Combogliz Prolong, 1000 mg+2, 5 mg 56 pcs.

Mechanism of Action

Combogliz Prolong combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes (T2DM): saxagliptin, a dipeptyl peptidase 4 (DPP-4) inhibitor, and metformin, a class of biguanides.

Saxagliptin

In response to food intake, incretin hormones such as glucagon-like peptide-1 (GFP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine.

These hormones promote insulin release from pancreatic beta cells, which is dependent on blood glucose concentration, but are inactivated by DPP-4 enzyme within minutes. PPP-1 also decreases glucagon secretion in pancreatic alpha cells, reducing glucose production in the liver. In patients with DM2, the concentration of GFP-1 is reduced, but the insulin response to GFP-1 is maintained. Saxagliptin, as a competitive inhibitor of DPP-4, reduces inactivation of the hormone incretins, thereby increasing their concentrations in the bloodstream and leading to decreased glucose concentrations on an empty stomach and after meals.

Metformin

Metformin is a hypoglycemic drug that improves glucose tolerance in patients with DM2 by lowering basal and postprandial glucose concentrations. Metformin reduces glucose production by the liver, reduces glucose absorption in the intestine, and increases insulin sensitivity by increasing peripheral glucose absorption and utilization. Unlike sulfonylurea drugs, metformin does not cause hypoglycemia in patients with DM2 or healthy people (except in special situations, see sections “Caution” and “Special indications”), and hyperinsulinemia. During therapy with metformin, insulin secretion remains unchanged, although fasting insulin concentrations and in response to meals during the day may decrease.

PHARMACOKINETICS
Saxagliptin

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy-saxagliptin, are similar in healthy volunteers and in patients with DM2. The Cmax values and the area under the AUC curve of saxagliptin and its active metabolite in plasma increased proportionally in the dose range from 2.5 mg to 400 mg. After a single oral dose of 5 mg of saxagliptin in healthy volunteers, the mean AUC values of saxagliptin and its major metabolite were 78 ng*h/mL and 214 ng*h/mL, and plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The mean variability of AUC and Cmax of saxagliptin and its active metabolite was less than 25%.

There is no appreciable cumulation of saxagliptin or its active metabolite when the drug is repeated once daily in any dosage. There is no dose and time dependence of clearance of saxagliptin and its active metabolite when used once daily for 14 days in doses from 2.5 mg to 400 mg of saxagliptin.

Metformin

The cmax of modified-release metformin is reached in an average of 7 hours. The absorption rate of metformin from modified-release tablets is increased by approximately 50% when taken with meals. At equilibrium, the AUC and Cmax of modified-release metformin increased disproportionately to the dosage in the dose range from 500 to 2000 mg. After repeated dosing, modified-release metformin did not accumulate in plasma. Metformin is excreted unchanged by the kidneys and is not metabolized in the liver.

Saxagliptin

At least 75% of the administered dose of saxagliptin is absorbed after oral administration. Food intake had no significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. High-fat meal had no effect on the Cmax of saxagliptin, whereas the AUC was increased by 27% compared with fasting meal. The time to reach Cmax (Tmax) for saxagliptin was increased by approximately 0.5 h when the drug was taken with food compared with fasting food intake. However, these changes are not clinically significant.

Metformin

After a single oral administration of modified-release metformin, Cmax is reached after an average of 7 hours, ranging from 4 to 8 hours. The AUC and Cmax of modified-release metformin increased disproportionately to the dosage in the dose range from 500 to 2000 mg. Maximum plasma concentrations of the drug were 0.6, 1.1, 1.4, and 1.8 µg/ml at doses of 500, 1000, 1500, and 2000 mg once daily, respectively. Although the degree of absorption (measured by AUC) of metformin from modified-release metformin tablets is increased by approximately 50% when taken with food, food intake had no effect on the Cmax and Tmax of metformin. Low- and high-fat foods had the same effect on the pharmacokinetic parameters of modified-release metformin.

Distribution

Saxagliptin

. The binding of saxagliptin and its major metabolite to serum proteins is insignificant, so it can be assumed that the distribution of saxagliptin will not be significantly altered by changes in serum proteins noted in hepatic or renal insufficiency.

Metformin

There have been no studies of the distribution of modified-release metformin, but the apparent distribution of metformin after a single oral dose of 850 mg immediate-release metformin tablets averaged 654±358 L. Metformin is slightly bound to plasma proteins.

Metabolism

Saxagliptin

. Saxagliptin is metabolized mainly with the participation of cytochrome P450 isoenzymes of CA4/5 (CYP3A4/5) to form the active main metabolite, whose inhibitory effect against DPP-4 is 2 times weaker than that of saxagliptin.

Metformin

Studies with single intravenous administration of the drug in healthy volunteers show that metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted through the intestine.

Saxagliptin

Saxagliptin is excreted by the kidneys and through the intestine. After a single dose of 50 mg of 14C-labeled saxagliptin, 24% of the dose was excreted by the kidneys as unchanged saxagliptin and 36% as the major metabolite saxagliptin. The total radioactivity detected in the urine corresponded to 75% of the dose taken.

The mean renal clearance of saxagliptin was approximately 230 ml/min, the mean glomerular filtration was approximately 120 ml/min. For the main metabolite, renal clearance was comparable to the average glomerular filtration values. About 22% of the total radioactivity was found in the feces.

Metformin

The renal clearance was approximately 3.5 times the creatinine clearance (CK), indicating that tubular secretion is the major route of metformin excretion. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, hence the erythrocyte mass may be part of the distribution.

Pharmacokinetics in special clinical situations

Renal impairment

Combogliz Prolong is not recommended in patients with renal impairment.

Saxagliptin

In patients with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% (respectively) higher than the AUC values in patients with normal renal function. Since this increase is not considered clinically significant, it is not recommended to adjust the dose of saxagliptin in patients with mild renal impairment.

Metformin

In patients with impaired renal function (based on CK measurements), the half-life of metformin from plasma and blood is prolonged and renal clearance decreases in proportion to the decrease in CK.

Hepatic impairment

Saxagliptin

In patients with mild, moderate and severe hepatic impairment no clinically significant changes in pharmacokinetic parameters of saxagliptin have been found, so no dose adjustment is required for these patients.

Metformin

There have been no pharmacokinetic studies of metformin in patients with hepatic impairment.

Gender

Saxagliptin

Dose adjustment of saxagliptin according to the gender of patients is not required.

Metformin

In clinical studies in patients with DM2, the hypoglycemic effects of metformin in men and women were comparable.

Elderly patients

Saxagliptin

There were no clinically significant differences in saxagliptin pharmacokinetic parameters in patients 65-80 years old compared with younger patients (18-40 years), so no dose adjustment in elderly patients is required. However, it should be taken into account that in this category of patients it is more likely to decrease renal function (see sections “Dosage and administration” and “Cautions”).

Metformin

Limited data from controlled studies of metformin pharmacokinetics in healthy elderly volunteers suggest that total plasma clearance of metformin is decreased, T1/2 is increased, and Cmax is increased compared to the values of these parameters in healthy young volunteers. According to these data, the change in metformin pharmacokinetic parameters with increasing age is mainly due to changes in renal function. Combogliz Prolong should not be administered to patients over 80 years of age unless normal renal function has been confirmed by CK measurements.

Children

Saxagliptin

No pharmacokinetic studies of saxagliptin have been performed in children.

Metformin

There have been no studies on the pharmacokinetics of modified-release metformin in children.

Race and ethnicity

Saxagliptin

It is not recommended to adjust the dose of saxagliptin according to the race of the patient.

Metformin

There have been no studies of metformin pharmacokinetic parameters depending on the race of patients.

Indications

Type 2 diabetes combined with diet and exercise to improve glycemic control.

Pharmacological effect

Mechanism of action

Comboglise Prolong combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): saxagliptin, a dipeptyl peptidase 4 (DPP-4) inhibitor, and metformin, a member of the biguanide class.

Saxagliptin

In response to food intake, incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine.

These hormones promote the release of insulin from the beta cells of the pancreas, depending on the concentration of blood glucose, but are inactivated by the DPP-4 enzyme within a few minutes. GLP-1 also reduces glucagon secretion in the alpha cells of the pancreas, reducing glucose production in the liver. In patients with T2DM, GLP-1 concentrations are reduced, but the insulin response to GLP-1 is maintained. Saxagliptin, being a competitive inhibitor of DPP-4, reduces the inactivation of incretin hormones, thereby increasing their concentrations in the bloodstream and leading to a decrease in fasting and postprandial glucose concentrations.

Metformin

Metformin is a hypoglycemic drug that improves glucose tolerance in patients with T2DM by lowering basal and postprandial glucose concentrations. Metformin reduces hepatic glucose production, reduces intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not cause hypoglycemia in patients with type 2 diabetes or healthy people (except in special situations, see sections “Precautions” and “Special Instructions”), and hyperinsulinemia. During metformin therapy, insulin secretion remains unchanged, although fasting and fasting insulin concentrations may decrease during the day.

PHARMACOKINETICS
Saxagliptin

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy-saxagliptin, are similar in healthy volunteers and patients with T2DM. The Cmax values ​​and area under the AUC curve of saxagliptin and its active metabolite in plasma increased proportionally over the dose range from 2.5 mg to 400 mg. After a single 5 mg oral dose of saxagliptin to healthy volunteers, the mean AUC values ​​of saxagliptin and its major metabolite were 78 ng*h/ml and 214 ng*h/ml, and plasma Cmax values ​​were 24 ng/ml and 47 ng/ml, respectively. The average variability of AUC and Cmax of saxagliptin and its active metabolite was less than 25%.

With repeated use of the drug once a day at any dosage, no noticeable accumulation of saxagliptin or its active metabolite is observed. There is no dose or time dependence of the clearance of saxagliptin and its active metabolite when used once daily for 14 days in doses ranging from 2.5 mg to 400 mg of saxagliptin.

Metformin

Cmax of modified release metformin is achieved on average in 7 hours. The extent of metformin absorption from modified-release tablets is increased by approximately 50% when taken with food. At steady state, the AUC and Cmax of modified-release metformin increased non-proportionally with dosage over the dose range from 500 to 2000 mg. After repeated dosing, modified-release metformin did not accumulate in plasma. Metformin is excreted unchanged by the kidneys and is not metabolized in the liver.

Suction

Saxagliptin

After oral administration, at least 75% of the administered dose of saxagliptin is absorbed. Food intake did not have a significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. A high-fat meal had no effect on the Cmax of saxagliptin, whereas the AUC increased by 27% compared to fasting. The time to reach Cmax (Tmax) for saxagliptin increased by approximately 0.5 hours when taking the drug with food compared to taking it on an empty stomach. However, these changes are not clinically significant.

Metformin

After a single oral dose of modified-release metformin, Cmax is achieved on average after 7 hours, with a range of 4 to 8 hours. The AUC and Cmax of modified-release metformin increased non-dose proportionally over the dose range from 500 to 2000 mg. The maximum concentrations of the drug in blood plasma are 0.6, 1.1, 1.4 and 1.8 mcg/ml when taking doses of 500, 1000, 1500 and 2000 mg once a day, respectively. Although the extent of absorption (measured by AUC) of metformin from metformin modified-release tablets was increased by approximately 50% when taken with food, the Cmax and Tmax of metformin were not affected by food intake. Low- and high-fat meals had similar effects on the pharmacokinetics of modified-release metformin.

Distribution

Saxagliptin

The binding of saxagliptin and its main metabolite to serum proteins is insignificant, so it can be assumed that the distribution of saxagliptin will not be subject to significant changes due to changes in the protein composition of the blood serum, observed in liver or renal failure.

Metformin

No studies have been conducted on the distribution of modified-release metformin, but the apparent volume of distribution of metformin after a single oral dose of 850 mg metformin immediate-release tablets averaged 654 ± 358 L. Metformin is slightly bound to plasma proteins.

Metabolism

Saxagliptin

Saxagliptin is metabolized mainly with the participation of cytochrome P450 3A4/5 isoenzymes (CYP3A4/5) with the formation of an active main metabolite, the inhibitory effect of which on DPP-4 is 2 times less pronounced than that of saxagliptin.

Metformin

Studies with a single intravenous dose of the drug in healthy volunteers show that metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites have been identified in humans), and is not excreted through the intestines.

Removal

Saxagliptin

Saxagliptin is excreted by the kidneys and intestines. After a single dose of 50 mg of 14C-labeled saxagliptin, 24% of the dose was excreted by the kidneys as unchanged saxagliptin and 36% as the main metabolite of saxagliptin. The total radioactivity detected in the urine corresponded to 75% of the dose taken.

The mean renal clearance of saxagliptin was approximately 230 ml/min, and the mean glomerular filtration rate was approximately 120 ml/min. For the main metabolite, renal clearance was comparable to mean glomerular filtration values. About 22% of the total radioactivity was found in feces.

Metformin

Renal clearance is approximately 3.5 times higher than creatinine clearance (CC), indicating that tubular secretion is the main route of elimination of metformin. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a plasma half-life of approximately 6.2 hours. In blood, the half-life is approximately 17.6 hours, therefore red blood cell mass may be part of the distribution.

Pharmacokinetics in special clinical situations

Kidney failure

It is not recommended to use Comboglise Prolong in patients with renal failure.

Saxagliptin

In patients with mild renal impairment, the AUC values ​​of saxagliptin and its active metabolite were 20% and 70% (respectively) higher than the AUC values ​​in patients with normal renal function. Since this increase in value is not considered to be clinically significant, it is not recommended to adjust the dose of saxagliptin in patients with mild renal impairment.

Metformin

In patients with impaired renal function (as measured by creatinine clearance), the half-life of metformin from plasma and blood is prolonged and renal clearance decreases in proportion to the decrease in creatinine clearance.

Liver failure

Saxagliptin

In patients with mild, moderate and severe hepatic impairment, no clinically significant changes in the pharmacokinetic parameters of saxagliptin were detected, therefore no dose adjustment is required for such patients.

Metformin

Pharmacokinetic studies of metformin have not been conducted in patients with hepatic impairment.

Floor

Saxagliptin

No dose adjustment of saxagliptin is required depending on the gender of patients.

Metformin

In clinical studies in patients with T2DM, the hypoglycemic effect of metformin was comparable in men and women.

Elderly patients

Saxagliptin

In patients 65-80 years old, no clinically significant differences in the pharmacokinetic parameters of saxagliptin were identified compared with younger patients (18-40 years old), so no dose adjustment is required in elderly patients. However, it should be borne in mind that in this category of patients a decrease in renal function is more likely (see sections “Dosage and Administration” and “Special Instructions”).

Metformin

Limited data from controlled studies of the pharmacokinetics of metformin in healthy elderly volunteers suggest that the total plasma clearance of metformin is reduced, T1/2 is increased, and Cmax is increased compared with the values ​​of these parameters in healthy young volunteers. According to these data, changes in the pharmacokinetics of metformin with increasing age are mainly due to changes in renal function. Comboglise Prolong should not be prescribed to patients over 80 years of age, unless normal renal function is confirmed by CC measurements.

Children

Saxagliptin

The pharmacokinetics of saxagliptin have not been studied in children.

Metformin

There have been no pharmacokinetic studies of modified-release metformin in children.

Race and ethnicity

Saxagliptin

It is not recommended to adjust the dose of saxagliptin based on the patient’s race.

Metformin

There have been no studies of the pharmacokinetics of metformin depending on the race of patients.

Special instructions

Lactic acidosis

Lactic acidosis is a rare, serious metabolic complication that can develop as a result of the accumulation of metformin during therapy with Comboglise Prolong. When lactic acidosis develops as a result of taking metformin, its concentration in the blood plasma exceeds 5 mcg/ml.

In patients with diabetes mellitus, lactic acidosis is more likely to develop with severe renal failure, including due to congenital kidney disease and insufficient renal perfusion, especially when taking multiple drugs. Patients with heart failure, particularly those with unstable angina or acute heart failure and risk of hypoperfusion and hypoxemia, are at increased risk of developing lactic acidosis. The risk of developing lactic acidosis increases in proportion to the degree of renal failure and the age of the patient. Renal function should be regularly monitored in patients taking metformin and the minimum effective dose of metformin should be prescribed. In elderly patients, monitoring of renal function is necessary. Metformin should not be prescribed to patients aged 80 years or older if renal function is impaired (as measured by CC), as these patients are more prone to developing lactic acidosis. In addition, it is necessary to immediately discontinue metformin therapy if conditions accompanied by hypoxemia, dehydration or sepsis develop. Because liver failure may significantly limit the ability to eliminate lactate, metformin should not be prescribed to patients with clinical or laboratory evidence of liver disease.

The onset of lactic acidosis often goes unnoticed and is accompanied by nonspecific symptoms such as malaise, myalgia, respiratory failure, increased drowsiness, pain and abdominal discomfort. Hypothermia, hypotension, and resistant bradyarrhythmia may occur. The patient should immediately report all these symptoms to the doctor. If such symptoms are detected, metformin therapy should be discontinued and serum electrolytes, ketone bodies, blood glucose, and, if indicated, blood pH, lactate concentration, and metformin blood concentration monitored. Gastrointestinal symptoms that develop late in metformin therapy may be caused by lactic acidosis or another disease.

Fasting venous plasma lactate concentrations above the upper limit of normal but below 5 mmol/L in patients taking metformin may indicate impending development of lactic acidosis, and may also be due to other causes, such as uncompensated diabetes mellitus, obesity, or excessive exercise.

The presence of lactic acidosis should be checked in all patients with diabetes mellitus and metabolic acidosis without signs of ketoacidosis (ketonuria and ketonemia). Lactic acidosis requires treatment in a hospital setting. If lactic acidosis is detected in a patient taking metformin, the drug should be stopped immediately and general supportive measures should be started immediately. It is recommended to immediately begin dialysis to correct acidosis and eliminate accumulated metformin.

Alcohol is known to potentiate the effect of metformin on lactate metabolism, which increases the risk of developing lactic acidosis. You should limit your alcohol consumption while taking Comboglise Prolong.

Liver failure

Comboglise Prolong is not recommended for use in patients with clinical and laboratory signs of liver disease due to the risk of developing lactic acidosis.

Renal function assessment

Renal function should be checked before starting therapy with Comboglise Prolong and at least annually thereafter. In patients with suspected renal impairment, renal function should be assessed more frequently and therapy with Comboglise Prolong should be discontinued if signs of renal failure occur.

Surgical procedures

Comboglyse Prolong should be temporarily suspended before any surgical procedure (except minor procedures not involving food and fluid restriction) and should not be resumed until the patient is able to take the medication by mouth and normal renal function has been confirmed.

Change in clinical status of patients with previously controlled T2DM

A patient with T2DM who has previously been well controlled on Comboglise Prolong and who develops laboratory abnormalities or disease development (especially if the diagnosis is unclear) should be immediately assessed for signs of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin concentrations. If any form of acidosis develops, Comboglise Prolong should be immediately discontinued and another hypoglycemic drug should be prescribed.

Use of drugs that can cause hypoglycemia

Saxagliptin

Drugs that stimulate insulin secretion, such as sulfonylureas, can cause hypoglycemia. Therefore, to reduce the risk of hypoglycemia when used in combination with saxagliptin, it may be necessary to reduce the dose of the drug that enhances insulin secretion.

Metformin

Hypoglycemia does not develop in patients taking metformin alone as usual, but may develop with insufficient carbohydrate intake, when active physical activity is not compensated for by carbohydrate intake, or when used concomitantly with other hypoglycemic drugs (such as sulfonylureas and insulin) or alcohol. Elderly, debilitated or malnourished patients and patients with adrenal or pituitary insufficiency or alcohol intoxication are most sensitive to hypoglycemic effects. In older adults and patients taking beta-blockers, diagnosing hypoglycemia may be difficult.

Concomitant therapy affecting renal function or metformin distribution

Caution should be exercised when prescribing concomitant drugs (such as cationic drugs eliminated by renal tubular secretion) that may affect renal function, lead to significant hemodynamic changes or impair the distribution of metformin (see section “Interactions with other drugs”).

Radiological studies with intravascular administration of iodinated contrast agents

Radiological studies with intravascular administration of iodine-containing contrast agents revealed acute renal dysfunction, which may be accompanied by the development of lactic acidosis in patients receiving metformin. Patients scheduled for such a study should discontinue therapy with Comboglyse Prolong 48 hours before performing such a procedure, refrain from taking the drug for 48 hours after the procedure, and resume therapy only after confirmation of normal renal function.

Hypoxic condition

Cardiovascular collapse (shock) of any origin, acute heart failure, acute myocardial infarction and other conditions accompanied by hypoxia and lactic acidosis can cause prerenal azotemia. If such phenomena develop, it is necessary to immediately discontinue therapy with Comboglise Prolong.

Impaired blood glucose levels

Fever, injury, infection, surgery can lead to disruption of blood glucose concentrations, which were previously controlled with Comboglise Prolong. In these cases, it may be necessary to temporarily discontinue therapy and transfer the patient to insulin therapy. After stabilizing the concentration of glucose in the blood and improving the general condition of the patient, treatment with Combogliz Prolong can be resumed.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during post-marketing use of saxagliptin. If a serious hypersensitivity reaction develops, you should stop using the drug, evaluate other possible causes of the phenomenon, and prescribe alternative therapy for diabetes mellitus (see sections “Contraindications” and “Side Effects”).

Pancreatitis

Spontaneous reports of acute pancreatitis have been reported during post-marketing use of saxagliptin. Patients taking Comboglise Prolong should be informed about the characteristic symptoms of acute pancreatitis: prolonged, intense pain in the abdominal area. If you suspect the development of pancreatitis, you should stop taking Comboglise Prolong (see sections “With caution” and “Side effects”).

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND WORK WITH MECHANISMS

No studies have been conducted to study the effect of saxagliptin on the ability to drive vehicles and operate machinery.

Please note that saxagliptin may cause headaches.

Active ingredient

Metformin, Saxagliptin

Composition

1 modified release tablet

film-coated, contains:
active ingredients:

metformin 1000 mg,

saxagliptin 2.5 mg

Pregnancy

Due to the fact that the use of Comboglise Prolong during pregnancy has not been studied, the drug should not be prescribed during pregnancy.

It is not known whether saxagliptin or metformin passes into breast milk. Since the possibility of penetration of the drug Comboglise Prolong into breast milk cannot be ruled out, the use of the drug during lactation is contraindicated.

Contraindications

increased individual sensitivity to any component of the drug;
serious hypersensitivity reactions (anaphylaxis or angioedema) to DPP-4 inhibitors;
diabetes mellitus type 1 (use not studied);
use in combination with insulin (not studied);
congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption;
pregnancy, lactation;
age under 18 years (safety and effectiveness have not been studied);
impaired renal function (serum creatinine ≥1.5 mg/dl [men], ≥1.4 mg/dl [women] or reduced creatinine clearance), including those caused by acute cardiovascular failure (shock), acute myocardial infarction and septicemia;
acute diseases in which there is a risk of developing renal dysfunction: dehydration (with vomiting, diarrhea), fever, severe infectious diseases, hypoxia conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);
acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma;
clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);
serious surgical operations and injuries (when insulin therapy is indicated);
liver dysfunction;
chronic alcoholism and acute ethanol poisoning;
lactic acidosis (including history);
a period of at least 48 hours before and within 48 hours after radioisotope or x-ray studies with the introduction of iodine-containing contrast agents;
adherence to a hypocaloric diet (less than 1000 kcal/day).

With caution

In persons over 60 years of age who perform heavy physical work (increased risk of developing lactic acidosis) and patients with a history of pancreatitis (the relationship between taking the drug and an increased risk of developing pancreatitis has not been established).

Side Effects

Monotherapy and additional combination therapy

Saxagliptin

Table 1 summarizes the adverse events observed in clinical trials (regardless of investigator assessment of causality) in ≥ 5% of patients receiving saxagliptin 5 mg.

Table 1. Adverse events

Number (%) of patients Saxagliptin 5 mg (N=882) Placebo (N=799) Upper respiratory tract infections 68 (7.7) 61 (7.6) Urinary tract infections 60 (6.8) 49 (6.1) Headache 57 (6.5) 47 (5.9)

The 5 placebo-controlled studies included two monotherapy studies and one each combination therapy study with the addition of metformin, thiazolidinedione or glibenclamide. The table presents data from a 24-week study regardless of the use of an additional hypoglycemic drug.

In patients receiving saxagliptin 2.5 mg, headache (6.5%) was the only adverse event reported with a frequency of ≥ 5% and occurred more frequently than in the placebo group.

Adverse events reported in ≥ 2% of patients treated with saxagliptin 2.5 mg or saxagliptin 5 mg and occurring ≥ 1% more often than placebo included sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%) and vomiting (2.2% and 2.3% versus 1.3%).

The incidence of fractures was 1.0 and 0.6 per 100 patient-years, respectively, with saxagliptin (pooled analysis of doses of 2.5 mg, 5 mg and 10 mg) and placebo. The incidence of fractures in patients taking saxagliptin did not increase over time. A causal relationship has not been established, and preclinical studies have not shown any adverse effects of saxagliptin on bone tissue.

During the clinical program, the development of thrombocytopenia was observed, consistent with the diagnosis of idiopathic thrombocytopenic purpura. The relationship between the development of this phenomenon and the use of saxagliptin is not known.

Adverse events associated with co-administration of saxagliptin and metformin in the treatment of patients with type 2 diabetes mellitus (T2DM) who have not previously received therapy

Saxagliptin

Table 2 summarizes the adverse events reported (regardless of investigator assessment of causation) in ≥ 5% of patients participating in an additional 24-week active-controlled study of saxagliptin and metformin in treatment-naïve patients.

Table 2. Adverse events

Number (%) of patients Saxagliptin 5 mg + metformin* (N=320) Metformin* (N=328) Headache 24 (7.5) 17 (5.2) Nasopharyngitis 22 (6.9) 13 (4.0)

*The initial metformin dose of 500 mg/day was increased to a maximum dose of 2000 mg/day.

In patients receiving the combination of saxagliptin and metformin, either as an add-on drug or as initial combination therapy, diarrhea was the only gastrointestinal adverse event that occurred in ≥5% of patients in either group. The incidence of diarrhea was 9.9%, 5.8% and 11.2% in the saxagliptin 2.5 mg, saxagliptin 5 mg and placebo groups, respectively, in the saxagliptin plus metformin study; The incidence of diarrhea was 6.9% and 7.3% in the combination therapy group of saxagliptin 5 mg and metformin and the metformin monotherapy group in the initial combination therapy with metformin study.

Hypoglycemia

Saxagliptin

Information on hypoglycemia as an adverse event was collected from reports of hypoglycemia; no concomitant measurement of glucose concentration was required. The incidence of hypoglycemia with saxagliptin 2.5 mg, saxagliptin 5 mg and placebo (all as monotherapy) was 4%, 5.6% and 4.1%, respectively, and 7.8%, 5.8% and 5%, respectively, with the addition of metformin. The incidence of hypoglycemia was 3.4% in treatment-naïve patients receiving saxagliptin 5 mg in combination with metformin and 4% in patients receiving metformin alone.

Hypersensitivity reactions

Saxagliptin

In an analysis of five pooled studies, hypersensitivity-related adverse events (such as urticaria and facial swelling) were reported in 1.5%, 1.5%, and 0.4% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. According to the researchers, none of these events in patients receiving saxagliptin required hospitalization or were life-threatening. In this pooled data analysis, one patient receiving saxagliptin was excluded from the study due to the development of generalized urticaria and facial edema.

Indicators of physiological functions

Saxagliptin

In patients receiving saxagliptin as monotherapy or in combination with metformin, no clinically significant changes in physiological function parameters were detected.

Monotherapy

Metformin

In placebo-controlled studies, the most common adverse events reported in >5% of patients treated with metformin modified release and occurring more frequently than in the placebo group were diarrhea and nausea/vomiting.

Post-marketing use

The following side effects have been reported during post-marketing use of saxagliptin: acute pancreatitis and hypersensitivity reactions, including anaphylaxis, angioedema, rash and urticaria. It is impossible to reliably estimate the incidence of these phenomena, since reports were received spontaneously from a population of unknown size (see sections “Contraindications” and “Special Instructions”).

Laboratory research

Absolute lymphocyte count

Saxagliptin

A dose-dependent mean decrease in the absolute lymphocyte count was observed with saxagliptin. In an analysis of pooled data from five 24-week, placebo-controlled studies, there was a mean reduction of approximately 100 and 120 cells/μL in absolute lymphocyte count from a baseline mean of 2200 cells/μL with saxagliptin 5 mg and 10 mg, respectively, compared with placebo. A similar effect was observed when taking saxagliptin at a dose of 5 mg in the original combination with metformin compared with metformin monotherapy. There were no differences between saxagliptin 2.5 mg and placebo treatments. The proportion of patients whose lymphocyte count was ≤ 750 cells/μL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo treatment groups, respectively. Most patients did not relapse when saxagliptin was re-administered, although in some patients lymphocyte counts relapsed when saxagliptin was reintroduced, leading to discontinuation of saxagliptin. The decrease in the number of lymphocytes was not accompanied by clinical manifestations.

The reasons for the decrease in lymphocyte counts during saxagliptin therapy compared with placebo are unknown. If an unusual or prolonged infection develops, the lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte count abnormalities (eg, human immunodeficiency virus) is unknown.

Platelets

Saxagliptin

Saxagliptin did not have a clinically significant or consistent effect on platelet counts across six double-blind, controlled clinical safety and efficacy studies.

Vitamin B12 concentration

In controlled clinical trials of metformin lasting 29 weeks, approximately 7% of patients experienced a decrease in previously normal serum vitamin B12 concentrations to subnormal values ​​without clinical manifestations. However, such a decrease is very rarely accompanied by the development of anemia and is quickly restored after discontinuation of metformin or additional intake of vitamin B12.

Interaction

Metformin

Some drugs increase hyperglycemia (thiazide and other diuretics, glucocorticosteroids, phenothiazines, iodine-containing thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers and isoniazid).

When prescribing or discontinuing such drugs in a patient taking Comboglise Prolong, the concentration of glucose in the blood should be carefully monitored. Metformin has low plasma protein binding and is therefore unlikely to interact with drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol and probenecid (unlike sulfonylureas, which are highly protein bound).

Inducers of CYP3A4/5 isoenzymes

Saxagliptin

Rifampin significantly reduces the exposure of saxagliptin without changing the AUC of its active metabolite, 5-hydroxy-saxagliptin. Rifampicin has no effect on DPP-4 inhibition in plasma during the 24-hour treatment interval.

Inhibitors of CYP3A4/5 isoenzymes

Saxagliptin

Diltiazem enhances the effect of saxagliptin when used together. Increased plasma concentrations of saxagliptin are expected with the use of amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, dose adjustments of saxagliptin are not recommended. Ketoconazole significantly increases plasma concentrations of saxagliptin. Similar significant increases in plasma concentrations of saxagliptin are expected with the use of other potent inhibitors of CYP3A4/5 enzymes (for example, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When used together with a strong inhibitor of CYP3A4/5 isoenzymes, the dose of saxagliptin should be reduced to 2.5 mg.

Cationic drugs

Metformin

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterone, trimethoprim, or vancomycin) that are eliminated by the kidneys by glomerular filtration could theoretically interact with metformin by competing for common renal tubular transport systems. In single-dose and repeated-dose drug interaction studies of metformin and cimetidine, an interaction between oral metformin and cimetidine was observed in healthy volunteers; At the same time, there was a 60% increase in the maximum concentration of metformin in plasma and whole blood and a 40% increase in the AUC of metformin in plasma and whole blood. In a single-dose study, no change in half-life was observed. Metformin does not affect the pharmacokinetic parameters of cimetidine. It is recommended to closely monitor patients and adjust the dose if necessary in patients taking cationic drugs that are excreted through the proximal renal tubular system.

Glibenclamide

Metformin

In a single-dose interaction study in patients with T2DM, coadministration of metformin and glibenclamide did not affect pharmacokinetic or pharmacodynamic parameters.

Furosemide

Metformin

A single-dose drug interaction study of metformin and furosemide conducted on healthy volunteers revealed their pharmacokinetic interaction. Furosemide increases the Cmax of metformin in plasma and blood by 22% and AUC in the blood by 15% without significantly changing the renal clearance of metformin. When co-administered with metformin, the Cmax and AUC of furosemide are reduced by 31% and 12%, respectively, and the half-life is reduced by 32% without a noticeable change in the renal clearance of furosemide. There is no data on the interaction of metformin and furosemide when used together for a long time.

Nifedipine

Metformin

In a single-dose drug interaction study of metformin and nifedipine in healthy volunteers, nifedipine increased metformin plasma Cmax by 20% and AUC by 9%, and increased renal excretion. Tmax and T1/2 did not change. Nifedipine increases the absorption of metformin. Metformin has virtually no effect on the pharmacokinetics of nifedipine.

Saxagliptin and metformin

Co-administration of single doses of saxagliptin (100 mg) and metformin (1000 mg) does not have a significant effect on the pharmacokinetics of saxagliptin or metformin in healthy volunteers.

No special pharmacokinetic drug interaction studies have been conducted with Comboglise Prolong, although such studies have been conducted with its individual components: saxagliptin and metformin.

Saxagliptin

Effect of other drugs on saxagliptin

Glibenclamide: Co-administration of a single dose of saxagliptin (10 mg) and glibenclamide (5 mg), a CYP2C9 substrate, increased the Cmax of saxagliptin by 8%, but the AUC of saxagliptin did not change.

Pioglitazone: Co-administration of saxagliptin once daily (10 mg) and pioglitazone (45 mg), a CYP2C8 (strong) and CYP3A4 (weak) substrate, does not affect the pharmacokinetics of saxagliptin.

Digoxin: Co-administration of once daily saxagliptin (10 mg) and digoxin (0.25 mg), a P-glycoprotein substrate, does not affect the pharmacokinetics of saxagliptin.

Simvastatin: Co-administration of once daily saxagliptin (10 mg) and simvastatin (40 mg), a CYP3A4/5 substrate, increased the Cmax of saxagliptin by 21%, but the AUC of saxagliptin did not change.

Diltiazem: Combined single use of saxagliptin (10 mg) and diltiazem (360 mg extended dosage form at steady state), a moderate inhibitor of CYP3A4/5 isoenzymes, increases saxagliptin Cmax by 63% and AUC by 2.1 times. This is accompanied by a corresponding decrease in Cmax and AUC of the active metabolite by 44% and 36%, respectively.

Ketoconazole: Coadministration of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours at steady state) increases the Cmax and AUC of saxagliptin by 2.4 and 3.7 times, respectively. This is accompanied by a corresponding decrease in Cmax and AUC of the active metabolite by 96% and 90%, respectively.

Rifampicin: Coadministration of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once daily at steady state) decreased the Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax (39%), but without a significant change in the AUC of the active metabolite.

Omeprazole: Combined repeated use of saxagliptin at a dose of 10 mg once daily and omeprazole at a dose of 40 mg, a substrate of the CYP2C19 isoenzyme (strong) and the CYP3A4 isoenzyme (weak), an inhibitor of the CYP2C19 isoenzyme and an MRP-3 inducer, does not affect the pharmacokinetics of saxagliptin.

Aluminum hydroxide + magnesium hydroxide + simethicone: Concomitant use of single doses of saxagliptin (10 mg) and a suspension containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg) and simethicone (240 mg) reduces the Cmax of saxagliptin by 26%, but the AUC of saxagliptin does not change.

Famotidine: Administration of single doses of saxagliptin (10 mg) 3 hours after a single dose of famotidine (40 mg), an inhibitor of hOCT-1, hOCT-2, and hOCT-3, increased saxagliptin Cmax by 14%, but saxagliptin AUC did not change.

Overdose

Saxagliptin

With long-term use of the drug in doses up to 80 times higher than recommended, no symptoms of intoxication are described.

In case of overdose, symptomatic therapy should be used. Saxagliptin and its main metabolite are eliminated from the body by hemodialysis (removal rate: 23% of the dose in 4 hours).

Metformin

Cases of metformin overdose have been reported, including taking more than 50 g. Hypoglycemia developed in approximately 10% of cases, but its causal relationship with metformin has not been established. In 32% of cases of metformin overdose, patients experienced lactic acidosis. Metformin is eliminated by dialysis, with clearance reaching 170 ml/min.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Manufacturer

AstraZeneca Pharmaceuticals LP, USA