Vipdomet^® (Tablets) Instructions for Use

ATC Code

A10BD13 (Metformin and alogliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Alogliptin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined oral hypoglycemic drug (dipeptidyl peptidase-4 inhibitor + biguanide)

Pharmacotherapeutic Group

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

Pharmacological Action

The drug Vipdomet^® 850 is a combination of two hypoglycemic agents with complementary and different mechanisms of action, designed to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): alogliptin, an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, and metformin, a representative of the biguanide class.

Alogliptin

Alogliptin is a potent and highly selective DPP-4 inhibitor. Its selectivity for DPP-4 is more than 10,000 times greater than its effect on other related enzymes, including DPP-8 and DPP-9. DPP-4 is the primary enzyme involved in the rapid degradation of incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin hormones are secreted in the intestine, and their concentration increases in response to food intake. GLP-1 and GIP increase insulin synthesis and its secretion by pancreatic β-cells. GLP-1 also inhibits glucagon secretion and reduces glucose production by the liver. Therefore, by increasing incretin concentrations, alogliptin increases glucose-dependent insulin secretion and reduces glucagon secretion at elevated blood glucose concentrations. In patients with T2DM and hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in glycated hemoglobin (HbA_1c) concentration and a reduction in plasma glucose concentration, both fasting and postprandial.

Metformin

Metformin is a biguanide with hypoglycemic action, reducing both basal and postprandial plasma glucose concentrations. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.

It increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. It reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. It delays the absorption of glucose in the intestine. Metformin stimulates the synthesis of intracellular glycogen by acting on glycogen synthase. It increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

Metformin has a beneficial effect on lipid metabolism: it reduces the concentration of total cholesterol, LDL, and triglycerides.

Pharmacokinetics

Alogliptin

The pharmacokinetics of alogliptin are similar in healthy volunteers and in patients with type 2 diabetes mellitus.

Absorption

The absolute bioavailability of alogliptin is approximately 100%.

In healthy volunteers, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug was observed, with the time to reach C_max in the plasma of alogliptin in the range of 1 to 2 hours after administration.

No clinically significant accumulation of alogliptin was observed after multiple doses, either in healthy volunteers or in patients with type 2 diabetes.

The AUC of alogliptin increases proportionally with a single dose in the therapeutic dose range from 6.25 mg to 100 mg. The interindividual variability coefficient of alogliptin AUC in patients is small (17%).

The AUC_(0-inf) of alogliptin after a single dose was similar to the AUC_(0-24) after administration of the same dose once daily for 6 days. This indicates the absence of time dependence in the kinetics of alogliptin after multiple doses.

Distribution

After a single intravenous administration of alogliptin at a dose of 12.5 mg in healthy volunteers, the V_d in the terminal phase was 417 L, indicating that alogliptin is well distributed in tissues. Plasma protein binding is approximately 20-30%.

Metabolism

Alogliptin does not undergo extensive metabolism; 60% to 70% of alogliptin is excreted unchanged by the kidneys.

After administration of ¹⁴C-labeled alogliptin orally, two minor metabolites were identified: N-demethylated alogliptin, M-I (<1% of the parent substance), and N-acetylated alogliptin, M-II (<6% of the parent substance). M-I is an active metabolite and a highly selective DPP-4 inhibitor, similar in action to alogliptin; M-II does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.

In vitro studies have shown that CYP2D6 and CYP3A4 are involved in the limited metabolism of alogliptin.

In vitro studies also show that alogliptin does not induce CYP1A2, CYP2B6, CYP2C9 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations achieved with the recommended 25 mg dose of alogliptin. Under in vitro conditions, alogliptin may slightly induce CYP3A4, but under in vivo conditions, alogliptin does not induce CYP3A4.

In vitro studies show that alogliptin does not inhibit human renal organic anion transporters type 1 (OAT1) and type 3 (OAT3), nor human renal organic cation transporters type 2 (OCT2).

Alogliptin exists predominantly as the (R)-enantiomer (>99%). Under in vivo conditions, it undergoes little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is administered at therapeutic doses.

Excretion

After oral administration of ¹⁴C-labeled alogliptin, 76% of the total radioactivity was excreted by the kidneys and 13% via the intestine.

The mean renal clearance of alogliptin (170 mL/min) was greater than the mean GFR (about 120 mL/min), suggesting that alogliptin is partially excreted by active renal secretion. The mean terminal T_1/2 of alogliptin is approximately 21 hours.

Pharmacokinetics in specific patient groups

Patients with renal impairment. A study of alogliptin at a dose of 50 mg/day was conducted in patients with varying degrees of chronic renal impairment. Patients included in the study, according to the Cockcroft-Gault formula, were divided into 4 groups: patients with mild renal impairment (CrCl from 50 to 80 mL/min), moderate renal impairment (CrCl from 30 to 50 mL/min), and severe renal impairment (CrCl less than 30 mL/min), as well as end-stage chronic renal disease requiring hemodialysis.

The AUC of alogliptin in patients with mild renal impairment increased approximately 1.7-fold compared to the control group. However, this increase in AUC was within the acceptable deviation for the control group, so dose adjustment of the drug in such patients is not required (see section “Dosage Regimen”).

An approximately 2-fold increase in alogliptin AUC compared to the control group was noted in patients with moderate renal impairment, an approximately fourfold increase in AUC was noted in patients with severe renal impairment, and in patients with end-stage chronic renal disease compared to the control group. Patients with end-stage renal disease underwent hemodialysis immediately after taking alogliptin. About 7% of the dose was removed from the body during a three-hour dialysis session.

Other patient groups. Age (65-81 years), sex, race, and body weight of patients did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin. No dose adjustment of alogliptin is required (see section “Dosage Regimen”).

Pharmacokinetics in children and adolescents under 18 years of age have not been studied (see section “Dosage Regimen”).

Metformin

Absorption

T_max after oral administration of metformin is about 2.5 hours. The absolute bioavailability of metformin is 50% to 60% in healthy volunteers. After oral administration, 20-30% of the unabsorbed fraction of metformin is excreted through the intestine.

The absorption of metformin is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are nonlinear.

When metformin is used at recommended doses and regimens, C_ss in plasma (usually <1 µg/mL) is achieved within approximately 24-48 hours. According to controlled clinical studies, maximum plasma concentrations of the drug did not exceed 4 µg/mL, even after taking maximum doses of the drug.

Distribution

The degree of binding to plasma proteins is negligible. Metformin is distributed in erythrocytes. The mean C_max in blood is lower than C_max in plasma and is reached at approximately the same time. The mean V_d ranges from 63-276 L.

Metabolism

No metabolites have been detected in humans.

Excretion

Metformin is excreted from the body unchanged by the kidneys. The renal clearance of metformin is >400 mL/min, indicating that metformin is excreted by glomerular filtration and tubular secretion. After oral administration, T_1/2 is about 6.5 hours.

Pharmacokinetics in specific patient groups

In impaired renal function, the clearance of metformin decreases in proportion to CrCl, and T_1/2 increases, which can lead to an increase in plasma metformin concentration.

Indications

Type 2 diabetes mellitus in adult patients aged 18 years and older to improve glycemic control in addition to diet therapy and physical exercise

• As monotherapy in patients who have not achieved adequate glycemic control with metformin monotherapy, or as a replacement for those already receiving combined treatment with metformin and alogliptin as single agents;
• In combination with pioglitazone (triple combination: metformin + alogliptin + pioglitazone), when therapy with metformin and pioglitazone does not lead to adequate glycemic control;
• In combination with insulin (triple combination: metformin + alogliptin + insulin), when therapy with insulin and metformin does not lead to adequate glycemic control.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally.

Vipdomet^® is prescribed as 1 tablet 2 times/day simultaneously with food intake to reduce gastrointestinal adverse reactions. Tablets should be swallowed whole, without chewing, with water.

If the patient misses a dose of Vipdomet^®, it should be taken as soon as they remember the missed dose. A double dose of Vipdomet^® should not be taken; in this case, the missed dose should be skipped.

The dose of Vipdomet^® is selected individually.

For patients who have not achieved adequate glycemic control with metformin monotherapy, the recommended dose of Vipdomet^® is 1 tablet of 12.5 mg + 500 mg or 12.5 mg + 1000 mg 2 times/day, depending on the already taken dose of metformin, which corresponds to 25 mg of alogliptin and 1000 mg or 2000 mg of metformin per day.

For patients who have not achieved adequate glycemic control with combined therapy with metformin and pioglitazone at the maximum tolerated dose, Vipdomet^® is prescribed in addition to pioglitazone, and the taken dose of pioglitazone should be maintained. The recommended dose of Vipdomet^® is 1 tablet of 12.5 mg + 500 mg or 12.5 mg + 1000 mg 2 times/day, depending on the already taken dose of metformin, which corresponds to 25 mg of alogliptin and 1000 mg or 2000 mg of metformin per day.

Caution should be exercised during this therapy due to the risk of hypoglycemia. If hypoglycemia develops, a reduction in the doses of metformin or pioglitazone used may be considered.

As a replacement for patients taking alogliptin and metformin as single agents (as a combination of alogliptin and metformin or as part of a combination with insulin – alogliptin, metformin and insulin), the daily dose of alogliptin and metformin as part of Vipdomet^® should correspond to the daily doses of alogliptin and metformin taken previously. The single dose of alogliptin as part of Vipdomet^® should be halved (12.5 mg), since the tablet is taken 2 times/day, while the single dose of metformin should remain unchanged (500 mg or 1000 mg).

For patients who have not achieved adequate glycemic control with therapy combining metformin at the maximum tolerated dose and insulin, the dose of Vipdomet^® should provide intake of alogliptin at a dose of 12.5 mg 2 times/day (total daily dose of alogliptin 25 mg) and intake of metformin at the previously taken dose. To avoid the risk of hypoglycemia, a reduction in the insulin dose may be possible. The maximum recommended daily dose of Vipdomet^® is 2 tablets (25 mg alogliptin).

Special patient groups

No dose adjustment of Vipdomet^® is required for elderly patients aged ≥65 years. Caution should be exercised when selecting doses of alogliptin due to possible impaired renal function in this group of patients.

Data on the efficacy and safety of the drug in patients under 18 years of age are not available.

In patients with mild renal impairment (CrCl ≥60 mL/min), no dose adjustment of Vipdomet^® is required. Vipdomet^® is not recommended for use in patients with moderate renal impairment (CrCl in the range ≥30 to <60 mL/min), as these patients are indicated for a lower dose of alogliptin than is presented in the fixed combination of Vipdomet^®. Patients with renal impairment are recommended to assess the glomerular filtration rate (GFR) before starting treatment with Vipdomet^® and then at least once a year during treatment. In patients at risk of progression of renal impairment and in elderly patients, renal function should be assessed more frequently, for example, every 3-6 months.

If it is impossible to use Vipdomet^® in existing dosages, its active ingredients should be used as single-component drugs in accordance with the table below.

* Dose adjustment of alogliptin is based on pharmacokinetic study data in which renal function was assessed based on CrCl calculated using the Cockcroft-Gault formula.

Vipdomet^® should not be used in patients with hepatic impairment.

Adverse Reactions

Adverse reactions (Table 1) when using the drug are distributed by system-organ classes in accordance with MedDRA, indicating the frequency of their occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be established from available data).

Table 1. Adverse Reactions

Gastrointestinal disorders

Gastrointestinal disorders occur most frequently during the initial period of treatment and in most cases resolve spontaneously. To prevent symptoms, it is recommended to take the drug 2 times/day during or after meals.

Metabolism and nutrition disorders

With long-term use of metformin, a decrease in vitamin B₁₂ absorption may be observed. If megaloblastic anemia is detected, the possibility of such etiology should be considered.

Contraindications

• type 1 diabetes mellitus;
• diabetic ketoacidosis, diabetic precoma, coma;
• lactic acidosis (including in history);
• moderate or severe renal failure (creatinine clearance less than 60 ml/min);
• acute conditions with a risk of renal function impairment:
  • dehydration (repeated vomiting, diarrhea);
  • fever, severe infectious diseases;
  • conditions of hypoxia (shock, sepsis, kidney infections, bronchopulmonary diseases);
• clinically significant manifestations of acute and chronic diseases/conditions that can lead to tissue hypoxia (including acute and chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
• hepatic failure, impaired liver function;
• acute alcohol intoxication, chronic alcoholism;
• adherence to a hypocaloric diet (less than 1000 kcal/day);
• use for less than 48 hours before and for 48 hours after radioisotope or X-ray studies with intravascular administration of iodine-containing contrast agent (see section “Drug Interactions”);
• extensive surgical operations and trauma, when insulin therapy is indicated (see section “Special Precautions”);
• pregnancy;
• breastfeeding period;
• patient age under 18 years due to lack of data on efficacy and safety;
• concomitant use with sulfonylurea derivatives due to lack of data on efficacy and safety (see section “Special Precautions”);
• hypersensitivity to alogliptin or metformin, or to any excipient, or serious hypersensitivity reactions to any DPP-4 inhibitor in history, including anaphylactic reactions, anaphylactic shock and angioedema.

With caution

• In patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis in them (see section “Special Precautions”);
• Use of Vipdomet^® 850 in combination with pioglitazone (see section “Special Precautions”);
• In patients with pancreatitis in history.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the safety of using Vipdomet^® 850 in pregnant women. Studies in pregnant rats showed toxicity of the combined therapy with alogliptin and metformin on the reproductive system when administering doses approximately 5-20 times higher than the recommended human doses (for metformin and alogliptin, respectively). The use of Vipdomet^® 850 during pregnancy is contraindicated.

Alogliptin

There are no data on the safety of using alogliptin in pregnant women. Animal studies have not shown any direct or indirect negative effects of alogliptin on the reproductive system.

Metformin

A limited amount of data indicates that the use of metformin in pregnant women does not increase the risk of congenital malformations in children. Animal studies have not shown any direct or indirect negative effects of metformin in clinically significant doses on the reproductive system.

Breastfeeding period

There are no data on the penetration into breast milk in animals of alogliptin and metformin during combined therapy. With monotherapy with alogliptin or metformin, animal studies have shown that alogliptin and metformin penetrate into the milk of lactating rats. There are no data on the penetration of alogliptin into human breast milk. Metformin penetrates into human breast milk in small amounts, so the risk of adverse reactions in a breastfed child cannot be excluded.

In this regard, the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure, impaired liver function.

Use in Renal Impairment

The use of the drug is contraindicated in moderate or severe renal failure (creatinine clearance less than 60 ml/min).

In patients with mild renal impairment (creatinine clearance ≥60 ml/min), no dose adjustment of the drug is required.

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age.

Geriatric Use

No dose adjustment of the drug is required in elderly patients (≥65 years). Caution should be exercised when selecting doses of alogliptin due to possible renal impairment in this group of patients.

Special Precautions

Lactic acidosis is a 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 while taking metformin occurred mainly in patients with diabetes mellitus with severe renal failure.

Other associated risk factors should be considered, such as decompensated diabetes, ketosis, prolonged fasting, alcoholism, hepatic failure and any condition associated with significant hypoxia. This can help reduce the incidence of lactic acidosis.

The risk of developing lactic acidosis should be considered if nonspecific signs appear, such as muscle cramps accompanied by dyspeptic disorders and/or abdominal pain and/or severe asthenia.

Lactic acidosis is characterized by acidotic dyspnea and hypothermia followed by coma. Diagnostic laboratory parameters are decreased blood pH (less than 7.35), plasma lactate concentration above 5 mmol/l, increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected, the patient should stop taking the drug and immediately consult a doctor (see section “Overdose”).

Renal function

Alogliptin and metformin are predominantly excreted by the kidneys. The risk of lactic acidosis associated with metformin intake increases with the degree of renal impairment, therefore, before starting treatment and regularly thereafter, it is necessary to determine creatinine clearance: at least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, as well as in patients with creatinine clearance at the lower limit of normal.

Particular caution should be exercised in case of possible renal impairment in elderly patients with simultaneous use of antihypertensive drugs, diuretics or NSAIDs.

Hepatic failure

There are no clinical data on the use of Vipdomet^® 850 in patients with severe hepatic failure (more than 9 points on the Child-Pugh scale). The use of the drug in such groups of patients is not recommended.

Surgical operations

The use of metformin should be discontinued 48 hours before planned surgical operations and can be resumed no earlier than 48 hours after, provided that renal function was found to be normal during the examination.

Use with other hypoglycemic drugs

Vipdomet^® 850 is not recommended for use in combination with sulfonylurea derivatives, since safety and efficacy have not been studied.

To reduce the risk of hypoglycemia, it is recommended to reduce the dose of insulin and pioglitazone when used concomitantly with Vipdomet^® 850 (see section “Dosage and Administration”).

Change in the clinical status of a patient with previously adequately controlled type 2 diabetes

If laboratory abnormalities or clinical symptoms of the disease appear in patients with previously adequately controlled type 2 diabetes while being treated with Vipdomet^® 850, patients should be immediately examined primarily to rule out ketoacidosis or lactic acidosis based on the results of blood tests for electrolytes and ketones, plasma glucose concentration, as well as blood pH, lactate and pyruvate concentrations, and plasma metformin concentration. If acidosis of any etiology develops, further use of Vipdomet^® 850 is discontinued and measures are taken to correct the acidosis.

Acute pancreatitis

In a pooled analysis of 13 clinical trials of alogliptin at a dose of 25 mg/day, 12.5 mg/day, comparator drug and placebo, the incidence of acute pancreatitis was 2, 1, 1, or 0 cases per 1000 patient-years in each group, respectively. In a cardiovascular outcomes study, the incidence of acute pancreatitis in patients treated with alogliptin or placebo was 3 and 2 cases per 1000 patient-years, respectively. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain that may radiate to the back. If acute pancreatitis is suspected, Vipdomet^® 850 should be discontinued; if acute pancreatitis is confirmed, the drug should not be resumed. There are no data on whether there is an increased risk of pancreatitis while taking alogliptin in patients with a history of pancreatitis. Therefore, patients with a history of pancreatitis should be cautious.

Effect on liver function

During post-marketing surveillance, reports of liver function disorders, including hepatic failure, while taking alogliptin have been received. Their relationship with the use of the drug has not been established. However, patients should be carefully examined for possible abnormalities in liver function tests. If abnormalities in liver function tests are detected and an alternative etiology for their occurrence is not established, discontinuation of treatment with the drug should be considered.

Effect on ability to drive vehicles and mechanisms

Vipdomet^® 850 has no or negligible influence on the ability to drive vehicles and mechanisms. Nevertheless, it is necessary to consider the risk of hypoglycemia when using the drug in combination with other hypoglycemic drugs (insulin or pioglitazone) and exercise caution when driving vehicles and mechanisms.

Overdose

There are no data on overdose of the combined drug Vipdomet^® 850.

Alogliptin

The maximum dose of alogliptin used in clinical studies was 800 mg/day in healthy volunteers and 400 mg/day in patients with type 2 diabetes for 14 days. This is 32 and 16 times, respectively, higher than the recommended daily dose of 25 mg of alogliptin.

There were no serious adverse events when taking the drug at these doses.

Treatment in case of overdose, gastric lavage and symptomatic treatment may be recommended. Alogliptin is poorly dialyzable. In clinical studies, only 7% of the dose was removed from the body during a three-hour hemodialysis session. There are no data on the effectiveness of peritoneal dialysis of alogliptin.

Metformin

Symptoms significant overdose or concomitant risk factors can lead to the development of lactic acidosis.

Treatment if signs of lactic acidosis appear, treatment with the drug must be immediately discontinued, the patient urgently hospitalized and, after determining the lactate concentration, the diagnosis clarified. The most effective measure to remove lactate and metformin from the body is hemodialysis.

In case of overdose of Vipdomet^® 850, in addition to the above methods of therapy, symptomatic treatment is carried out.

Drug Interactions

Alogliptin and metformin

Concomitant administration of alogliptin (100 mg once daily) and metformin (1000 mg twice daily) for 6 days in healthy volunteers was not accompanied by clinically significant changes in the pharmacokinetic parameters of alogliptin or metformin.

Studies of the pharmacokinetic interaction of Vipdomet^® 850 with other drugs have not been conducted; data on interactions available for each of the active substances of the drug separately are provided below.

Alogliptin

Effect of other drugs on alogliptin

Alogliptin is mainly excreted unchanged by the kidneys and only to a small extent metabolized by the cytochrome P450 (CYP) enzyme system. Therefore, interactions with CYP inhibitors have not been observed and are not expected.

In clinical drug interaction studies, the following drugs did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin: gemfibrozil (CYP2C8/9 inhibitor), fluconazole (CYP2C9 inhibitor), ketoconazole (CYP3A4 inhibitor), cyclosporine (P-glycoprotein inhibitor), voglibose (α-glucosidase inhibitor), digoxin, metformin, cimetidine, pioglitazone and atorvastatin.

Effect of alogliptin on other drugs

In vitro studies have shown that alogliptin does not inhibit or induce CYP450 isoforms at concentrations achieved when using alogliptin at the recommended dose of 25 mg. Interactions with substrates of CYP450 isoforms have not been observed and are not expected.

In vitro studies have revealed that alogliptin is neither a substrate nor an inhibitor of OAT1, OAT3 or OCT2. Furthermore, clinical data do not show interactions with P-glycoprotein inhibitors or substrates.

In clinical drug interaction studies, alogliptin did not have a clinically significant effect on the pharmacokinetics of the following drugs: caffeine, (R)- and (S)-warfarin, pioglitazone, glibenclamide, tolbutamide, dextromethorphan, atorvastatin, midazolam, oral contraceptives (norethisterone and ethinyl estradiol), digoxin, fexofenadine, metformin or cimetidine. Based on these data, alogliptin does not inhibit the cytochrome system isoenzymes CYP1A2, CYP3A4, CYP2D6, CYP2C9, P-glycoprotein and OCT2.

Alogliptin did not affect the prothrombin index or INR in healthy volunteers when taken concomitantly with warfarin.

Combination of alogliptin with other hypoglycemic drugs

Administration of alogliptin in combination with metformin or pioglitazone (thiazolidinedione), or an α-glucosidase inhibitor, or glibenclamide (sulfonylurea derivative) did not show clinically significant pharmacokinetic interaction.

Metformin

Contraindicated combinations

Iodinated X-ray contrast agents against the background of functional renal failure in patients with diabetes, radiological examination using iodinated X-ray contrast agents can cause the development of lactic acidosis. Vipdomet^® 850 should be discontinued depending on renal function 48 hours before or during an X-ray examination using iodinated X-ray contrast agents and should not be resumed earlier than 48 hours after, provided that renal function was found to be normal during the examination.

Not recommended combinations

Alcohol in acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in case of

• Insufficient nutrition (fasting), adherence to a low-calorie diet;
• Hepatic failure.

Consumption of alcohol and intake of medicines containing ethanol should be avoided.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin, cimetidine), secreted in the renal tubules, compete with metformin for tubular transport systems and can lead to an increase in its C_max. It is recommended to carefully monitor glycemia and adjust the dose of Vipdomet^® 850 and cationic drugs excreted by tubular secretion, in accordance with the recommended method of use, in case of their simultaneous use.

Combinations requiring caution

Drugs with indirect hyperglycemic action, for example, corticosteroids (systemic and topical) and tetracosactide, beta₂-adrenergic agonists, danazol, chlorpromazine when taken in high doses (100 mg/day) and diuretics more frequent monitoring of blood glucose concentration may be required, especially at the beginning of treatment.

Some drugs may have an adverse effect on renal function, which may increase the risk of lactic acidosis, for example, NSAIDs, including selective COX-2 inhibitors and angiotensin II receptor antagonists. In case of using these drugs in combination with metformin, renal function should be carefully monitored.

Antihypertensive drugs of the ACE inhibitor class may reduce blood glucose concentration.

Diuretics simultaneous use of “loop” diuretics can lead to the development of lactic acidosis due to possible functional renal failure. Vipdomet^® 850 should not be prescribed if creatinine clearance is below 60 ml/min.

When metformin is used concomitantly with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemia may develop.

Nifedipine increases the absorption and C_max of metformin.

The hypoglycemic effect of metformin can be reduced by phenothiazines, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, slow calcium channel blockers, levothyroxine sodium.

Concomitant use with cimetidine reduces the excretion rate of metformin, which can lead to the development of lactic acidosis.

In healthy volunteers, no changes in their pharmacokinetic parameters were observed with simultaneous use of metformin and propranolol, as well as with the use of metformin and ibuprofen.

Metformin may reduce the effect of indirect anticoagulants.

Substrates of organic cation transporter 1 and 2 (OCT1 and OCT2)

Metformin is a substrate of organic cations OCT1 and OCT2.

When used concomitantly with metformin

• OCT1 inhibitors (such as verapamil) may reduce the hypoglycemic effect of metformin.
• OCT1 inducers (such as rifampicin) may increase the absorption of metformin in the gastrointestinal tract and enhance its hypoglycemic effect.
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin and lead to an increase in its plasma concentration.
• OCT1 and OCT2 inhibitors (such as crizotinib, olaparib) may reduce the hypoglycemic effect of metformin.

Storage Conditions

Store the drug out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.