did not cause a decrease in glucose concentration and did not cause hypoglycemia, which confirms the glucose-dependent nature of insulinotropic action and suppression of glucagon synthesis. Effect on ADV randomized placebo-controlled study involving patients with arterial hypertension combined receiving antihypertensive drugs (one or more of the list: ACE inhibitors, ARA II, BPC, beta-blockers, diuretics) with sitagliptin generally well tolerated by patients. In this category of patients, sitagliptin showed a slight hypotensive effect: at a daily dose of 100 mg, sitagliptin reduced the average daily outpatient SBP by 2 mm Hg. compared to the placebo group. No hypotensive effect was observed in patients with normal blood pressure. Effect on cardiac electrophysiology In a randomized, placebo-controlled, cross-sectional study in healthy volunteers, sitagliptin was administered once at a dose of 100 or 800 mg (8-fold excess of the recommended dose) or placebo. After taking the recommended therapeutic dose, no effect of the drug on the duration of the QT interval, both at the time of its plasma Cmax and at other check points throughout the study, was not observed.After administration of 800 mg, the maximum increase in the placebo-adjusted average change in the duration of the QT interval compared to the initial value 3 h after administration of the drug was 8 ms. This increase was assessed as clinically insignificant. After administration of 800 mg, the value of plasma Cmax of sitagliptin is approximately 11 times higher than the corresponding value after administration of a therapeutic dose of 100 mg.
The results of the study on bioequivalence in healthy volunteers showed that the combined pills (metformin + sitagliptin) 500/50 mg and 1000/50 mg are bioequivalent to separate administration of the corresponding doses of sitagliptin and metformin. an intermediate dose of metformin (metformin + sitagliptin) 850/50 mg was also assigned bioequivalence, provided that the combination in the tablet of fixed doses of drugs. vanieSitagliptin. The absolute bioavailability of sitagliptin is approximately 87%. Reception of a sitagliptin along with fat food does not exert impact on combination pharmacokinetics. Metformin. The absolute bioavailability of metformin when taken on an empty stomach at a dose of 500 mg is 50-60%. The results of studies of a single dose of metformin in doses from 500 to 1500 mg and from 850 to 2550 mg indicate a violation of dose proportionality with an increase in dose, which is more likely due to reduced absorption, rather than accelerated elimination. Simultaneous intake with food reduces the rate and amount of metformin absorbed, as evidenced by a decrease in plasma C max by about 40%, a decrease in AUC by about 25%, and a 35-minute delay in achieving C max after a single dose of metformin at a dose of 850 mg along with food compared with the values of the corresponding parameters after taking a similar dose of the drug on an empty stomach. The clinical significance of reducing pharmacokinetic parameters has not been established. The distribution of Sitagliptin. The average Vss after a single IV administration of 100 mg of sitagliptin in healthy volunteers is approximately 198 liters. The fraction of reversibly binding to plasma proteins of sitagliptin is relatively small (38%). Metformin.Vd metformin after a single oral dose at a dose of 850 mg averaged (654 ± 358) l. Metformin only very slightly bound to plasma proteins. Metformin is partially and temporarily distributed in red blood cells. When using metformin in recommended doses and plasma Css regimens (usually <1 μg / ml) are reached in about 24–48 hours. According to controlled studies, plasma Cmax did not exceed 5 μg / ml even after taking the maximum doses. Metabolism of Sitagliptin. Approximately 79% of sitagliptin is excreted unchanged by the kidneys, the metabolic transformation is minimal. After 14C-labeled sitagliptin was introduced into the body, approximately 16% of the administered radioactivity was excreted as sitagliptin metabolites. Trace concentrations of 6 sitagliptin metabolites that did not contribute to the plasma DPP-4 inhibitory activity of sitagliptin were detected. In in vitro studies, cytochrome CYP3A4 and CYP2C8 system isoenzymes have been identified as major participants in limited sitagliptin metabolism. Metformin. After a single IV administration to healthy volunteers of metformin, almost all the administered dose was excreted unchanged by the kidneys. Metabolic changes in the liver and biliary excretion does not occur. Excretion of Sitagliptin. After ingestion of 14C-labeled sitagliptin by healthy volunteers, almost all of the administered radioactivity was eliminated from the body within a week, including 13% through the intestines and 87% through the kidneys. The average T1 / 2 of sitagliptin when administered orally with 100 mg is approximately 12.4 h, the renal clearance is approximately 350 ml / min. Sitagliptin is eliminated mainly by renal excretion by the mechanism of active tubular secretion. Sitagliptin is a substrate of a transporter of human organic anions of the third type (hOAT-3), which is involved in the process of elimination of sitagliptin by the kidneys. Clinically, the significance of participation of hOAT-3 in transport of sitagliptin has not been established. P-gp may be involved in the renal elimination of sitagliptin (as a substrate), but the P-gp inhibitor cyclosporine does not decrease the renal clearance of sitagliptin. Metformin. Renal clearance of metformin exceeds creatinine clearance 3.5 times, indicating active renal secretion as the main route of elimination.After taking metformin, about 90% of the absorbed drug is excreted by the kidneys during the first 24 hours with a plasma T1 / 2 value of about 6.2 hours; this value in the blood lengthens to 17.6 hours, indicating the possible participation of red blood cells as a potential distribution compartment.
Janumet is indicated as an adjunct to diet and exercise regimen to improve glycemic control in patients with type II diabetes who have not achieved adequate control during monotherapy with metformin or sitagliptin, or after unsuccessful combination treatment with two drugs. Janumet is indicated in combination with sulfonylurea derivatives (a combination of three drugs) as an addition to the diet and exercise regimen to improve glycemia control in patients with type 2 diabetes who have not achieved adequate control after treatment with two of the following three drugs: metformin, sitagliptin or derivatives sulfonylureas. Is Janumet shown in combination with PPAR- agonists? (for example, thiazolidinediones) as an adjunct to diet and exercise regimen to improve glycemia control in patients with type 2 diabetes who did not achieve adequate control after treatment with two of the following three drugs: metformin, sitagliptin or a PPAR-он agonist. Janumet is indicated for patients with type 2 diabetes mellitus (a combination of three drugs) as an addition to the diet and exercise regimen to improve glycemic control in combination with insulin.
- hypersensitivity to sitagliptin phosphate, metformin hydrochloride or to any other component of the drug; - acute conditions that can affect kidney function: dehydration, severe infections, shock; - acute or chronic diseases that can lead to tissue hypoxia, such as heart disease. or respiratory failure, recently suffered a heart attack — myocardium, shock; moderate or severe renal dysfunction (creatinine clearance, liver dysfunction; acute alcohol intoxication, alcoholism; period to breastfeeding; type I diabetes; acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without a coma); radiological studies (intravascular administration of iodine-containing contrast agents).
Combination of Metformin + Sitagliptin Pancreatitis In the post-registration observation period, there were reports of the development of acute pancreatitis, including hemorrhagic or necrotic with a lethal and non-lethal outcome, in patients taking sitagliptin (see “Side effects”, Post-registration observations). population of uncertain size, it is impossible to reliably estimate the frequency of these messages or to establish a causal relationship with the duration of use drug. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent severe abdominal pain. Clinical manifestations of pancreatitis disappeared after cessation of sitagliptin. If pancreatitis is suspected, it is necessary to stop taking a combination of metformin + sitagliptin and other potentially dangerous drugs. Monitoring of kidney function The predominant way of removing metformin and sitagliptin is renal excretion. The risk of metformin accumulation and the development of lactic acidosis increases in proportion to the degree of renal dysfunction, therefore, the combination of metformin + sitagliptin should not be administered to patients with serum creatinine levels above the age of VGN. In elderly patients, in view of the age-related decline in renal function, one should strive to achieve adequate glycemic control at the minimum dose of the metformin + sitagliptin combination. Elderly patients, especially those over 80 years of age, regularly monitor their renal function. Before starting treatment with a combination of metformin + sitagliptin, and at least once a year after starting treatment with proper tests, normal kidney function is confirmed. With an increased likelihood of developing renal dysfunction, kidney function is monitored more often, and when it is detected, the combination of metformin + sitagliptin is canceled. The development of hypoglycemia with simultaneous use with sulfonylurea derivatives or insulin. with insulin or sulfonylurea derivatives (see “Side Effects”).To reduce the risk of sulfonyl-induced or insulin-induced hypoglycemia, the dose of a sulfonylurea or insulin derivative should be reduced.
Use during pregnancy and lactation
Adequately controlled studies of the combination of metformin + sitagliptin or its components in pregnant women were not conducted, therefore, there are no data on the safety of use in pregnant women. The combination of metformin + sitagliptin, like other oral hypoglycemic drugs, was not recommended for use during pregnancy. No experimental studies were conducted on the combination of metformin + sitagliptin to assess the effect on reproductive function. Experimental studies to determine the secretion of the components of the combination metformin + sitagliptin in breast milk were not conducted . According to research on individual components, both sitagliptin and metformin are secreted into the breast milk of rats. There is no data on the secretion of sitagliptin into human breast milk. Therefore, the combination of metformin + sitagliptin should not be prescribed during lactation.
Dosage and administration
The dosage regimen of Janumet should be selected individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of sitagliptin 100 mg. The drug Janumet usually prescribed 2 times a day with meals, with a gradual increase in dose, in order to minimize the possible side effects of the gastrointestinal tract (GIT), characteristic of metformin. The initial dose of Janumet drug depends on the current hypoglycemic therapy.
On the part of the gastrointestinal tract: at the beginning of the course of treatment - anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduced when taken during meals); metallic taste in the mouth (3%). From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): in rare cases - megaloblastic anemia (the result of a violation of the absorption of vitamin B12 and folic acid). From the side of metabolism: hypoglycemia; in rare cases - lactic acidosis (weakness, drowsiness, hypotension, resistant bradyarrhythmia, respiratory disorders, abdominal pain, myalgia, hypothermia). From the skin: rash, dermatitis.
Sitagliptin During clinical studies, a single dose of sitagliptin up to 800 mg was generally well tolerated by healthy volunteers. Minimal changes in the QT interval, not considered clinically significant, were noted in one of the studies of sitagliptin at a daily dose of 800 mg (see Pharmacodynamics, Effect on cardiac electrophysiology). A dose of over 800 mg / day has not been studied in humans. In clinical studies, repeated use of sitagliptin (phase I) did not indicate any adverse reactions related to treatment with sitagliptin when taken in a daily dose of up to 400 mg for 28 days. In case of overdose, it is necessary to start standard supportive measures: removal of non-absorbed sitagliptin from the gastrointestinal tract, monitoring of vital signs, including ECG, and the appointment of symptomatic therapy, if necessary. Sitagliptin is poorly dialyzed: according to clinical trials, during the 3–4 hour dialysis session, only 13.5% of the dose was eliminated. In case of clinical need, prolonged hemodialysis is prescribed. There are no data on the efficacy of peritoneal dialysis. Metformin had a place for cases of metformin overdose, including administration in quantities exceeding 50 g (50,000 mg). Hypoglycemia was observed in approximately 10% of all cases of overdose, but a clear connection with overdose of metformin has not been established. The development of lactic acidosis was accompanied by approximately 32% of all cases of metformin overdose (see “Precautions”, Metformin). Emergency hemodialysis is possible (metformin is dialyzed at a rate of up to 170 ml / min in conditions of good hemodynamics) to accelerate the removal of excess metformin in case of suspected overdose.
Interaction with other drugs
Sitagliptin and metformin Simultaneous administration of multiple doses of sitagliptin (50 mg 2 times a day) and metformin (1000 mg 2 times a day) was not accompanied by significant changes in the pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes mellitus. Research on the inter-drug effect on the pharmacokinetic parameters of the combination Metformin + saxagliptin was not performed, however, a sufficient number of similar studies were carried out for each of the components of the combination - sitagliptin and metformin. Sitagliptin did not have a clinically significant effect on the pharmacokinetics of metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, and oral contraceptives.Based on these data, sitagliptin does not inhibit CYP3A4, CYP2C8 or CYP2C9 isoenzymes. In vitro data suggests that sitagliptin also does not inhibit CYP2D6, CYP1A2, CYP2C19 and CYP2B6 isoenzymes and does not induce CYP3A4. According to population-based pharmacokinetic analysis in patients with type 2 diabetes mellitus, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitaglapitis type 2 diabetes mellitus and diabetes mellitus type 2. The study evaluated a number of drugs most commonly used by patients with type 2 diabetes, including hypocholesterolemic drugs (statins, fibrates, ezetimibe), antiaggregants (clopidogrel), ciphers (ACE inhibitors, APA II, beta-blockers, BPC, hydrochlorothiazide, analgesics and NSAIDs (naproxen, diclofenac, celecoxybrae, celecoxybrah, celecoxybromes, analgesics and NPVS ), antihistamines (cetirizine), proton pump inhibitors (omeprazole, lansoprazole) and for the treatment of erectile dysfunction (sildenafil). An increase in AUC (11%), as well as an average Cmax (18%) of digoxin was observed with combined use with sitagliptin. It is considered clinically significant, however, while taking digoxin, patient monitoring is recommended. An increase in AUC and Cmax of sitagliptin by 29 and 68%, respectively, was observed with a joint single oral dose of Saxagliptin in a dose of 100 mg and cyclosporine (a strong inhibitor of P-gp) in a dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin are not clinically significant. Metformin Glibenclamide: in a study of the interaction of single doses of metformin and glibenclamide in patients with sugar Type 2 diabetes did not observe any changes in the pharmacokinetic and pharmacodynamic parameters of metformin. Changes in the values of AUC and Cm of glibenclamide were highly variable. Insufficient information (single dose) and the mismatch of plasma concentration of glibenclamide with the observed pharmacodynamic effects put into question the clinical significance of this interaction. Furosemide: In the study of the inter-drug interaction of single doses of metformin and furosemide in healthy volunteers, a change in the pharmacokinetic parameters of both drugs was observed. Furosemide increased the Cmax value of metformin in plasma and whole blood by 22%, the AUC value of metformin in whole blood by 15%, without altering the renal clearance of the drug.The values of Cmax and AUC of furosemide, in turn, decreased by 31 and 12%, respectively, and T1 / 2 decreased by 32% without significant changes in the kidney clearance of furosemide. There is no information about the interaction between the two drugs with long-term joint use. Nifedipine: in the study of the interactions between nifedipine and metformin after a single dose of healthy volunteers, the plasma Cmax and AUC of metformin increased by 20 and 9%, respectively, as well as an increase in the amount of metformin excreted by the kidneys. Tmax and T1 / 2 metformin did not change. The basis is an increase in the absorption of metformin in the presence of nifedipine. The effect of metformin on the pharmacokinetics of nifedipine is minimal. Cationic drugs: cationic drugs (i.e. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) secreted by tubular secretion can theoretically interact with metrom by competing for a shared renal tubular transport system. A similar competition was observed with simultaneous administration of metformin and cimetidine by healthy volunteers in single and multiple dose studies, with a 60% increase in the Cm concentration of metformin in plasma and whole blood and a 40% increase in the AUC value of metformin in plasma and whole blood. In the study of single doses of T1 / 2, metformin did not change. Metformin did not affect the pharmacokinetics of cimetidine. And although these inter-drug interactions are mainly of theoretical importance (with the exception of cimetidine), careful monitoring of the patient and dose adjustment of the combination of metformin + sitagliptin and / or the above cationic drugs excreted by proximal renal tubules in cases of their simultaneous reception are recommended. Others: some drugs possess hyperglycemic potential and can interfere with the established control over glycemia. These include thiazide and other diuretics, GCS, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, BPC, and isoniazid. When prescribing the listed drugs to a patient receiving a combination of metformin + sitagliptin,careful monitoring of glycemic control parameters is recommended. When healthy volunteers were taking metformin and propranolol or metformin and ibuprofen, no changes in the pharmacokinetic parameters of these drugs were observed. Only a small part of metformin binds to plasma proteins, therefore, the interactions between metformin and drugs that are actively associated with plasma proteins salicylates, sulfonamides, chloramphenicol and probenecid) are unlikely, unlike sulfonylureas Which are also actively bound to plasma proteins.
Sitagliptin Development of hypoglycemia with simultaneous use with sulfonylurea or insulin derivatives Sitagliptin was close to frequency in the group of patients taking placebo. As with other hypoglycemic agents, hypoglycemia was observed with simultaneous use of sitagliptin in combination with insulin or sulfonylurea derivatives (see “Side Effects”). In order to reduce the risk of sulfonyl-induced or insulin-induced hypoglycemia, the dose of a sulfonylurea or insulin derivative must be reduced. . These reactions included anaphylaxis, angioedema, exfoliative skin diseases, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from a population of uncertain size, it is impossible to determine the frequency and cause-effect relationship with the therapy of these adverse reactions. These reactions occurred during the first 3 months after the start of treatment with sitagliptin, some were observed after taking the first dose.If a hypersensitivity reaction is suspected, it is necessary to stop taking the metformin + sitagliptin combination, evaluate other possible causes of the development of an adverse event, and prescribe another lipid-lowering therapy (see Contraindications and Side Effects, Post-registration Observations). Metformin Lactoacidosis Lactic acidosis is a rare but serious metabolic disorder. that develops due to accumulation of metformin during treatment with a combination of metformin + sitagliptin. Mortality in lactic acidosis reaches approximately 50%. The development of lactic acidosis can also occur against the background of some somatic diseases, in particular diabetes mellitus or any other pathological condition, accompanied by severe hypoperfusion and hypoxemia of tissues and organs. Lactic acidosis is characterized by increased plasma lactate concentration (> 5 mmol / l), low blood pH, electrolyte disturbances with an increase in the anion interval, an increase in the lactate / pyruvate ratio. If the cause of acidosis is metformin, its plasma concentration is usually> 5 μg / ml. According to the available data, lactic acidosis developed very rarely in the treatment of metformin (approximately 0.03 cases per 1000 patient-years, with a death rate of approximately 0.015 cases per 1000 patient-years). In 20,000 patient-years of treatment with metformin, no cases of lactic acidosis have been reported in clinical studies. Notable cases occurred predominantly in patients with diabetes mellitus with severe renal insufficiency, including pronounced pathology and renal hypoperfusion, often in combination with concomitant multiple somatic / surgical diseases and polyphragmas. Significantly increased risk of lactic acidosis in patients with CHF, requiring significant medical correction, especially in unstable angina / CHF in the acute stage, accompanied by severe hypoperfusion and hypoxemia. The risk of developing lactic acidosis increases in proportion to the degree of renal dysfunction and the patient's age, so adequate monitoring of renal function, as well as the use of the minimum effective dose of metformin, help to significantly reduce the risk of developing lactic acidosis.Careful monitoring of renal function is especially necessary in the treatment of elderly patients, and patients older than 80 years of treatment with metformin begin only after confirmation of adequate renal function according to the results of creatinine clearance, since these patients are more at risk of developing lactic acidosis. In addition, in any condition, accompanied by the development of hypoxemia, dehydration or sepsis, metformin should be immediately canceled. Considering that in case of impaired liver function, lactate excretion is significantly reduced, it should not be prescribed metformin in patients with clinical or laboratory signs of liver disease. During treatment with metformin, alcohol intake should be limited, since alcohol potentiates the effect of metformin on lactate metabolism. In addition, treatment with metformin is temporarily stopped for the period of intravascular X-ray contrast studies and surgical interventions. The onset of lactic acidosis is often difficult to detect, and it is accompanied only by nonspecific symptoms such as malaise, myalgia, respiratory distress syndrome, increased sleepiness and non-specific dyspeptic symptoms. With the aggravation of the course of lactic acidosis, hypothermia, arterial hypotension and resistant bradyarrhythmia can join the above-mentioned symptoms. The physician and patient should be aware of the possible significance of such symptoms, and the patient should