Velmetia 1000 mg + 50 mg 56 coated tablets

Monotherapy
The drug Velmetia® is indicated as a first-line therapy for patients with type 2 diabetes mellitus to improve glycemic control when adherence to diet and exercise regimen does not achieve adequate control.
The drug Velmetia® is indicated as an adjunct to diet and exercise regimen to improve glycemic control in patients with type 2 diabetes mellitus who have not achieved adequate control on monotherapy with metformin or sitagliptin, or after unsuccessful combination therapy with two drugs.

Combination therapy
The drug Velmetia® is indicated for patients with type 2 diabetes mellitus to improve glycemic control in combination with sulfonylurea derivatives (triple combination: metformin + sitagliptin + sulfonylurea derivative) when diet and exercise regimen combined with two of these three drugs: metformin, sitagliptin, or sulfonylurea derivatives do not lead to adequate glycemic control.
The drug Velmetia® is indicated for patients with type 2 diabetes mellitus to improve glycemic control in combination with thiazolidinediones (PPARy receptor agonists activated by peroxisome proliferator), when diet and exercise regimen combined with two of these three drugs: metformin, sitagliptin, or thiazolidinedione do not lead to adequate glycemic control.
The drug Velmetia® is indicated for patients with type 2 diabetes mellitus to improve glycemic control in combination with insulin when diet and exercise regimen combined with insulin do not lead to adequate glycemic control.

General Information
The dosing regimen for Velmetia® should be tailored individually, based on current therapy, effectiveness, and tolerability, but should not exceed the maximum recommended daily dose of sitagliptin 100 mg.
Velmetia® is usually prescribed at a dosage of 2 times a day with meals, with a gradual increase in dosage to minimize possible gastrointestinal side effects associated with metformin.
Dosage Recommendations
The initial dose of Velmetia® depends on the current hypoglycemic therapy. Velmetia® is taken 2 times a day with meals.
The following dosages are suggested:
850 mg of metformin + 50 mg of sitagliptin,
1000 mg of metformin + 50 mg of sitagliptin.
Starting Therapy
For patients with type 2 diabetes who have inadequate glycemic control despite adherence to diet and exercise, the recommended starting dose is 500 mg of metformin + 50 mg of sitagliptin* 2 times a day. Subsequently, the dose can be increased to 1000 mg of metformin + 50 mg of sitagliptin 2 times a day.
For patients who have not achieved adequate control on monotherapy with metformin
The recommended starting dose of Velmetia® for patients who have not achieved adequate control on monotherapy with metformin should provide the recommended therapeutic daily dose of sitagliptin 100 mg, i.e., 50 mg of sitagliptin 2 times a day plus the current dose of metformin.
For patients who have not achieved adequate control on monotherapy with sitagliptin
The recommended starting dose for patients who have not achieved adequate control on monotherapy with sitagliptin is 500 mg of metformin + 50 mg of sitagliptin* 2 times a day. The dose can then be increased to 1000 mg of metformin + 50 mg of sitagliptin 2 times a day. For patients receiving a dose of sitagliptin adjusted due to renal insufficiency, treatment with Velmetia® is contraindicated (see "Contraindications" section).
For patients taking a combination of sitagliptin and metformin
When transitioning from combined treatment with sitagliptin and metformin, the starting dose of Velmetia® may be equivalent to the doses of sitagliptin and metformin taken separately.
For patients taking two of the three hypoglycemic agents - sitagliptin, metformin, or sulfonylurea derivatives
The starting dose of Velmetia® should provide the recommended therapeutic daily dose of sitagliptin 100 mg, i.e., 50 mg of sitagliptin 2 times a day. The starting dose of metformin is determined based on the level of glycemic control and the current (if the patient is taking this medication) dose of metformin.
The increase in the dose of metformin should be gradual to minimize associated gastrointestinal side effects. For patients taking a sulfonylurea derivative, it would be reasonable to reduce the current dose to lower the risk of sulfonylurea-induced hypoglycemia (see "Special Instructions" section).
For patients taking two of the three hypoglycemic agents - sitagliptin, metformin, or PPARy receptor agonists (thiazolidinediones)
The starting dose of Velmetia® should correspond to the daily dose of sitagliptin 100 mg, i.e., 50 mg of sitagliptin 2 times a day and the previously taken dose of metformin. If an increase in the dose of metformin is necessary, gradual titration of the medication is recommended to avoid gastrointestinal side effects.
For patients taking two of the three hypoglycemic agents - sitagliptin, metformin, or insulin
The starting dose of Velmetia® should correspond to the daily dose of sitagliptin 100 mg, i.e., 50 mg of sitagliptin 2 times a day and the previously taken dose of metformin. If an increase in the dose of metformin is necessary, gradual titration of the medication is recommended to avoid gastrointestinal side effects. Patients may require a reduction in insulin dosage to prevent the risk of hypoglycemia (see "Special Instructions" section).
No specific studies have been conducted to assess the safety and efficacy of transitioning from treatment with other hypoglycemic agents to treatment with the combined medication Velmetia. Any changes in the treatment of type 2 diabetes should be made with caution and under the control of relevant parameters, considering possible changes in glycemic control.
Use in Children
The safety of Velmetia® in children and adolescents under 18 years of age has not been studied.

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• When prescribing starting therapy, it should be noted that Velmetia® in the dosage of 500 mg of metformin + 50 mg of sitagliptin is not registered in the Russian Federation.

Active ingredients: sitagliptin phosphate monohydrate 64.25 mg (equivalent to 50 mg of sitagliptin) and metformin hydrochloride 1000 mg.
Excipients: microcrystalline cellulose 112.3 mg, povidone K-29/32 91.00 mg, sodium stearyl fumarate 26.00 mg, sodium lauryl sulfate 6.500 mg.
The tablet coating Opadry® II red, 85F15464 (32.50 mg) contains: polyvinyl alcohol 48.300%, titanium dioxide (E 171) 6.000%, macrogol 3350 (polyethylene glycol) 24.380%, talc 17.870%, iron oxide black (E 172) 0.150%, iron oxide red (E 172) 3.300%.

Oval biconvex film-coated tablets, reddish-brown in color, with the engraving "577" on one side of the tablet.

• Known hypersensitivity to sitagliptin, metformin, or any component of the Velmetia® preparation.

• Type 1 diabetes mellitus.

• Kidney disease or impaired kidney function (with serum creatinine concentration ≥1.5 mg/dL and ≥1.4 mg/dL in men and women respectively or creatinine clearance 65 years) were comparable to those in younger patients (

Velmetia®
Pancreatitis
Reports have been received regarding the development of acute pancreatitis, including hemorrhagic or necrotizing forms with fatal and non-fatal outcomes, in patients taking sitagliptin (see "Side Effects" section). Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis resolved after discontinuation of sitagliptin. If pancreatitis is suspected, the use of Velmetia® and other potentially harmful medications should be discontinued.
Monitoring of Kidney Function
The primary route of elimination for metformin and sitagliptin is renal excretion. The risk of metformin accumulation and the development of lactic acidosis increases proportionally with the degree of renal function impairment; therefore, Velmetia® should not be prescribed to patients with serum creatinine levels above the upper age limit of normal. In elderly patients, due to age-related decline in kidney function, efforts should be made to achieve adequate glycemic control at the minimum dose of Velmetia®. In elderly patients, especially those over 80 years of age, regular monitoring of kidney function is conducted.
Before starting treatment with metformin + sitagliptin, and at least once a year thereafter, normal kidney function should be confirmed through appropriate tests. In cases of increased likelihood of renal dysfunction, kidney function should be monitored more frequently, and if dysfunction is detected, Velmetia® should be discontinued.
Development of Hypoglycemia with Concurrent Use of Sulfonylureas or Insulin
As with other hypoglycemic agents, hypoglycemia has been observed with the concurrent use of sitagliptin and metformin in combination with insulin or sulfonylureas (see "Side Effects" section). To reduce the risk of sulfonylurea-induced or insulin-induced hypoglycemia, the dose of the sulfonylurea or insulin should be reduced (see "Dosage and Administration" section).
Sitagliptin
Development of Hypoglycemia with Concurrent Use of Sulfonylureas or Insulin
In clinical studies of sitagliptin, both as monotherapy and in combination with non-hypoglycemic agents (i.e., metformin or PPARy-thiazolidinedione agonists), the frequency of hypoglycemia in the sitagliptin group was similar to that in the placebo group. As with other hypoglycemic agents, hypoglycemia has been observed with the concurrent use of sitagliptin in combination with insulin or sulfonylureas (see "Side Effects" section). To reduce the risk of sulfonylurea-induced or insulin-induced hypoglycemia, the dose of the sulfonylurea or insulin should be reduced (see "Dosage and Administration" section).
Hypersensitivity Reactions
During post-marketing surveillance of the combination of metformin + sitagliptin or sitagliptin as monotherapy and/or in combination with other hypoglycemic agents, hypersensitivity reactions have been identified. These reactions included anaphylaxis, angioedema, exfoliative skin diseases, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from a population of undefined size, the frequency and causal relationship with therapy cannot be determined. These reactions occurred within the first 3 months after starting sitagliptin, with some observed after the first dose of the drug. If a hypersensitivity reaction is suspected, the use of Velmetia® should be discontinued, other possible causes of the adverse event should be evaluated, and alternative hypolipidemic therapy should be initiated (see "Contraindications" and "Side Effects. Post-Marketing Observations" sections).
Metformin
Lactic Acidosis
Lactic acidosis is a rare but serious metabolic complication that can develop due to the accumulation of metformin during treatment with metformin + sitagliptin. The mortality rate for lactic acidosis is approximately 50%. Lactic acidosis may also occur against the background of certain somatic diseases, particularly diabetes mellitus or any other pathological condition associated with significant hypoperfusion and hypoxemia of tissues and organs. Lactic acidosis is characterized by elevated plasma lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. If metformin is the cause of acidosis, its plasma concentration is usually >5 mcg/mL.
According to available data, lactic acidosis during metformin treatment has developed very rarely (approximately 0.03 cases per 1000 patient-years, with a mortality rate of about 0.015 cases per 1000 patient-years). Over 20,000 patient-years of metformin treatment in clinical trials, not a single case of lactic acidosis was reported. Known cases primarily occurred in patients with diabetes and significant renal impairment, including severe kidney pathology and renal hypoperfusion, often in conjunction with multiple comorbidities and polypharmacy. The risk of lactic acidosis is significantly increased in patients with chronic heart failure requiring substantial medication correction, especially during unstable angina/chronic heart failure exacerbations accompanied by significant hypoperfusion and hypoxemia. The risk of lactic acidosis increases proportionally with the degree of renal function impairment and patient age; therefore, adequate monitoring of kidney function and the use of the minimum effective dose of metformin significantly help reduce the risk of lactic acidosis. Careful monitoring of kidney function is especially necessary when treating elderly patients, and in patients over 80 years of age, metformin treatment should only be initiated after confirming adequate kidney function based on creatinine clearance assessment, as these patients are at higher risk for lactic acidosis. Additionally, in any condition associated with hypoxemia, dehydration, or sepsis, metformin should be immediately discontinued. Given that lactate clearance is significantly reduced in patients with liver dysfunction, metformin should not be prescribed to patients with clinical or laboratory signs of liver disease. During metformin treatment, alcohol consumption should be limited, as alcohol potentiates the effect of metformin on lactate metabolism. Furthermore, metformin treatment should be temporarily suspended during intravascular radiocontrast studies and surgical interventions.
The onset of lactic acidosis is often difficult to detect and is accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress syndrome, increased drowsiness, and nonspecific dyspeptic symptoms. As lactic acidosis progresses, the aforementioned symptoms may be joined by hypothermia, arterial hypotension, and resistant bradyarrhythmia. Both the physician and the patient should be aware of the potential significance of such symptoms, and the patient should promptly inform the physician of their occurrence. Metformin treatment should be discontinued until the situation is clarified. Plasma concentrations of electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate concentration should be determined. Sometimes, information about plasma metformin concentration may also be useful. After the patient has adapted to the optimal dose of metformin, gastrointestinal symptoms characteristic of the initial stages of treatment should disappear. If such symptoms appear, they are likely a signal of developing lactic acidosis or another serious condition.
If, during metformin treatment, the plasma lactate concentration exceeds the upper limit of normal, remaining below 5 mmol/L, this is not pathognomonic for lactic acidosis and may be due to conditions such as poorly controlled diabetes or obesity, excessive physical exertion, or technical measurement error.
Any patient with diabetes and metabolic acidosis in the absence of confirmed ketoacidosis (ketonuria and ketonemia) is at risk for lactic acidosis.
Lactic acidosis is a condition requiring emergency medical assistance in a healthcare facility. Metformin treatment should be discontinued, and necessary supportive therapy measures should be promptly initiated. Since metformin is dialyzed at a rate of up to 170 mL/min under good hemodynamic conditions, immediate hemodialysis is recommended for rapid correction of acidosis and removal of accumulated metformin. The listed measures often lead to the rapid resolution of all lactic acidosis symptoms and restoration of the patient's condition (see "Contraindications" section).
Hypoglycemia
Under normal circumstances, hypoglycemia does not develop with metformin monotherapy; however, it may occur in the context of fasting, after significant physical exertion without subsequent compensation of expended calories, with concurrent use of other hypoglycemic agents (sulfonylureas and insulin) or alcohol. Elderly, weakened, or malnourished patients, patients who abuse alcohol, and patients with adrenal or pituitary insufficiency are more prone to hypoglycemia. Hypoglycemia can be difficult to recognize in elderly patients and those taking beta-blockers.
Concomitant Therapy
Concomitant pharmacotherapy may negatively affect kidney function or the distribution of metformin. The concurrent use of drugs that negatively impact kidney function, hemodynamics, or the distribution of metformin (such as cationic drugs that are eliminated from the body via tubular secretion) should be prescribed with caution (see "Interactions with Other Drugs. Metformin" section).
Radiological Studies with Intravascular Administration of Iodine-Containing Contrast Agents (e.g., intravenous urogram, intravenous cholangiography, angiography, computed tomography with intravenous contrast agents)
Intravascular administration of iodine-containing contrast agents has been associated with the development of lactic acidosis in patients taking metformin and may cause acute kidney function impairment (see "Contraindications" section). Therefore, patients scheduled for such studies should temporarily discontinue Velmetia® for 48 hours before and for 48 hours after the study. Resumption of treatment is permissible only after laboratory confirmation of normal kidney function.
Hypoxic Conditions
Vascular collapse (shock) of any etiology, acute heart failure, acute myocardial infarction, and other conditions accompanied by hypoxemia may provoke the development of lactic acidosis and pre-renal azotemia. If these conditions develop in a patient receiving metformin + sitagliptin, the medication should be immediately discontinued.
Surgical Interventions
The use of Velmetia® should be discontinued during any surgical intervention (except for minor procedures that do not require restrictions on fluid intake and fasting) and until the resumption of the normal diet, provided that normal kidney function is confirmed by laboratory tests.
Alcohol Consumption
Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned about the dangers of alcohol abuse (either a single large intake or continuous small doses) during treatment with metformin + sitagliptin.
Liver Function Impairment
Since cases of lactic acidosis have been reported in patients with liver dysfunction, it is not recommended to prescribe Velmetia® to patients with clinical or laboratory signs of liver disease.
Plasma Concentration of Cyanocobalamin (Vitamin B12)
In studies of metformin, 7% of patients experienced a decrease in initially normal plasma concentrations of cyanocobalamin (vitamin B12) without the development of clinical symptoms of deficiency. This decrease may be due to selective impairment of vitamin B12 absorption (specifically, disruption of the formation of the complex with intrinsic factor necessary for vitamin B12 absorption) and very rarely leads to anemia, which can be easily corrected by discontinuing metformin or supplementing with vitamin B12. When treating with metformin + sitagliptin, it is recommended to check hematological parameters annually, and any deviations should be investigated and corrected.
Patients predisposed to vitamin B12 deficiency (due to reduced intake or absorption of vitamin B12 or calcium) are advised to determine plasma vitamin B12 concentration every 2-3 years.
Changes in Clinical Status of Patients with Adequately Controlled Type 2 Diabetes
In the event of laboratory deviations or clinical symptoms of disease (especially any condition that cannot be clearly identified) in a patient with previously adequately controlled type 2 diabetes during treatment with metformin + sitagliptin, ketoacidosis or lactic acidosis should be immediately ruled out. The assessment of the patient's condition should include blood tests for electrolytes and ketones, blood glucose concentration, and, if indicated, blood pH, plasma concentrations of lactate, pyruvate, and metformin. If acidosis of any etiology develops, the use of Velmetia® should be immediately discontinued, and appropriate measures to correct the acidosis should be taken.
Loss of Glycemic Control
In situations of physiological stress (hyperthermia, trauma, infection, or surgical intervention), a patient with previously stable glycemic control may experience a temporary loss of glycemic control. During such periods, temporary substitution of Velmetia® with insulin therapy is permissible, and after resolution of the acute situation, the patient may resume previous treatment.
Study on Cardiovascular Safety of Sitagliptin (TECOS)
In the study evaluating the cardiovascular safety of sitagliptin (TECOS), patients received sitagliptin or placebo, which were added to standard therapy according to existing national standards for defining target HbA1C levels and controlling cardiovascular risk factors. At the end of an average follow-up period of 3 years, in patients with type 2 diabetes, the use of sitagliptin in addition to standard treatment did not increase the risk of serious adverse cardiovascular events or the risk of hospitalization due to heart failure compared to standard treatment without additional sitagliptin.
Effect on Ability to Drive and Operate Machinery:
No studies have been conducted to assess the effect of Velmetia® on the ability to drive vehicles and operate machinery. However, cases of dizziness and drowsiness have been noted with the use of sitagliptin.
Additionally, patients should be aware of the risk of hypoglycemia when using Velmetia® concurrently with sulfonylureas or insulin.

In studies, the combination treatment of sitagliptin and metformin was generally well tolerated by patients with type 2 diabetes. The frequency of side effects with the combination treatment of sitagliptin and metformin was comparable to the frequency observed with metformin in combination with placebo.

Combination treatment with sitagliptin and metformin
Initial therapy
In the study of initial combination therapy with sitagliptin and metformin (sitagliptin 50 mg + metformin 500 mg or 1000 mg twice daily), the following drug-related adverse reactions were observed with a frequency of ≥1% in the combination therapy group compared to the metformin monotherapy groups (500 mg or 1000 mg twice daily), sitagliptin (100 mg once daily), or placebo: diarrhea (sitagliptin + metformin - 3.5%, metformin - 3.3%, sitagliptin - 0.0%, placebo - 1.1%), nausea (1.6%, 2.5%, 0.0% and 0.6%), dyspepsia (1.3%, 1.1%, 0.0% and 0.0%), flatulence (1.3%, 0.5%, 0.0% and 0.0%), vomiting (1.1%, 0.3%, 0.0% and 0.0%), headache (1.3%, 1.1%, 0.6% and 0.0%) and hypoglycemia (1.1%, 0.5%, 0.6% and 0.0%).

Addition of sitagliptin to current metformin therapy
In the study where sitagliptin was added at a dose of 100 mg/day to ongoing metformin treatment, the only drug-related adverse reaction observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group was nausea (sitagliptin + metformin - 1.1%, placebo + metformin - 0.4%).

Hypoglycemia and gastrointestinal adverse reactions
In studies of combination treatment with sitagliptin and metformin, the frequency of hypoglycemia (regardless of causality) in the combination therapy groups was comparable to the frequency in metformin treatment groups combined with placebo (1.3-1.6% and 2.1%, respectively). The frequency of monitored gastrointestinal adverse reactions (regardless of causality) in the combination treatment groups of sitagliptin and metformin was comparable to the frequency in metformin monotherapy groups: diarrhea (sitagliptin + metformin - 7.5%, metformin - 7.7%), nausea (4.8%, 5.5%), vomiting (2.1%, 0.5%), abdominal pain (3.0%, 3.8%).
In all studies, adverse reactions in the form of hypoglycemia were recorded based on all reports of clinically significant hypoglycemia symptoms; additional blood glucose measurements were not required.

Combination treatment with sitagliptin, metformin, and sulfonylurea derivative
In a study using sitagliptin at a dose of 100 mg/day in the background of ongoing combination treatment with glimepiride at a dose of ≥4 mg/day and metformin at a dose of ≥1500 mg/day, the following drug-related adverse reactions were observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group: hypoglycemia (sitagliptin - 13.8%, placebo - 0.9%), constipation (1.7% and 0.0%).

Combination treatment with sitagliptin, metformin, and FPARy agonist
According to the study using sitagliptin at a dose of 100 mg/day in the background of ongoing combination treatment with rosiglitazone and metformin at the 18th week of treatment, the following drug-related adverse reactions were observed with a frequency of ≥1% in the sitagliptin treatment group more frequently than in the placebo group: headache (sitagliptin - 2.4%, placebo - 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), vomiting (1.2%, 0.0%). At the 54th week of combination treatment, the following drug-related adverse reactions were observed with a frequency of ≥1% in the sitagliptin treatment group more frequently than in the placebo group: headache (sitagliptin - 2.4%, placebo - 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory infections (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), skin fungal infections (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), vomiting (1.2%, 0.0%).

Combination treatment with sitagliptin, metformin, and insulin
In a study using sitagliptin at a dose of 100 mg/day in the background of ongoing combination treatment with metformin at a dose of ≥1500 mg/day and a constant dose of insulin, the only drug-related adverse reaction observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the placebo group was hypoglycemia (sitagliptin - 10.9%, placebo - 5.2%). In another study where patients received sitagliptin as an add-on therapy to insulin therapy (with or without metformin), the only adverse reaction observed with a frequency of ≥1% in the sitagliptin and metformin treatment group and more frequently than in the placebo and metformin group was vomiting (sitagliptin and metformin - 1.1%, placebo and metformin - 0.4%).

Pancreatitis
In a pooled analysis of studies using sitagliptin (at a dose of 100 mg/day) or the corresponding control drug (active or placebo), the frequency of unconfirmed acute pancreatitis was 0.1 cases per 100 patient-years of treatment in each group. See also the study on the cardiovascular safety of sitagliptin (TECOS) below (see "Special Instructions. Pancreatitis" section). No clinically significant deviations in vital signs or ECG (including QTc interval duration) were observed during combination therapy with sitagliptin and metformin.

Adverse reactions related to the use of sitagliptin
No adverse reactions related to the use of sitagliptin were observed in patients with a frequency of ≥1%.

Adverse reactions related to the use of metformin
Adverse reactions observed in the metformin group in >5% of patients and more frequently than in the placebo group include diarrhea, nausea/vomiting, flatulence, asthenia, dyspepsia, abdominal discomfort, and headache.

Study on the assessment of cardiovascular safety of sitagliptin (TECOS)
The study on the assessment of cardiovascular safety of sitagliptin (TECOS) included 7332 patients who received sitagliptin and 7339 patients who received placebo, in the overall population of patients assigned to treatment. The studied drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for selecting the target HbA1C level and controlling cardiovascular risk factors. A total of 2004 patients aged 75 years and older were included in the study. The overall frequency of serious adverse events in patients receiving sitagliptin was the same as in patients receiving placebo. Assessment of previously designated complications related to diabetes revealed comparable frequencies of adverse events between groups, including infections (18.4% in patients receiving sitagliptin and 17.7% in patients receiving placebo) and renal function impairment (1.4% in patients receiving sitagliptin and 1.5% in patients receiving placebo). The profile of adverse events in patients aged 75 years and older was generally similar to that of the overall population.
In the population of patients assigned to treatment ("intention-to-treat"), among those who initially received insulin therapy and/or sulfonylurea drugs, the frequency of severe hypoglycemia episodes was 2.7% in patients receiving sitagliptin and 2.5% in patients receiving placebo. Among patients who initially did not receive insulin and/or sulfonylurea drugs, the frequency of severe hypoglycemia episodes was 1.0% in patients receiving sitagliptin and 0.7% in patients receiving placebo. The frequency of confirmed cases of pancreatitis was 0.3% in patients receiving sitagliptin and 0.2% in patients receiving placebo. The frequency of confirmed cases of malignant neoplasms was 3.7% in patients receiving sitagliptin and 4.0% in patients receiving placebo.

Post-marketing surveillance
During post-marketing monitoring of the use of the combination of metformin + sitagliptin or sitagliptin as monotherapy and/or in combination therapy with other hypoglycemic agents, additional adverse events were identified. Since these data were obtained voluntarily from a population of uncertain size, the frequency and causality of these adverse events with therapy cannot be determined. These include: hypersensitivity reactions, including anaphylaxis; angioedema; skin rash; urticaria; cutaneous vasculitis; exfoliative skin diseases, including Stevens-Johnson syndrome; acute pancreatitis, including hemorrhagic and necrotizing forms with fatal and non-fatal outcomes; worsening of renal function, including acute renal failure (sometimes requiring dialysis); upper respiratory infections; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; limb pain; back pain; itching; pemphigoid.

Laboratory parameter changes
Sitagliptin
The frequency of laboratory parameter deviations in the sitagliptin and metformin treatment groups was comparable to the frequency in the placebo and metformin treatment groups. In most, but not all clinical studies, a slight increase in leukocyte count (approximately 200/μL compared to placebo, with a mean count at baseline of 6600/μL) was noted, attributed to an increase in neutrophils. This change is not considered clinically significant.
Metformin
In studies of metformin, a decrease in normal serum concentrations of cyanocobalamin (vitamin B12) to subnormal values was noted in approximately 7% of patients, without clinical manifestations. Such a decrease, caused by selective malabsorption of vitamin B12 (specifically, impairment of the formation of the complex with intrinsic factor Castle, necessary for the absorption of vitamin B12), very rarely leads to the development of anemia and is easily corrected by discontinuation of metformin or additional intake of vitamin B12 (see "Special Instructions. Metformin" section).

Sitagliptin
During clinical trials in healthy volunteers, a single dose of sitagliptin up to 800 mg was generally well tolerated. Minimal changes in the QT interval, not considered clinically significant, were noted in one study of sitagliptin at a daily dose of 800 mg (see "Pharmacodynamics. Effect on Cardiac Electrophysiology"). Doses exceeding 800 mg per day in humans have not been studied.
In clinical studies of multiple dosing (Phase I), no treatment-related adverse reactions were observed with sitagliptin at a daily dose of up to 400 mg for 28 days.
In case of overdose, standard supportive measures should be initiated: removal of any unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including ECG, and symptomatic therapy as needed.
Sitagliptin is poorly dialyzed: clinical studies show that only 13.5% of the dose was eliminated during a 3-4 hour dialysis session. In case of clinical necessity, prolonged hemodialysis may be indicated. There is no data on the effectiveness of peritoneal dialysis for sitagliptin.

Metformin
There have been cases of metformin overdose, including ingestion of amounts exceeding 50 g (50000 mg). Hypoglycemia was observed in approximately 10% of all overdose cases; however, a clear link to metformin overdose has not been established. The development of lactic acidosis accompanied approximately 32% of all cases of metformin overdose (see "Special Precautions. Metformin"). Emergency hemodialysis may be performed (metformin is dialyzed at a rate of up to 170 ml/min under good hemodynamic conditions) for the accelerated removal of excess metformin in suspected overdose cases.

Sitagliptin and Metformin
The simultaneous administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily) did not result in significant changes in the pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes mellitus.
No studies on drug interactions affecting the pharmacokinetic parameters of Velmetia® have been conducted; however, a sufficient number of such studies have been performed for each component of the drug, sitagliptin and metformin.
Sitagliptin
In drug interaction studies, sitagliptin did not have a clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on this data, sitagliptin does not inhibit the isoenzymes of the CYP cytochrome system CYP3A4, 2C8, or 2C9. In vitro data indicate that sitagliptin also does not inhibit the isoenzymes CYP2D6, 1A2, 2C19, and 2B6 and does not induce CYP3A4.
According to population pharmacokinetic analysis in patients with type 2 diabetes mellitus, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin. The study evaluated a number of drugs most commonly used by patients with type 2 diabetes mellitus, including hypocholesterolemic agents (statins, fibrates, ezetimibe), antiplatelet agents (clopidogrel), antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory drugs (naproxen, diclofenac, celecoxib), antidepressants (bupropion, fluoxetine, sertraline), antihistamines (cetirizine), proton pump inhibitors (omeprazole, lansoprazole), and erectile dysfunction treatments (sildenafil).
An increase in AUC (11%) and average Cmax (18%) of digoxin was noted when used concurrently with sitagliptin. This increase is not considered clinically significant; however, monitoring of the patient is recommended when digoxin is taken simultaneously. An increase in AUC and Cmax of sitagliptin by 29% and 68%, respectively, was observed with the concurrent single oral administration of sitagliptin at a dose of 100 mg and cyclosporine (a potent P-glycoprotein inhibitor) at a dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin are not clinically significant.
Metformin
Glibenclamide: In a drug interaction study of single doses of metformin and glibenclamide in patients with type 2 diabetes mellitus, no changes in the pharmacokinetic and pharmacodynamic parameters of metformin were observed.
Changes in AUC and Cmax values of glibenclamide were highly variable. Insufficient information (single dose) and the discrepancy between the plasma concentration of glibenclamide and the observed pharmacodynamic effects raise questions about the clinical significance of this interaction.
Furosemide: In a drug interaction study of single doses of metformin and furosemide in healthy volunteers, changes in the pharmacokinetic parameters of both drugs were observed. Furosemide increased the Cmax concentration of metformin in plasma and whole blood by 22%, and the AUC of metformin in whole blood by 15%, without changing the renal clearance of the drug. The Cmax and AUC values of furosemide, in turn, decreased by 31% and 12%, respectively, and the half-life decreased by 32% without significant changes in the renal clearance of furosemide. There is no information on drug interaction between the two drugs with prolonged concurrent use.
Nifedipine: In a drug interaction study of nifedipine and metformin after a single administration of the drugs to healthy volunteers, an increase in plasma Cmax and AUC of metformin by 20% and 9%, respectively, as well as an increase in the amount of metformin excreted by the kidneys was observed. Tmax and the half-life of metformin did not change. This is based on the increased 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), eliminated by tubular secretion, may theoretically interact with metformin by competing for the shared renal tubular transport system. Such competition was observed with the simultaneous administration of metformin and cimetidine in healthy volunteers in single and multiple dose studies, with a 60% increase in Cmax concentration of metformin in plasma and whole blood and a 40% increase in AUC of metformin in plasma and whole blood. In the single dose study, the half-life of metformin did not change. Metformin did not affect the pharmacokinetics of cimetidine. Although these drug interactions are primarily of theoretical significance (except for cimetidine), careful monitoring of the patient and dose adjustment of Velmetia® and/or the aforementioned cationic drugs, excreted by the proximal parts of the renal tubules, is recommended in cases of their simultaneous administration.
Others: Some drugs have a hyperglycemic potential and may interfere with established glycemic control. These include thiazide and other diuretics, glucocorticoids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When prescribing the listed drugs to a patient receiving Velmetia®, careful monitoring of glycemic control parameters is recommended.
No changes in the pharmacokinetic parameters of metformin were observed when metformin was taken simultaneously with propranolol or ibuprofen in healthy volunteers.
Only a small proportion of metformin binds to plasma proteins; therefore, drug interactions of metformin with drugs that actively bind to plasma proteins (salicylates, sulfonamides, chloramphenicol, and probenecid) are unlikely, unlike sulfonylurea derivatives, which also actively bind to plasma proteins.

The drug Velmetia® is a combination of two hypoglycemic agents with complementary mechanisms of action, intended to improve glycemic control in patients with type 2 diabetes: sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), and metformin, a representative of the biguanide class.
Sitagliptin is an active oral medication, a highly selective DPP-4 inhibitor, designed for the treatment of type 2 diabetes. The pharmacological effects of DPP-4 inhibitor class medications are mediated by the activation of incretins. By inhibiting DPP-4, sitagliptin increases the concentration of two known active hormones from the incretin family: glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are part of the internal physiological system regulating glucose homeostasis. At normal or elevated blood glucose levels, GLP-1 and GIP promote increased synthesis and secretion of insulin from pancreatic beta cells. GLP-1 also suppresses glucagon secretion from pancreatic alpha cells, thereby reducing glucose synthesis in the liver. This mechanism of action differs from that of sulfonylurea derivatives, which stimulate insulin release even at low blood glucose levels, posing a risk of sulfonylurea-induced hypoglycemia not only in patients with type 2 diabetes but also in healthy individuals. As a highly selective and effective DPP-4 enzyme inhibitor, sitagliptin at therapeutic concentrations does not suppress the activity of related enzymes DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogs, insulin, sulfonylurea derivatives or meglitinides, biguanides, PPARy agonists, alpha-glucosidase inhibitors, and amylin analogs.
Metformin
Metformin is a hypoglycemic agent that increases glucose tolerance in patients with type 2 diabetes by reducing both basal and postprandial blood glucose levels. Its pharmacological mechanisms of action differ from those of oral hypoglycemic agents from other classes.
Metformin reduces glucose synthesis in the liver, decreases glucose absorption in the intestine, and increases insulin sensitivity by enhancing peripheral glucose uptake and utilization. Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia in either patients with type 2 diabetes or healthy individuals (except under certain circumstances, see the "Caution" section on Metformin) and does not induce hyperinsulinemia. During metformin treatment, insulin secretion remains unchanged, while fasting insulin levels and daily plasma insulin concentrations may decrease.
Oral administration of a single dose of sitagliptin in patients with type 2 diabetes leads to inhibition of DPP-4 enzyme activity for 24 hours, accompanied by a two- to threefold increase in circulating active GLP-1 and GIP concentrations, an increase in plasma insulin and C-peptide levels, a decrease in glucagon concentration, and a reduction in fasting plasma glucose levels, as well as a decrease in the amplitude of glycemic fluctuations after glucose or food intake.
Administration of sitagliptin at a daily dose of 100 mg for 4-6 months significantly improved pancreatic beta cell function in patients with type 2 diabetes, as evidenced by corresponding changes in markers such as HOMA-? (homeostasis model assessment), proinsulin/insulin ratio, and assessment of beta cell response based on repeated food tolerance test panels. According to phase II and III clinical studies, the efficacy of glycemic control with sitagliptin at a regimen of 50 mg twice daily was comparable to that of a regimen of 100 mg once daily.
In a study involving healthy volunteers, the effect of sitagliptin in combination with metformin, either sitagliptin alone, metformin alone, or placebo on changes in plasma concentrations of active and total GLP-1 and glucose after meals was investigated. The mean concentrations of active GLP-1 four hours after a meal increased approximately twofold after administration of either sitagliptin alone or metformin alone compared to placebo. The combined administration of sitagliptin and metformin provided a summation effect with a fourfold increase in active GLP-1 concentration compared to the dynamics in the placebo group. Administration of sitagliptin alone was associated with an increase in only active GLP-1 concentration due to DPP-4 enzyme inhibition, while administration of metformin alone was associated with a symmetrical increase in both total and active GLP-1 concentrations.
The obtained data reflect the different mechanisms underlying the increase in active GLP-1 concentration after the administration of these two drugs. The results of the study also demonstrated that it is sitagliptin, not metformin, that provides the increase in active GLP-1 concentration.
In studies involving healthy volunteers, administration of sitagliptin was not associated with a decrease in glucose concentration and did not cause hypoglycemia, confirming the glucose-dependent nature of its insulinotropic action and suppression of glucagon synthesis.
Effect on Blood Pressure
In a study involving patients with arterial hypertension, the combined administration of antihypertensive medications (one or more from the list: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, "slow" calcium channel blockers, beta-blockers, diuretics) with sitagliptin was generally well tolerated by patients. In this category of patients, sitagliptin demonstrated a slight hypotensive effect: at a daily dose of 100 mg, sitagliptin reduced the mean daily ambulatory systolic blood pressure (BP) by 2 mmHg compared to the placebo group. No hypotensive effect was observed in patients with normal BP.
Effect on Cardiac Electrophysiology
In a study involving healthy volunteers, sitagliptin was administered as a single dose of 100 mg or 800 mg (8 times the recommended dose), or placebo. After administration of the recommended therapeutic dose, no effect of the drug on the QT interval duration was observed at its maximum plasma concentration or at other checkpoints throughout the study. After administration of 800 mg, the maximum increase in placebo-corrected mean change in QT interval duration compared to baseline value three hours after drug administration was 8.0 msec. This slight increase was assessed as clinically insignificant. After administration of the 800 mg dose, the maximum plasma concentration of sitagliptin was approximately 11 times higher than the corresponding value after administration of the therapeutic dose of 100 mg.

Results of the bioequivalence study in healthy volunteers demonstrated that the combined tablets of metformin + sitagliptin 500 mg + 50 mg and 1000 mg + 50 mg are bioequivalent to the separate administration of the corresponding doses of sitagliptin and metformin.

Considering the proven bioequivalence of the tablets with the lowest and highest doses of metformin, the intermediate dose tablet (metformin + sitagliptin) 850 mg + 50 mg was also assigned bioequivalence when combined in a fixed-dose tablet.

Absorption
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%. The intake of sitagliptin with fatty food does not affect the pharmacokinetics of the drug.
Metformin
The absolute bioavailability of metformin when taken on an empty stomach at a dose of 500 mg is 50-60%. Results from studies of single doses of metformin ranging from 500 mg to 1500 mg and from 850 mg to 2550 mg indicate a loss of dose-proportionality with increasing doses, which is more likely due to reduced absorption rather than accelerated elimination. The simultaneous intake of the drug with food decreases the rate and amount of absorbed metformin, as evidenced by a reduction in the maximum plasma concentration (Cmax) by approximately 40%, a decrease in the area under the concentration-time curve (AUC) by approximately 25%, and a 35-minute delay in reaching the maximum plasma concentration (Tmax) after a single dose of metformin 850 mg taken with food compared to the corresponding parameters after taking the same dose of the drug on an empty stomach. The clinical significance of the reduction in pharmacokinetic parameters has not been established.

Distribution
Sitagliptin
The average volume of distribution at steady state after a single intravenous administration of 100 mg of sitagliptin in healthy volunteers is approximately 198 L. The fraction of sitagliptin that reversibly binds to plasma proteins is relatively small (38%).
Metformin
The volume of distribution of metformin after a single oral dose of 850 mg was on average 654±358 L. Metformin binds only to a very small extent to plasma proteins. Metformin is partially and temporarily distributed in erythrocytes. When metformin is used at recommended doses and regimens, steady-state plasma concentrations (usually