Kombiglyze, sustained release pills 1000+5mg, 28pcs

Composition

Active ingredients: metformin – 1000 mg; saxagliptin – 2.5 mg

Pharmacological 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.

Indications

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

Contraindications

— increased individual sensitivity 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 and lactation;

— age up to 18 years (safety and effectiveness has not been studied);

— violations of renal function (serum creatinine ≥1.5 mg/DL [males], ≥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);

— disorders of the liver;

chronic alcoholism, acute alcohol poisoning;

— lactic acidosis (including history);

— the company not less than 48 hours before and within 48 hours after the radioisotope or radiological examinations with use of iodinated contrast media;

— adherence to a reduced-calorie diet (

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 and complementary 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

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

*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 B Concentration₁₂

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 theplasma and blood cmax of metformin by 22% and blood AUC by 15% without significantly altering the renal clearance of metformin. When co-administered with metformin, the_max and AUC of furosemide are reduced by 31% and 12%, respectively, and the elimination 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 plasma metformin cmax by 20% and AUC by 9%, and increased renal excretion. Tmax and T 1/2 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: Co-use of a single dose of saxagliptin (10 mg) and glibenclamide (5 mg), a substrate of the CYP2C9 isoenzyme, increased the_cmaxof 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_maxof saxagliptin by 21%, but the AUC of saxagliptin did not change.

Diltiazem: Co-use of saxagliptin (10 mg) and diltiazem (360 mg long-acting steady-state dosage form), a moderate inhibitor of CYP3A4/5 isoenzymes, increases the C_maxof 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: Couse of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours at steady state) increases the C_max 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: Couse of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once daily at steady state) reduces the C_max and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in C_max(39%), but without significant changes 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_maxof 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, 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 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.

Storage conditions

At a temperature not exceeding 30°C. Keep out of reach of children.

Shelf life

3 years

Active ingredient

Metformin Hydrochloride, Saxagliptin

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets