Kombiglyze, sustained release pills 1000+2.5mg, 56pcs

Composition

1 modified release

film-coated tablet contains: active ingredients:

metformin 1000 mg,

saxagliptin 2.5 mg

Pharmacological action

Mechanism of action

Comboglys Prolong combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus( DM2): 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 from the small intestine into the bloodstream.

These hormones promote the release of insulin from the pancreatic beta cells, which depends on the concentration of glucose in the blood, but are inactivated by the DPP-4 enzyme within a few minutes. GLP-1 also lowers the secretion of glucagon in the alpha cells of the pancreas, reducing the production of glucose in the liver. In patients with DM2, the GLP-1 concentration is reduced, but the insulin response to GLP-1 remains. Saxagliptin, being a competitive DPP-4 inhibitor, reduces the inactivation of incretin hormones, thereby increasing their concentrations in the bloodstream and leading to a decrease in fasting and post-meal glucose concentrations.

Metformin

Metformin is a hypoglycemic drug that improves glucose tolerance in patients with type 2 diabetes by lowering basal and postprandial glucose concentrations. Metformin reduces liver glucose production, lowers intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not cause hypoglycemia in patients with DM2 or healthy people (except in special situations, see the sections “With caution” and “Special instructions”), and hyperinsulinemia. During metformin therapy, insulin secretion remains unchanged, although fasting insulin concentrations and in response to food intake may decrease throughout the day.

Pharmacokinetics

of 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 main metabolite were 78 ng * h / ml and 214 ng * h/ml, and the plasma Cmax values were 24 ng / ml and 47 ng/ml, respectively. The mean variability in the AUC and Cmax of saxagliptin and its active metabolite was less than 25%.

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

Metformin

The cmax of modified-release metformin is achieved in an average of 7 hours. The degree of absorption of metformin from modified-release tablets increases by approximately 50% when taken with a meal. At steady state, the AUC and Cmax of modified-release metformin increased out of proportion to the dosage in the dose range from 500 to 2000 mg. After repeated use, 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 use, at least 75% of the saxagliptin dose is absorbed. Food intake did not significantly affect the pharmacokinetics of saxagliptin in healthy volunteers. High-fat food intake did not affect the Cmax of saxagliptin, while 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 in an average of 7 hours, ranging from 4 to 8 hours. The AUC and Cmax of modified-release metformin increased out of proportion to the dosage in 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 degree of absorption (measured by AUC) of metformin from modified-release metformin tablets increases by approximately 50% when taken with a meal, food intake did not affect the Cmax and Tmax of metformin. Low-fat and high-fat foods had the same effect on the pharmacokinetic parameters 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 with changes in the protein composition of blood serum, observed in hepatic or renal insufficiency, will not be significantly affected.

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 of immediate-release metformin tablets averaged 654±358 l. Metformin is slightly bound to plasma proteins.

Metabolism

Saxagliptin

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

Metformin

Studies with a single intravenous injection of the drug to healthy volunteers show that metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites were detected in humans), and is not excreted through the intestine.

Deduction

Saxagliptin

Saxagliptin is excreted by the kidneys and through the 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 drug 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 the mean glomerular filtration rate. About 22% of the total radioactivity was detected in feces.

Metformin

Renal clearance is approximately 3.5 times higher than creatinine clearance (CC), which indicates that tubular secretion is the main route of elimination of metformin. After oral use, 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 the blood, the elimination half-life is approximately 17.6 hours, so the red blood cell mass may be part of the distribution.

Pharmacokinetics in special clinical situations

Kidney failure

It is not recommended to use Kombogliz Prolong in patients with renal insufficiency.

Saxagliptin

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

Metformin

In patients with impaired renal function (according to the results of creatinine clearance measurements), 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

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

Metformin

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Gender

Saxagliptin

There is no need to adjust the dose of saxagliptin depending on the gender of patients.

Metformin

In clinical trials in patients with DM2, the hypoglycemic effect of metformin in men and women was comparable.

Elderly patients

Saxagliptin

There were no clinically significant differences in the pharmacokinetics of saxagliptin in patients aged 65-80 years compared to younger patients (18-40 years), so no dose adjustment is required in elderly patients. However, it should be borne in mind that this category of patients is more likely to have decreased renal function (see sections “Dosage and use” 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 decreases, T1 / 2 increases, and Cmax increases compared to the values of these parameters in healthy young volunteers. According to these data, changes in the pharmacokinetic parameters of metformin with increasing age are mainly due to changes in renal function.Do not prescribe Kombogliz Prolong to patients over 80 years of age, except in cases where the results of creatinine clearance confirmed normal renal function.

Children

Saxagliptin

The pharmacokinetics of saxagliptin in children have not been studied.

Metformin

No studies have been conducted on the pharmacokinetics of metformin modified release in children.

Race and ethnicity

Saxagliptin

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

Metformin

The pharmacokinetic parameters of metformin were not studied depending on the race of patients.

Indications

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

Use during pregnancy and lactation

Due to the fact that the use of Kombogliz 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 Kombogliz Prolong into breast milk is not excluded, the use of the drug during lactation is contraindicated.

Contraindications

• individual hypersensitivity to any component of the drug;
• serious hypersensitivity reactions (anaphylaxis or angioedema) to the DPP-4 inhibitors;
• diabetes mellitus type 1 (application has not been studied);
• the use in combination with insulin (not studied);
• congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption;
• pregnancy, lactation;
• age to 18 years (safety and effectiveness has not been studied);
• the renal dysfunction (serum creatinine ≥1.5 mg/DL [men], ≥1.4 mg/DL [women] or reduced creatinine clearance), including those caused by acute heart failure (shock), acute myocardial infarction and septicemia;
• acute diseases in which there is a risk of kidney problems: dehydration (vomiting, diarrhea), fever, severe infectious diseases, the condition of hypoxia (shock, sepsis, kidney infection, chronic lung disease);
• acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma coma;
• symptomatic manifestations of acute and chronic diseases, which can lead to the development of tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);
• major surgery or trauma (when shown holding insulin);
• the liver;
• chronic alcoholism and acute alcohol poisoning;
• lactic acidosis (including history);
• a period of at least 48 hours prior to and within 48 hours after the radioisotope or radiological examinations with use of iodinated contrast media;
• adherence to a reduced-calorie diet (less than 1000 kcal/day).

With caution

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

Side effects

Monotherapy n supplemental combination therapy

Saxagliptin

Table 1 shows the adverse events reported in clinical trials (regardless of the researcher’s assessment of causality) in ≥ 5% of patients treated with saxagliptin 5 mg.

Table 1. Undesirable phenomena

 Number (% ) of patients with 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)

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

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

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

The incidence of fractures was 1.0 and 0.6 per 100 patient-years, respectively, when taking saxagliptin (combined dose analysis of 2.5 mg,5 mg and 10 mg) and placebo. The incidence of fractures in patients taking saxagliptin did not increase over time. No causal relationship has been established, and preclinical studies have not shown an undesirable effect of saxagliptin on bone tissue.

During the clinical program, the development of thrombocytopenia was observed, corresponding to 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-use of saxagliptin and metformin in the treatment of patients with type 2 diabetes mellitus (DM2) who have not previously received therapy

Saxagliptin

Table 2 shows the adverse events reported (regardless of the researcher’s causal assessment) in ≥ 5% of patients who participated in an additional 24-week, active-control study of the combined use of saxagliptin and metformin in patients who had not previously received therapy.

Table 2. Adverse events

 Number (% ) of patients with 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 dose of metformin 500 mg / day was increased to a maximum dosage of 2000 mg / day.

In patients receiving a combination of saxagliptin and metformin, either as an adjunct or as the 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-to-metformin addition study; the incidence of diarrhea was 6.9% and 7.3% in the saxagliptin 5 mg-to-metformin combination therapy group and the metformin monotherapy group in the metformin-to-metformin combination therapy study.

Hypoglycemia

Saxagliptin

Data on hypoglycemia as an adverse event were collected based on 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 metformin supplementation. The incidence of hypoglycemia was 3.4% in previously untreated patients taking saxagliptin 5 mg in combination with metformin, and 4% in patients on metformin monotherapy.

Hypersensitivity reactions

Saxagliptin

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

Indicators of physiological functions

Saxagliptin

Patients treated with saxagliptin alone or in combination with metformin showed no clinically significant changes in physiological function parameters.

Monotherapy

Metformin

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

Post-marketing application

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 not possible to reliably estimate the frequency of these events, since the reports were received spontaneously, from a population of unknown size (see the sections “Contraindications” and “Special instructions”).

Laboratory tests

Absolute number of lymphocytes

Saxagliptin

When using saxagliptin, a dose-dependent average decrease in the absolute number of lymphocytes was observed. When analyzing combined data from five 24-week, placebo-controlled studies, there was an average decrease of approximately 100 and 120 cells/µl in the absolute number of lymphocytes from the initial average of 2200 cells/µl when using saxagliptin at a dose of 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 initial combination with metformin compared to metformin monotherapy. There were no differences between saxagliptin 2.5 mg and placebo. The proportion of patients whose lymphocyte count was < 750 cells/µl was 0.5%,1.5%,1.4%, and 0.4% in the 2.5 mg,5 mg,10 mg, and placebo treatment groups, respectively.Most patients did not relapse with repeated use of saxagliptin, although in some patients the number of lymphocytes decreased again with the resumption of saxagliptin therapy, which led to the withdrawal of saxagliptin. The decrease in the number of lymphocytes was not accompanied by clinical manifestations.

The reasons for the decrease in the number of lymphocytes during saxagliptin therapy compared to placebo are unknown. If an unusual or long-term infection develops, it is necessary to measure the number of lymphocytes. The effect of saxagliptin on lymphocyte counts in patients with abnormal lymphocyte counts (e. g., human immunodeficiency virus) is unknown.

Platelets

Saxagliptin

Saxagliptin did not have a clinically significant or consistent effect on platelet count in six double-blind, controlled clinical trials of safety and efficacy.

Vitamin B12 Concentration

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

Interaction

Metformin

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

When prescribing or discontinuing such medications in a patient taking Kombiglyze Prolong, the blood glucose concentration should be carefully monitored. The degree of binding of metformin to plasma proteins is low, so it is unlikely that it will interact with drugs that bind significantly to plasma proteins, such as salicylates, sulfonamides, chloramphenicol and probenecid (in contrast to sulfonylurea derivatives, which bind significantly to serum proteins).

Inducers of CYP3A4/5 isoenzymes

Saxagliptin

Rifampicin significantly reduces the exposure of saxagliptin without changing the AUC of its active metabolite,5-hydroxy-saxagliptin. Rifampicin did not affect the inhibition of DPP-4 in blood plasma during the 24-hour treatment interval.

Inhibitors of CYP3A4/5 isoenzymes

Saxagliptin

Diltiazem enhances the effect of saxagliptin when used together. An increase in the concentration of saxagliptin in blood plasma is expected with the use of amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, it is not recommended to adjust the dose of saxagliptin. Ketoconazole significantly increases the concentration of saxagliptin in plasma. A similar significant increase in the concentration of saxagliptin in blood plasma is expected with the use of other powerful inhibitors of the nsoenzymes CYP3A4 / 5 (for example, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When co-administered with a potent CYP3A4/5 isoenzyme inhibitor, the dose of saxagliptin should be reduced to 2.5 mg.

Cationic preparations

Metformin

Cationic drugs (for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterone, trimethoprim, or vancomycin) that are eliminated by the kidneys through glomerular filtration can theoretically interact with metformin, competing for the common transport systems of the renal tubules. Metformin and cimetidine oral interactions were observed in healthy volunteers in single-and repeated-dose metformin-cimetidine drug interaction studies, with a 60% increase in maximum plasma and whole blood metformin concentrations and a 40% increase in plasma and whole blood metformin AUC. During the study with a single dose of the drug, there was no change in the half-life. Metformin does not affect the pharmacokinetics of cimetidine. It is recommended that patients be closely monitored and, if necessary, the dose adjusted in patients taking cationic drugs that are excreted through the proximal renal tubule system.

Glibenclamide

Metformin

In a single-dose interaction study in patients with DM2, the combined use of metformin and glibenclamide did not affect the pharmacokinetic or pharmacodynamic parameters.

Furosemide

Metformin

A study of the drug interaction between metformin and furosemide with a single dose of the drug, conducted on healthy volunteers, revealed their pharmacokinetic interaction. Furosemide increases the Cmax of metformin in plasma and blood by 22% and AUC in 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 are no data on the interaction of metformin and furosemide when used together for a long time.

Nifedipine

Metformin

In a single-dose metformin-nifedipine drug interaction study conducted in healthy volunteers, nifedipine increased the Cmax of metformin in plasma 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-use of single doses of saxagliptin (100 mg) and metformin (1000 mg) did not significantly affect the pharmacokinetics of saxagliptin or metformin in healthy volunteers.

No specific pharmacokinetic studies of drug interaction with the use of Kombogliz Prolong have been conducted, although such studies have been conducted with its individual components: saxagliptin and metformin.

Saxagliptin

Effect of other drugs on saxagliptin

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

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

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

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

Diltiazem: A single dose of saxagliptin (10 mg) and diltiazem (360 mg long-acting steady-state dosage form), a moderate inhibitor of CYP3A4/5 isoenzymes, increases the Cmax of saxagliptin by 63%, and the 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: The combined use 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: Co-use of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once daily at steady state) reduces 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: Co – use of saxagliptin 10 mg once daily and omeprazole 40 mg, a substrate of the CYP2C19 isoenzyme (strong) and the CYP3A4 isoenzyme (weak), an inhibitor of the CYP2C19 isoenzyme and an inducer of MRP-3, does not affect the pharmacokinetics of saxagliptin.

Aluminum hydroxide+magnesium hydroxide+simethicone: The combined 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: Taking 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, increases the Cmax of saxagliptin by 14%, but the AUC of saxagliptin does not change.

How to take it, course of use and dosage

Inside, once a day during dinner. Tablets should be swallowed whole, without chewing, crushing or breaking. The dose should be selected individually.

Usually, when treated with a combination drug containing saxagliptin and metformin, the dose of saxagliptin is 5 mg once a day. The recommended starting dose of modified-release metformin is 500 mg once daily, and it can be increased to 2000 mg once daily, which is achieved by taking 2 2.5 mg/1000 mg tablets taken once a day. The metformin dose is increased gradually to reduce the risk of gastrointestinal side effects. Maximum daily dose: saxagliptin 5 mg and metformin modified release 2000 mg.

No specific studies have been conducted on the safety and efficacy of Kombogliz Prolong in patients previously treated with other hypoglycemic agents and transferred to Kombogliz Prolong.

Changes in DM2 therapy should be made with caution and with appropriate monitoring of blood glucose concentrations. When co-administered with potent inhibitors of the CYP3A4/5 isoenzymes (for example, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), the dose of saxagliptin should be 2.5 mg once a day.

Inactive ingredients of the drug Kombogliz Prolong can be excreted through the intestines in the form of a soft, moist mass, which can retain the shape of the tablet taken.

Use in special patient groups

Elderly patients

Since saxagliptin and metformin are partially excreted by the kidneys, and elderly patients are likely to have decreased renal function, Comboglys Prolong should be used with caution in the elderly.

Saxagliptin

There were no differences in the safety or efficacy of the drug in patients ≥ 65 years of age and young patients. Although there are no differences in response to therapy in elderly patients and young patients, greater sensitivity cannot be excluded in some elderly patients.

Metformin

Controlled clinical trials of metformin did not include a sufficient number of elderly patients to determine differences in response to therapy compared to young patients, although clinical experience did not establish differences in response in the elderly and young patients. It is known that metformin is largely excreted by the kidneys, and therefore there is a risk of serious adverse events in patients with renal insufficiency.

Comboglysis Prolong should only be used in patients with normal renal function. Initial and maintenance doses of metformin should be given to elderly patients, taking into account the possible decline in renal function. Any dose adjustment should be made after careful assessment of renal function.

Children

The safety and efficacy of the drug in patients under 18 years of age has not been studied.

Overdose

Saxagliptin

With prolonged 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 (elimination 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. Lactic acidosis was observed in 32% of metformin overdose cases. Metformin is eliminated on dialysis, with a clearance of up to 170 ml/min.

Special instructions

Lactic acidosis

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

In patients with diabetes mellitus, lactic acidosis is more likely to develop with severe renal insufficiency, including due to congenital kidney disease and insufficient renal perfusion, especially when taking several medications. Patients with heart failure, particularly those with unstable angina or acute heart failure and a risk of hypoperfusion and hypoxemia, have an increased risk of developing lactic acidosis. The risk of developing lactic acidosis increases in proportion to the degree of renal failure and the patient’s age. 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 and older who have impaired renal function (according to the CC), as these patients are more likely to develop lactic acidosis. In addition, metformin therapy should be discontinued immediately if conditions associated with hypoxemia, dehydration, or sepsis develop. Since hepatic insufficiency can significantly limit the ability to remove lactate, metformin should not be prescribed to patients with clinical or laboratory signs of liver disease.

The onset of lactic acidosis often goes unnoticed and is accompanied by non-specific symptoms such as malaise, myalgia, respiratory failure, increased drowsiness, abdominal pain and 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, serum electrolytes, ketone bodies, blood glucose should be monitored, and if indicated, blood pH, lactate concentration, and blood metformin concentration. Gastrointestinal symptoms that develop in the late stage of metformin therapy may be caused by lactic acidosis or another medical condition.

The concentration of lactate in the venous blood plasma on an empty stomach, exceeding the upper limit of normal, but below 5 mmol/l, in patients taking metformin, may indicate the approaching development of lactic acidosis, and may also be explained by other causes, such as uncompensated diabetes mellitus, obesity, excessive physical activity.

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, you should immediately stop taking the drug and immediately begin general maintenance measures. It is recommended to start dialysis immediately to correct acidosis and eliminate cumulative metformin.

Alcohol is known to potentiate the effect of metformin on lactate metabolism, which increases the risk of lactic acidosis. It is necessary to limit the use of alcohol while taking the drug Kombiglyze Prolong.

Liver failure

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

Assessment of kidney function

Before starting therapy with Kombiglyze Prolong and at least annually afterwards, it is necessary to check the renal function. In patients with suspected renal impairment, renal function should be evaluated more frequently and Kombiglyze Prolong therapy should be discontinued if signs of renal failure occur.

Surgical procedures

You should temporarily stop taking Kombogliz Prolong before any surgical procedure (except for minor procedures that do not involve limiting the intake of food and liquids), and do not resume its use until the patient is able to take the medication inside and normal renal function is confirmed.

Changes in the clinical status of patients with previously controlled DM 2

In a patient with DM2 who has previously been well monitored on Kombiglyze Prolong therapy and who has developed laboratory abnormalities or developed a disease (especially if the diagnosis is unclear), signs of ketoacidosis or lactic acidosis should be immediately evaluated. Assessment should include determination of serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin concentrations. If any form of acidosis develops, you should immediately cancel Kombogliz Prolong and prescribe another hypoglycemic drug.

Use of drugs that may cause hypoglycemia

Saxagliptin

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

Metformin

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

Concomitant therapy affecting renal function or metformin distribution

Caution should be exercised when prescribing concomitant medications (such as cationic drugs that are excreted in the renal tubules) that may affect renal function, lead to significant hemodynamic changes, or disrupt the distribution of metformin (see section “Interaction with other drugs”).

Radiological studies with intravascular administration of iodine-containing 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 who are scheduled for such a study should cancel therapy with Comboglys Prolong 48 hours before performing such a procedure, refrain from taking the drug for 48 hours after the procedure, and resume therapy only after confirming normal renal function.

Hypoxic conditions

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. With the development of such phenomena, it is necessary to immediately cancel therapy with Kombogliz Prolong.

Violation of the concentration of glucose in the blood

Fever, trauma, infection, or surgery can lead to a violation of the concentration of glucose in the blood, which was previously controlled with the drug Kombiglyze Prolong. In these cases, it may be necessary to temporarily cancel therapy and transfer the patient to insulin therapy. After stabilization of the blood glucose concentration and improvement of the patient’s general condition, treatment with Comboglys 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, the drug should be discontinued, other possible causes of the development of the phenomenon should be evaluated, and alternative therapy for diabetes mellitus should be prescribed (see the sections “Contraindications” and “Side effects”).

Pancreatitis

As part of the post-marketing use of saxagliptin, spontaneous reports of cases of acute pancreatitis were received. Patients taking Kombogliz Prolong should be informed about the characteristic symptoms of acute pancreatitis: prolonged, intense abdominal pain. If you suspect the development of pancreatitis, you should stop taking the drug Kombiglyze Prolong (see the sections “With caution” and “Side effect”).

INFLUENCE ON THE ABILITY TO DRIVE MOTOR VEHICLES AND WORK WITH MECHANISMS

No studies have been conducted to study the effect of saxagliptin on the ability to drive motor vehicles and manage mechanisms.

Keep in mind that saxagliptin can cause headaches.

Form of production

Modified release film-coated tablets

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Metformin Hydrochloride, Saxagliptin

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets