Kombiglyze Prolong^® (Tablets) Instructions for Use

ATC Code

A10BD10 (Metformin and Saxagliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Saxagliptin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

A combined oral hypoglycemic drug. It combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin, a representative 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 stimulate insulin release from pancreatic beta-cells in a blood glucose concentration-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, decreasing hepatic glucose production. In patients with type 2 diabetes mellitus, GLP-1 concentrations are decreased, but the insulin response to GLP-1 is preserved. 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 postprandial glucose concentrations.

Metformin.Metformin is a hypoglycemic drug that improves glucose tolerance in patients with type 2 diabetes mellitus by lowering basal and postprandial glucose concentrations. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and increases insulin sensitivity by enhancing peripheral glucose uptake and utilization. Unlike sulfonylurea drugs, Metformin does not cause hypoglycemia in patients with type 2 diabetes or in healthy individuals, and does not cause hyperinsulinemia. During metformin therapy, insulin secretion remains unchanged, although fasting insulin concentrations and the insulin response to food intake throughout the day may decrease.

Pharmacokinetics

Metformin

At steady state, the AUC and C_max of modified-release metformin increased non-proportionally to the dose in the range from 500 mg to 2000 mg. After repeated administration, modified-release Metformin did not accumulate in plasma. Metformin is excreted unchanged by the kidneys and is not metabolized in the liver.

After a single oral dose of modified-release metformin, C_max is reached on average in 7 hours, ranging from 4 to 8 hours. The AUC and C_max of modified-release metformin increased non-proportionally to the dose in the range from 500 mg to 2000 mg. Plasma C_max values are 0.6, 1.1, 1.4, and 1.8 µg/ml when administered at doses of 500, 1000, 1500, and 2000 mg once daily, respectively.

No distribution studies of modified-release metformin have been conducted; however, the apparent V_d 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.

Metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites have been identified in humans), and is not excreted via the intestines.

Renal clearance is approximately 3.5 times higher than creatinine clearance, indicating that tubular secretion is the main route of metformin elimination. After oral administration, approximately 90% of the absorbed metformin is excreted by the kidneys within the first 24 hours, with a plasma T_1/2 of approximately 6.2 hours. The blood T_1/2 is approximately 17.6 hours, suggesting that the red blood cell mass may be part of the distribution.

In patients with impaired renal function (based on creatinine clearance measurements), the plasma and blood T_1/2 of metformin is prolonged and renal clearance decreases proportionally to the decrease in creatinine clearance.

Saxagliptin

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy-saxagliptin, are similar in healthy volunteers and patients with T2DM. The C_max and AUC values 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 saxagliptin in healthy volunteers, the mean AUC values for saxagliptin and its main metabolite were 78 ng×h/ml and 214 ng×h/ml, and the plasma C_max values were 24 ng/ml and 47 ng/ml, respectively. The mean variability of AUC and C_max for saxagliptin and its active metabolite was less than 25%.

No significant accumulation of saxagliptin or its active metabolite is observed with repeated once-daily administration at any dose. No dependence of saxagliptin and its active metabolite clearance on dose and time was observed during 14 days of once-daily administration at doses from 2.5 mg to 400 mg of saxagliptin.

After oral administration, at least 75% of the saxagliptin dose is absorbed.

The binding of saxagliptin and its main metabolite to serum proteins is negligible; therefore, it can be assumed that the distribution of saxagliptin will not be significantly altered by changes in serum protein composition observed in hepatic or renal impairment.

Saxagliptin is metabolized mainly by cytochrome P450 isoenzymes 3A4/5 (CYP3A4/5) to form an active main metabolite, whose inhibitory effect on DPP-4 is 2 times weaker than that of saxagliptin.

Saxagliptin is excreted by the kidneys and through the intestines. After a single 50 mg dose of radiolabeled ¹⁴C-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 urine corresponded to 75% of the administered dose.

The mean renal clearance of saxagliptin was about 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 values. About 22% of the total radioactivity was found in feces.

In patients with mild renal impairment, 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 is not considered clinically significant, dose adjustment of saxagliptin is not recommended in patients with mild renal impairment.

Indications

Type 2 diabetes mellitus in combination with diet and exercise to improve glycemic control.

ICD codes

Dosage Regimen

Tablets

Take orally once daily with the evening meal. The dose should be individually selected.

Usually, during therapy with a combined drug containing Saxagliptin and Metformin, the dose of saxagliptin is 5 mg once daily. The recommended initial dose of modified-release metformin is 500 mg once daily, which can be increased to 2000 mg once daily.

The dose of metformin should be increased gradually to reduce the risk of gastrointestinal side effects.

Maximum daily dose: saxagliptin 5 mg and modified-release metformin 2000 mg.

Adverse Reactions

Respiratory system nasopharyngitis, upper respiratory tract infections.

Excretory system urinary tract infections.

Nervous system headache.

Metabolism hypoglycemia, decrease in serum previously normal vitamin B₁₂ concentration to subnormal values without clinical manifestations (quickly recovers after metformin discontinuation or additional vitamin B₁₂ intake).

Allergic reactions urticaria, facial edema.

Digestive system abdominal pain, gastroenteritis, vomiting.

Hematopoietic system dose-dependent mean decrease in absolute lymphocyte count (without clinical manifestations).

Contraindications

Serious hypersensitivity reactions (anaphylaxis or angioedema) to DPP-4 inhibitors; type 1 diabetes mellitus (use not studied); concomitant use with insulin (not studied); renal impairment (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 conditions with a risk of renal impairment: dehydration (with vomiting, diarrhea), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases); acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; clinically significant manifestations of acute and chronic diseases that can lead to tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction); major surgical operations and trauma (when insulin therapy is indicated); hepatic impairment; chronic alcoholism and acute ethanol poisoning; lactic acidosis (including history); period at least 48 hours before and within 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast agents; adherence to a hypocaloric diet (<1000 kcal/day); pregnancy, lactation; age under 18 years (safety and efficacy not studied); hypersensitivity to the components of the combination.

With caution

In persons over 60 years of age performing heavy physical work (increased risk of lactic acidosis) and patients with a history of pancreatitis (a link between taking this combination and an increased risk of pancreatitis has not been established).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Use of the drug in hepatic impairment is contraindicated.

Use in Renal Impairment

Use of the drug in renal impairment (serum creatinine ≥1.5 mg/dl [men], ≥1.4 mg/dl [women] or reduced creatinine clearance) is contraindicated.

Pediatric Use

Use of the drug is contraindicated in children under 18 years of age (safety and efficacy not studied).

Geriatric Use

Since Saxagliptin and Metformin are partially excreted by the kidneys, and elderly patients are likely to have reduced renal function, Kombiglyze Prolong^® should be used with caution in the elderly.

Special Precautions

Lactic acidosis is a rare, serious metabolic complication that can develop as a result of metformin accumulation during therapy with this combination. When lactic acidosis develops due to metformin intake, its plasma concentration exceeds 5 µg/ml.

In patients with diabetes, lactic acidosis develops more often in severe renal failure, including due to congenital kidney disease and inadequate renal perfusion, especially when taking multiple drugs. Patients with heart failure, particularly those with unstable angina or acute heart failure and at risk of hypoperfusion and hypoxemia, have an increased risk of developing lactic acidosis. The risk of developing lactic acidosis increases proportionally to the degree of renal impairment and the patient’s age. 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 monitoring is necessary. Metformin should not be prescribed to patients aged 80 years and older if renal function is impaired (based on creatinine clearance), as these patients are more prone to developing lactic acidosis. Furthermore, metformin therapy should be immediately discontinued if conditions accompanied by hypoxemia, dehydration, or sepsis develop. Since hepatic impairment can significantly limit the ability to eliminate lactate, Metformin should not be prescribed to patients with clinical or laboratory signs of liver disease.

A fasting venous plasma lactate concentration above the upper limit of normal but below 5 mmol/L in patients taking Metformin may indicate impending lactic acidosis, but may also be explained by other causes, such as uncontrolled diabetes, obesity, or excessive physical exertion.

The presence of lactic acidosis should be checked in all diabetic patients with metabolic acidosis without signs of ketoacidosis (ketonuria and ketonemia). Lactic acidosis requires inpatient treatment. If lactic acidosis is detected in a patient taking Metformin, the drug should be immediately discontinued and general supportive measures should be promptly initiated. Immediate dialysis is recommended to correct the acidosis and remove the accumulated metformin.

It is known that alcohol potentiates the effect of metformin on lactate metabolism, which increases the risk of lactic acidosis. Alcohol consumption should be limited during the use of this combination.

It is not recommended to prescribe to patients with clinical and laboratory signs of liver disease due to the risk of lactic acidosis.

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

The intake of the drug containing this combination should be temporarily suspended before any surgical procedure (except for minor procedures not associated with restriction of food and fluid intake), and should not be resumed until the patient is able to take oral medications and normal renal function is confirmed.

In a patient with T2DM who was previously well controlled on therapy with a drug containing this combination and who shows abnormal laboratory test results or develops an illness (especially in the case of an unclear diagnosis), signs of ketoacidosis or lactic acidosis should be immediately assessed. The 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, this combination should be immediately discontinued and another hypoglycemic drug should be prescribed.

Drugs that stimulate insulin secretion, such as sulfonylurea derivatives, can cause hypoglycemia. Therefore, to reduce the risk of hypoglycemia when used in combination with saxagliptin, a dose reduction of the insulin secretagogue may be required.

Hypoglycemia does not develop in patients taking only Metformin in the usual regimen, but may develop with insufficient carbohydrate intake, when vigorous physical exertion is not compensated by carbohydrate intake, or with concomitant use of other hypoglycemic drugs (such as sulfonylurea derivatives and insulin) or alcohol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are most sensitive to the hypoglycemic effects. In the elderly and patients taking beta-blockers, diagnosis of hypoglycemia may be difficult.

Concomitant drugs (such as cationic drugs excreted by tubular secretion) that may affect renal function, lead to significant hemodynamic changes, or interfere with the distribution of metformin should be prescribed with caution.

Acute renal impairment has been observed during radiological studies with intravascular administration of iodine-containing contrast agents, which may be accompanied by the development of lactic acidosis in patients receiving Metformin. Patients scheduled for such an examination should discontinue therapy with the drug containing this combination 48 hours before such a procedure, refrain from taking the drug for 48 hours after the procedure, and resume therapy only after normal renal function is confirmed.

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, therapy with this combination should be immediately discontinued.

Fever, trauma, infection, and surgery can lead to disturbances in blood glucose concentrations that were previously controlled with this combination. In these cases, temporary discontinuation of therapy and switching to insulin therapy may be required. After blood glucose concentrations stabilize and the patient’s general condition improves, treatment with this combination can be resumed.

Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during post-marketing use of saxagliptin. If a serious hypersensitivity reaction occurs, the use of the drug should be discontinued, other possible causes for the event should be assessed, and alternative therapy for diabetes should be prescribed.

Effect on ability to drive vehicles and operate machinery

It should be taken into account that Saxagliptin may cause headache.

Drug Interactions

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

Diltiazem enhances the effect of saxagliptin when used concomitantly.

An increase in saxagliptin plasma concentration is expected with the use of amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil; however, dose adjustment of saxagliptin is not recommended.

A significant increase in saxagliptin plasma concentration is expected with the use of potent inhibitors of CYP3A4/5 isoenzymes (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). When used concomitantly with a potent inhibitor of CYP3A4/5 isoenzymes, the dose of saxagliptin should be reduced to 2.5 mg.

Cationic drugs (for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin), which are eliminated by the kidneys via glomerular filtration, can theoretically interact with metformin by competing for common renal tubular transport systems.

In studies of the drug interaction between metformin and cimetidine with single and repeated administration, an interaction between metformin and oral cimetidine was observed in healthy volunteers; a 60% increase in the maximum plasma and whole blood concentration of metformin and a 40% increase in the AUC of metformin in plasma and whole blood were noted.

It is recommended to closely monitor patients and adjust the dose if necessary in patients taking cationic drugs that are eliminated through the proximal renal tubular system.

In a study of the drug interaction between metformin and furosemide with single administration, conducted in healthy volunteers, their pharmacokinetic interaction was revealed.

Furosemide increases the C_max of metformin in plasma and blood by 22% and the AUC in blood by 15% without a significant change in the renal clearance of metformin.

When taken concomitantly with metformin, the C_max and AUC of furosemide decrease by 31% and 12%, respectively, and the T_1/2 decreases by 32% without a noticeable change in the renal clearance of furosemide.

There are no data on the interaction of metformin and furosemide with long-term concomitant use.

Simvastatin Concomitant repeated administration of saxagliptin once daily (10 mg) and simvastatin (40 mg), a substrate of CYP3A4/5 isoenzymes, increased the C_max of saxagliptin by 21%, but the AUC of saxagliptin does not change.

Diltiazem Concomitant single administration of saxagliptin (10 mg) and diltiazem (360 mg extended-release formulation at steady state), a moderate inhibitor of CYP3A4/5 isoenzymes, increases the C_max of saxagliptin by 63%, and the AUC by 2.1 times.

This is accompanied by a corresponding decrease in the C_max and AUC of the active metabolite by 44% and 36%, respectively.

Ketoconazole Concomitant administration 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 the C_max and AUC of the active metabolite by 96% and 90%, respectively.

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

Aluminum hydroxide + magnesium hydroxide + simethicone Concomitant administration of single doses of saxagliptin (10 mg) and a suspension containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg), and simethicone (240 mg) decreases the C_max 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, increases the C_max of saxagliptin by 14%, but the AUC of saxagliptin does not change.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.