Combogliz Prolong tablets 1000 + 5mg, no. 28

I take it orally 1 time / day during dinner. The dose should be selected individually.

Usually, when treating with a combination drug containing saxagliptin and metformin, the dose of saxagliptin is 5 mg 1 time / day. The recommended starting dose for modified release metformin is 500 mg once daily, and can be increased to 2000 mg 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.

Modified release film-coated tablets

1 tab.

metformin 1000 mg

saxagliptin 5 mg

• Serious hypersensitivity reactions (anaphylaxis or angioedema) to DPP-4 inhibitors; type 1 diabetes mellitus (use not studied);

• use in conjunction with insulin (not studied);

• impaired renal function (serum creatinine? 1.5 mg / dL [men],? 1.4 mg / dL [women], or decreased CC), incl. caused by acute cardiovascular failure (shock), acute myocardial infarction and septicemia;

• acute diseases in which there is a risk of developing renal dysfunction: dehydration (with vomiting, diarrhea), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, broncho-pulmonary diseases);

• acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma;

• clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);

• serious surgery and trauma (when insulin therapy is indicated);

• liver dysfunction;

• chronic alcoholism and acute ethanol poisoning;

• lactic acidosis (including history);

• a period of at least 48 hours before and within 48 hours after carrying out radioisotope or X-ray studies with the introduction of iodine-containing contrast agents;

• adherence to a hypocaloric diet (<1000 kcal / day);

• pregnancy, lactation;

• age up to 18 years (safety and efficacy have not been studied);

• hypersensitivity to the components of the combination.

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

pharmachologic effect

Combined hypoglycemic drug for oral prema. Combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): saxagliptin, an inhibitor of dipeptyl peptidase 4 (DPP-4), 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 into the bloodstream. These hormones promote the release of insulin from the beta cells of the pancreas, depending 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, decreasing the production of glucose in the liver. In patients with type 2 diabetes mellitus, the concentration of GLP-1 is decreased, but the insulin response to GLP-1 remains. Saxagliptin, being a competitive inhibitor of DPP-4, reduces the inactivation of incretin hormones, thereby increasing their concentration 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 the production of glucose by the liver, lowers the absorption of glucose in the intestine and increases insulin sensitivity, increasing peripheral absorption and utilization of glucose. Unlike sulfonylurea preparations, metformin does not cause hypoglycemia in patients with type 2 diabetes mellitus or in healthy people, 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

Metformin

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 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 administration of modified release metformin, Cmax is achieved on average after 7 hours, in the range from 4 to 8 hours. AUC and Cmax of modified release metformin increased out of proportion to the dose in the dose range from 500 to 2000 mg. Cmax in blood plasma is 0.6, 1.1, 1.4 and 1.8 ?g / ml when taken in doses of 500, 1000, 1500 and 2000 mg 1 time / day, respectively.

There were no studies of the distribution of modified release metformin, however, the apparent Vd of metformin after a single oral administration of immediate release metformin tablets at a dose of 850 mg, on average, was 654 ± 358 L. Metformin binds to a small extent with blood 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 through the intestines.

Renal clearance is approximately 3.5 times higher than CC, indicating that tubular secretion is the main route of excretion of metformin. After oral administration, approximately 90% of the absorbed metformin is excreted by the kidneys within the first 24 hours, while the T1 / 2 from the plasma is approximately 6.2 hours. In the blood, the T1 / 2 is approximately 17.6 hours, therefore, the red blood cell mass may be part of the distribution.

In patients with impaired renal function (according to the results of CC measurements), T1 / 2 of metformin from plasma and blood is lengthened and renal clearance decreases in proportion to the decrease in CC.

Saxagliptin

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

With repeated use of the drug 1 time / day at any dose, there is no noticeable cumulation 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 1 time / day in doses from 2.5 mg to 400 mg of saxagliptin.

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

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

Saxagliptin is metabolized mainly with the participation of cytochrome P450 ZA4 / 5 (CYP3A4 / 5) isoenzymes with the formation of an active main metabolite, the inhibitory effect of which against DPP-4 is 2 times weaker than that of saxagliptin.

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

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

In patients with mild renal failure, the AUC values ??of saxagliptin and its active metabolite were 20% and 70% (respectively) higher than the AUC values ??in patients with normal renal function. Since 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 impairment.

Side effect

From the respiratory system: nasopharyngitis, upper respiratory tract infections.

From the excretory system: urinary tract infections.

From the nervous system: headache.

From the side of metabolism: hypoglycemia, a decrease in serum of a previously normal concentration of vitamin B12 to subnormal values ??without clinical manifestations (it quickly recovers after discontinuation of metformin or additional intake of vitamin B12).

Allergic reactions: urticaria, swelling of the face.

From the digestive system: abdominal pain, gastroenteritis, vomiting.

From the hematopoietic system: dose-dependent average decrease in the absolute number of lymphocytes (without clinical manifestations).

Application during pregnancy and lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Application for violations of liver function

The use of the drug for violations of liver function is contraindicated.

Application for impaired renal function

The use of the drug for impaired renal function (serum creatinine? 1.5 mg / dL [men],? 1.4 mg / dL [women] or decreased creatinine clearance) is contraindicated.

Application in children

The use of the drug is contraindicated in children under 18 years of age (safety and efficacy have not been studied).

Use in elderly patients

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

special instructions

Lactic acidosis is a rare, serious metabolic complication that can result from the accumulation of metformin during therapy with this combination. With the development of lactic acidosis due to the intake of metformin, its concentration in the blood plasma exceeds 5 ?g / ml.

In patients with diabetes mellitus, lactic acidosis often develops with severe renal failure, incl. due to congenital kidney disease and insufficient renal perfusion, especially with multiple drugs. In patients with heart failure, in particular in patients with unstable angina or acute heart failure and the risk of hypoperfusion and hypoxemia, there is 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 monitored regularly in patients taking metformin and the minimum effective dose of metformin should be prescribed. In elderly patients, monitoring of renal function is necessary. Do not give metformin to patients 80 years of age or older whoif renal function is impaired (according to QC), since these patients are more prone to the development of lactic acidosis. In addition, it is necessary to immediately cancel metformin therapy with the development of conditions accompanied by hypoxemia, dehydration or sepsis. Since liver failure can significantly limit the ability to excrete lactate, metformin should not be prescribed to patients with clinical or laboratory signs of liver disease.

The concentration of lactate in the plasma of venous blood on an empty stomach, exceeding the ULN, but below 5 mmol / l, in patients taking metformin, may indicate the impending development of lactic acidosis, and may also be explained by other reasons, 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 supportive measures. It is recommended that dialysis be started immediately to correct acidosis and remove cumulated metformin.

As you know, alcohol potentiates the effect of metformin on lactate metabolism, which increases the risk of lactic acidosis. You should limit the use of alcohol while using this combination.

Not recommended for patients with clinical and laboratory signs of liver disease due to the risk of lactic acidosis.

Renal function should be checked prior to initiation of 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.

You should temporarily stop taking the drug containing this combination before any surgical procedure (except for minor procedures not related to the restriction of food and liquids), and do not resume its use until the patient is able to take medications by mouth and is confirmed normal kidney function.

In a patient with type 2 diabetes, who was previously well controlled on therapy with a drug containing this combination, and who has laboratory abnormalities or developed a disease (especially in the case of an unclear diagnosis), it is necessary to immediately assess for signs of ketoacidosis or lactic acidosis. Evaluation 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 discontinue this combination and prescribe another hypoglycemic drug.

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

Hypoglycemia does not develop in patients taking only metformin on a regular basis, but it can develop with insufficient carbohydrate intake, when active physical activity is not compensated by carbohydrate intake, or with concomitant use with 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 susceptible to hypoglycemic effects. In the elderly and patients taking beta-blockers, the diagnosis of hypoglycemia can be difficult.

Caution should be exercised in prescribing concomitant drugs (such as cationic drugs excreted by secretion in the renal tubules), which can affect renal function, lead to significant hemodynamic changes, or disrupt the distribution of metformin.

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 discontinue therapy with a drug containing this combination 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.

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 the therapy with this combination.

Fever, trauma, infection, surgery can lead to a violation of the concentration of glucose in the blood, which previously could be controlled with this combination. In these cases, it may be necessary to temporarily discontinue therapy and transfer the patient to insulin therapy. After stabilization of the concentration of glucose in the blood and improvement of the general condition of the patient, treatment with this combination can be resumed.

During the post-marketing use of saxagliptin, serious hypersensitivity reactions have been noted, including anaphylaxis and angioedema. If a serious hypersensitivity reaction develops, the drug should be discontinued, other possible reasons for the development of the phenomenon should be evaluated and alternative therapy for diabetes mellitus should be prescribed.

Influence on the ability to drive vehicles and mechanisms

It should be borne in mind that saxagliptin can cause headaches.

Drug interactions

Some drugs 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).

Diltiazem enhances the effect of saxagliptin when used together.

Increases in plasma concentration of saxagliptin are expected with amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil; however, dosage adjustment of saxagliptin is not recommended.

A significant increase in the concentration of saxagliptin in blood plasma is expected with the use of potent inhibitors of CYP3A4 / 5 isoenzymes (for example, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When used together 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 excreted by the kidneys through glomerular filtration, can theoretically interact with metformin, competing for the general transport systems of the renal tubules. In the course of studies of the drug interaction of metformin and cimetidine with single and repeated administration of the drug, the interaction of metformin and cimetidine for oral administration was observed in healthy volunteers; at the same time, there was a 60% increase in the maximum concentration of metformin in plasma and whole blood and a 40% increase in the AUC of metformin in plasma and whole blood. It is recommended to closely monitor patients and, if necessary, adjust the dose in patients taking cationic drugs,which are excreted through the proximal renal tubule system.

In a study of the drug interaction of metformin and furosemide with a single dose of the drug, conducted on healthy volunteers, their pharmacokinetic interaction was revealed. Furosemide increases the Cmax of metformin in plasma and blood by 22% and AUC in the blood by 15% without a significant change in the renal clearance of metformin. When taken together with metformin, the Cmax and AUC of furosemide decrease by 31% and 12%, respectively, and T1 / 2 decreases by 32% without a noticeable change in the renal clearance of furosemide. There is no data on the interaction of metformin and furosemide with long-term co-administration.

Simvastatin: the combined repeated use of saxagliptin 1 time / day (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: combined single use of saxagliptin (10 mg) and diltiazem (360 mg prolonged dosage form in an equilibrium state), a moderate inhibitor of CYP3A4 / 5 isoenzymes, increases Saxagliptin Cmax by 63%, and AUC - 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: the combined use of a single dose of saxagliptin (5 mg) and rifampicin (600 mg 1 time / day at steady state) lowers the Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax (39%), but without a significant changes in the AUC of the active metabolite.

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), lowers the Cmax of saxagliptin by 26%, but AUC 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.