Combogliz, 1000 mg+5 mg 28 pcs

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, 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 DPP-4 inhibitor, 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 uptake 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.

Indications

How to take, the dosage

To be taken by mouth, once daily with dinner. The tablets should be swallowed whole, without chewing, crushing or breaking. The dose should be chosen individually. Usually, during therapy with a combined 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, which can be increased to 2000 mg once daily, provided by taking 2 tablets of 2.5 mg/1000 mg taken once daily. The dose of metformin is increased gradually to reduce the risk of gastrointestinal side effects. Maximum daily dose: saxagliptin 5 mg and modified-release metformin 2000 mg.

There have been no specific studies of the safety and efficacy of Combogliz Prolong in patients previously treated with other hypoglycemic agents and switched to Combogliz Prolong.

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

The inactive ingredients in Combogliz Prolong may be excreted through the intestine as a soft, moist mass that may retain the shape of the tablet taken.

Use in special patient groups

Patients in the elderly

Because saxagliptin and metformin are partially excreted by the kidneys, and decreased renal function is likely in elderly patients, Combogliz Prolong should be used with caution in the elderly.

Saxagliptin

No differences in safety or efficacy of the drug have been noted in patients ≥65 years old and younger patients. Although no differences in response to therapy have been established in elderly and younger patients, greater sensitivity in some elderly patients cannot be excluded. Metformin Controlled clinical trials of metformin have not included sufficient older patients to determine differences in response to therapy compared with younger patients, although clinical experience has not established differences in response in older and younger patients.

Metformin is known to be largely excreted by the kidneys, and therefore there is a risk of serious adverse events in patients with renal impairment. Combogliz Prolong should only be administered to patients with normal renal function. Initial and maintenance doses of metformin should be administered to elderly patients, taking into account the possible reduction of renal function. Any dose adjustment should be made after careful evaluation of renal function.

Children

The safety and effectiveness of the drug in patients younger than 18 years has not been studied.

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 such drugs are prescribed or withdrawn in a patient taking Combogliz Prolong, blood glucose concentrations should be carefully monitored. Metformin has low plasma protein binding, so it is unlikely to interact with drugs that bind significantly to plasma proteins, such as salicylates, sulfonamides, chloramphenicol and probenecid (unlike sulfonylurea derivatives, which do bind significantly to serum proteins).

CYP3A4/5 isoenzyme inducers

Saxagliptin

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

CYP3A4/5 isoenzyme inhibitors

Saxagliptin

Diltiazem enhances the effect of saxagliptin when used together. Increased plasma concentrations of saxagliptin are expected with amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, the dose of saxagliptin should not be adjusted. Ketoconazole significantly increases the plasma concentration of saxagliptin. A similar significant increase in plasma concentrations of saxagliptin is expected when using other potent inhibitors of CYP3A4/5 enzymes (e.g., 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 drugs

Metformin

. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterone, trimethoprim, or vancomycin) that are eliminated by the kidneys via glomerular filtration could theoretically interact with metformin by competing for common renal tubular transport systems. Drug interaction studies of metformin and cimetidine with single and repeated drug administration have observed metformin and cimetidine for oral administration in healthy volunteers, with a 60% increase in maximum metformin concentration in plasma and whole blood and a 40% increase in AUC of metformin in plasma and whole blood. No change in the elimination half-life was observed in the study with single drug administration. Metformin has no effect on the pharmacokinetic parameters of cimetidine. It is recommended that patients should be closely monitored and, if necessary, the dose should be 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, co-administration of metformin and glibenclamide did not affect pharmacokinetic or pharmacodynamic parameters.

Furosemide

Metformin

The drug interaction study of metformin and furosemide with single drug administration conducted in healthy volunteers revealed their pharmacokinetic interaction. Furosemide increases Cmax metformin in plasma and blood by 22% and AUC in blood by 15% with no significant change in renal clearance of metformin. When co-administered with metformin, the Cmax and AUC of furosemide are decreased by 31% and 12%, respectively, and the elimination half-life is reduced by 32% without a marked change in renal clearance of furosemide. There are no data on the interaction of metformin and furosemide in long-term coadministration.

Nifedipine

Metformin

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

Saxagliptin and metformin

The co-administration of single doses of saxagliptin (100 mg) and metformin (1000 mg) has no significant effect on the pharmacokinetics of saxagliptin or metformin in healthy volunteers.

There have been no specific pharmacokinetic studies of drug interactions with Combogliz Prolong, although such studies have been performed with its individual components: saxagliptin and metformin.

Saxagliptin

The effect of other drugs on saxagliptin

Glibenclamide: Co-administration 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 was not altered.

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

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

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

Diltiazem: Co-administration of saxagliptin (10 mg) and diltiazem (360 mg sustained release form in equilibrium), a moderate CYP3A4/5 isoenzyme inhibitor, increased Cmax saxagliptin 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: Co-administration of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours in equilibrium), increases 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-administration of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once daily in equilibrium) decreases Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax(39%), but no significant change in AUC of the active metabolite.

Omeprazole: Co-administration of saxagliptin 10 mg once daily and omeprazole 40 mg, a CYP2C19 (strong) and CYP3A4 (weak) isoenzyme substrate, CYP2C19 isoenzyme inhibitor and MRP-3 inducer, does not affect the pharmacokipetics of saxagliptin.

Aluminum hydroxide+magnesium hydroxide+simethicone: Co-administration of single doses of saxagliptin (10 mg) and suspension containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg), and simethicone (240 mg) decreases the Cmax of saxagliptin by 26%, but the AUC of saxagliptin is not changed.

Famotidine: Taking a single dose 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 Cmax saxagliptin by 14%, but the AUC of saxagliptin is not altered.

Special Instructions

Lactoacidosis is a rare, serious metabolic complication that can develop as a result of metformin cumulation during therapy with Combogliz Prolong. When lactoacidosis develops due to metformin administration, its plasma concentration exceeds 5 mcg/mL.

In patients with diabetes mellitus, lactoacidosis more often develops in severe renal insufficiency, including those due to congenital renal disease and insufficient renal perfusion, especially when taking several drugs. Patients with heart failure, particularly those with unstable angina or acute heart failure and risk of hypoperfusion and hypoxemia, have an increased risk of developing lactoacidosis.

The risk of lactoacidosis increases in proportion to the degree of renal failure and the age of the patient. Regular monitoring of renal function should be performed in patients taking metformin, and the minimum effective dose of metformin should be prescribed. In elderly patients, renal function should be monitored.

Patients aged 80 years and older with impaired renal function (as determined by CK) should not be prescribed metformin, since these patients are more prone to develop lactoacidosis. In addition, metformin therapy should be discontinued immediately in case of conditions accompanied by hypoxemia, dehydration or sepsis. Since hepatic impairment may significantly limit the ability to excrete lactate, metformin should not be administered to patients with clinical or laboratory signs of liver disease.

Contraindications

– individual hypersensitivity to any component of the drug;

– serious hypersensitivity reactions (anaphylaxis or angioedema) to DPP-4 inhibitors;

– type 1 diabetes mellitus (use not studied);

– use in conjunction with insulin (not studied);

– congenital galactose intolerance, lactase deficiency, and glucose-galactose malabsorption;

– pregnancy, lactation;

– age less than 18 years (safety and effectiveness have not been studied);

– Renal dysfunction (serum creatinine ≥1.5mg/dL [men], ≥1.4 mg/dL [women] or decreased creatinine clearance), including those due to acute cardiovascular failure (shock), acute myocardial infarction, and septicemia;

– acute illness with risk for renal dysfunction Dehydration (with vomiting, diarrhea), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, renal infections, bronchopulmonary disease);

– Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma;

– clinically manifest acute and chronic conditions that can lead to tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);

– serious surgical operations and trauma (when insulin therapy is indicated);

– liver function disorders;

– chronic alcoholism and acute ethanol poisoning;

– lactoacidosis (includingч.

– a period of at least 48 hours before and 48 hours after radioisotopic or fluoroscopic studies with iodine-based contrast agents;

– keeping a low-calorie diet (

With caution

In persons older than 60 years of age who perform strenuous physical labor (increased risk of lactoacidosis) and patients with a history of pancreatitis (no association between taking the drug and an increased risk of pancreatitis has been established).

Side effects

Monotherapy and adjunctive combination therapy

Saxagliptin

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

Table 1. Adverse events

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

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

. Adverse events noted in ≥ 2% of patients taking saxagliptin at a dose of 2.5 mg or saxagliptin at a dose of 5 mg and developing ≥ 1% more frequently than in the placebo group 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 fracture development was 1.0 and 0.6 per 100 patient-years, respectively, with saxagliptin (combined analysis of 2.5 mg, 5 mg, and 10 mg doses) and placebo. The frequency of fractures in patients taking saxagliptin did not increase over time. No causal relationship has been established, and preclinical studies have shown no adverse effects of saxagliptin on bone tissue.

The development of thrombocytopenia consistent with the diagnosis of idiopathic thrombocytopenic purpura has been observed in a clinical program. The relationship of this phenomenon to saxagliptin administration is not known.

Indications associated with co-administration of saxagliptin and metformin in patients with previously untreated type 2 diabetes mellitus (T2DM)

Saxagliptin

. Table 2 presents adverse events noted (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of combined use of saxagliptin and metformin in patients not previously receiving therapy.

Table 2. Adverse events

Overdose

Saxagliptin

In long-term administration of the drug in doses up to 80 times higher than recommended, no intoxication symptoms have been described. In case of overdose symptomatic therapy should be used. Saxagliptin and its main metabolite are excreted from the body by hemodialysis (excretion rate: 23% of the dose in 4 hours).

Metformin

There have been recorded cases of metformin overdose, including administration of more than 50 g. Approximately 10% of cases developed hypoglycemia, but its causal relationship to metformin has not been established. In 32% of cases of metformin overdose patients had lactoacidosis. Metformin is excreted by dialysis, with a clearance of up to 170 ml/min.