Saterex^® (Tablets) Instructions for Use

ATC Code

A10BD (Oral hypoglycemic drugs in combination)

Active Substances

Metformin (Rec.INN registered by WHO)

Gosogliptin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined oral hypoglycemic drug (dipeptidyl peptidase-4 inhibitor + biguanide)

Pharmacotherapeutic Group

Hypoglycemic agent for oral administration, dipeptidyl peptidase-4 inhibitor and hypoglycemic agent of the biguanide group for oral administration in a kit

Pharmacological Action

Gosogliptin is an active, highly selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, intended for the treatment of type 2 diabetes mellitus. By inhibiting DPP-4 activity, gosogliptin increases the concentration of incretin family hormones synthesized in the intestine: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The increase in GLP-1 and GIP concentrations causes an increase in the sensitivity of pancreatic β-cells to glucose, leading to increased synthesis and secretion of insulin. The increase in GLP-1 concentration causes an increase in the sensitivity of pancreatic α-cells to glucose, leading to improved glucose-dependent regulation of glucagon secretion. The reduction of elevated glucagon secretion during meals reduces insulin resistance. The decrease in glucagon concentration against the background of an increase in insulin concentration, due to the increase in GLP-1 and GIP concentrations, causes a decrease in hepatic glucose production, leading to a reduction in blood glucose levels. In patients with type 2 diabetes mellitus and hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in glycated hemoglobin HbA1c concentration and a reduction in plasma glucose concentration both fasting and after a meal.

Metformin reduces hyperglycemia without causing hypoglycemia. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals. It increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. It reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. It delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthase. It increases the transport capacity of all types of membrane glucose transporters. In addition, it has a beneficial effect on lipid metabolism: it reduces the content of total cholesterol, LDL, and triglycerides.

Pharmacokinetics

Gosogliptin

It is rapidly absorbed after oral administration with an absolute bioavailability of more than 99%. C_max in plasma is reached within 1 hour after administration. Mean plasma concentrations increase proportionally with increasing dose. The decrease in gosogliptin plasma concentration after reaching C_max is biphasic. Food intake has a moderate effect on the rate of absorption of gosogliptin. Gosogliptin is practically not bound to plasma proteins. The main metabolic pathway of gosogliptin is associated with the hydroxylation of the pyrimidine group. Other metabolites are associated with amide hydrolysis, carbamoyl glucuronidation, formamide conjugation, glucose conjugation, and creatinine conjugation. Gosogliptin is eliminated from the body primarily by the kidneys. After oral administration, about 77% of the gosogliptin dose is excreted in the urine, with 48.5% unchanged. 10.5% of the dose is excreted through the intestine, with a significant portion being gosogliptin metabolites. T_1/2 after oral administration is about 20 hours.

Metformin

After oral administration, metformin is sufficiently completely absorbed from the gastrointestinal tract. The absolute bioavailability is 50-60%. C_max, averaging 2 μg/ml, is reached after 2.5 hours. Simultaneous food intake reduces and slows the absorption of metformin. Metformin is rapidly distributed into tissues and is practically not bound to plasma proteins. It accumulates in muscle tissue, salivary glands, kidneys, and liver. It is metabolized to a very weak extent. Clearance in healthy volunteers is 440 ml/min (4 times greater than CC), indicating the presence of active tubular secretion of metformin. T_1/2 is 6 hours; it is excreted in the urine unchanged.

Indications

Type 2 diabetes mellitus (in combination with diet therapy and physical exercise) as initial therapy or when diet and exercise in combination with monotherapy with one of the drugs do not lead to adequate glycemic control.

ICD codes

Dosage Regimen

Take tablets orally, with or immediately after food to reduce gastrointestinal adverse effects.

Swallow the tablet whole with a glass of water; do not crush or chew.

The fixed-dose combination provides gosogliptin 30 mg and metformin in two strengths: 500 mg or 1000 mg.

The recommended dose is one tablet twice daily.

For the 500 mg metformin strength, take one tablet in the morning and one in the evening.

For the 1000 mg metformin strength, take one tablet in the morning and one in the evening.

Initiate therapy with the lower metformin strength to improve gastrointestinal tolerance.

Titrate the dose based on glycemic control and tolerability, under medical supervision.

The maximum recommended daily dose of metformin in this combination is 2000 mg.

Do not use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

Assess renal function before initiation and at least annually during treatment.

In patients with moderate renal impairment (creatinine clearance 30-59 mL/min), monitor renal function every 3-6 months.

Temporarily discontinue therapy for 48 hours before and after procedures involving intravascular iodinated contrast media.

Withhold therapy during periods of hemodynamic instability, severe infection, or dehydration.

Adverse Reactions

Allergic reactions infrequently – allergic dermatitis.

Metabolism and nutrition disorders very rarely – lactic acidosis; with long-term use of metformin, decreased absorption of vitamin B₁₂ may be observed.

Nervous system disorders frequently – taste disturbance; infrequently – dizziness, headache, drowsiness.

Gastrointestinal disorders very frequently – nausea, vomiting, diarrhea, abdominal pain, lack of appetite; infrequently – constipation, diarrhea, dyspepsia, pancreatitis.

Hepatobiliary disorders infrequently – increased ALT activity, AST activity, cholecystitis, steatosis, increased bilirubin concentration, gallbladder polyp; very rarely – impaired liver function tests or hepatitis.

Renal and urinary disorders infrequently – urinary tract infections.

Skin and subcutaneous tissue disorders very rarely – skin reactions such as erythema, skin itching, rash.

General disorders and administration site conditions infrequently – asthenia, feeling of tiredness, peripheral edema, back pain.

Contraindications

Hypersensitivity to the active substances; type 1 diabetes mellitus; diabetic ketoacidosis, diabetic precoma, coma; lactic acidosis (including history); severe renal failure (CC less than 30 ml/min); hepatic failure; acute conditions with a risk of impaired renal function (dehydration (due to diarrhea, vomiting), severe infectious diseases, shock); clinically significant manifestations of acute or chronic diseases that can lead to the development of tissue hypoxia, including acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction; extensive surgical operations and trauma, when insulin therapy is indicated; chronic alcoholism, acute alcohol poisoning; pregnancy; breastfeeding period; use for less than 48 hours before and for 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast medium; adherence to a hypocaloric diet (less than 1000 kcal/day); age under 18 years.

With caution in patients with a history of pancreatitis; in patients with moderate chronic renal failure; in persons over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis in them.

Use in Pregnancy and Lactation

The use of this combination during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Contraindicated in hepatic failure.

Use in Renal Impairment

Contraindicated in severe renal failure (CC less than 30 ml/min).

Use with caution in patients with moderate chronic renal failure.

Pediatric Use

Contraindicated for use under 18 years of age.

Geriatric Use

Use with caution in patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis in them.

Special Precautions

Due to the possibility of an increase in the plasma concentration of gosogliptin in patients with moderate renal failure, it is recommended to use this combination with caution in these patients.

This combination is not recommended for use in patients with severe liver dysfunction (ALT or AST more than 2.5 times the ULN) due to limited experience with the drug in this category of patients.

Lactic acidosis is a rare but serious (high mortality in the absence of emergency treatment) complication that can occur due to the accumulation of metformin. Cases of lactic acidosis while taking metformin occurred mainly in diabetic patients with severe renal failure. Other associated risk factors should be considered, such as decompensated diabetes, ketosis, prolonged fasting, alcoholism, hepatic failure, and any condition associated with significant hypoxia. If metabolic acidosis is suspected, the drug should be discontinued.

The use of metformin should be discontinued during surgical operations under general, spinal, or epidural anesthesia. Metformin therapy can be resumed no earlier than 48 hours after the surgical operation or resumption of food intake, provided that renal function has been examined and recognized as normal.

Since metformin is excreted by the kidneys, CC should be determined before starting treatment and regularly thereafter: at least once a year in patients with normal renal function; every 3-6 months in patients with CC 45-59 ml/min; every 3 months in patients with CC 30-44 ml/min.

Particular caution should be exercised in cases of possible impairment of renal function in elderly patients, in dehydration (chronic or severe diarrhea, repeated episodes of vomiting), with simultaneous use of antihypertensive drugs, diuretics, or NSAIDs.

Patients with heart failure have a higher risk of developing hypoxia and renal failure. Patients with chronic heart failure should regularly monitor cardiac function and renal function while taking metformin. The use of metformin in heart failure with unstable hemodynamic parameters is contraindicated.

Intravascular administration of iodine-containing X-ray contrast agents can lead to the development of renal failure and accumulation of metformin, which increases the risk of lactic acidosis. Metformin must be discontinued, depending on renal function, 48 hours before or during an X-ray examination using iodine-containing X-ray contrast agents and not resumed earlier than 48 hours after it, provided that renal function was recognized as normal during the examination.

Patients are advised to continue following a diet with uniform carbohydrate intake throughout the day. Patients with excess body weight are advised to continue following a hypocaloric diet (but not less than 1000 kcal/day).

It is recommended to regularly perform standard laboratory tests to monitor diabetes mellitus.

Effect on ability to drive vehicles and operate machinery

During the use of this combination, the risk of developing hypoglycemia must be taken into account. If dizziness develops during treatment, patients should not drive vehicles or operate machinery.

Drug Interactions

Gosogliptin has a low potential for drug interactions.

Against the background of functional renal failure in diabetic patients, radiological examination using iodine-containing X-ray contrast agents can cause the development of lactic acidosis. Metformin treatment must be discontinued, depending on renal function, 48 hours before or during an X-ray examination using iodine-containing X-ray contrast agents and not resumed earlier than 48 hours after, provided that renal function was recognized as normal.

In acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in case of insufficient nutrition, adherence to a low-calorie diet, and hepatic failure. When using this combination, alcohol intake and medicines containing ethanol should be avoided.

Concomitant use of danazol is not recommended to avoid the hyperglycemic effect of the latter. If treatment with danazol is necessary and after its discontinuation, dose adjustment of metformin under the control of blood glucose concentration is required.

Chlorpromazine, when taken in large doses (100 mg/day), increases blood glucose concentration by reducing insulin release. When treating with antipsychotics and after their discontinuation, dose adjustment of the drug under the control of blood glucose concentration is required.

Systemic and local glucocorticoids reduce glucose tolerance, increase blood glucose concentration, and sometimes cause ketosis. When treating with glucocorticoids and after their discontinuation, dose adjustment of metformin under the control of blood glucose concentration is required.

Concomitant use of “loop” diuretics may lead to the development of lactic acidosis due to possible functional renal failure. Metformin should not be prescribed if CC is below 60 ml/min.

Beta₂-adrenomimetics administered by injection increase blood glucose concentration due to stimulation of β₂-adrenergic receptors. In this case, blood glucose concentration control is necessary. If necessary, insulin administration is recommended. When using the above-mentioned drugs concomitantly, more frequent monitoring of blood glucose levels may be required, especially at the beginning of treatment. If necessary, the dose of metformin can be adjusted during treatment and after its discontinuation.

Antihypertensive drugs, except for ACE inhibitors, may reduce blood glucose concentration. If necessary, the dose of metformin should be adjusted.

When metformin is used concomitantly with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemia may develop.

Nifedipine increases the absorption and C_max of metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin), which are secreted in the renal tubules, compete with metformin for tubular transport systems and can lead to an increase in its C_max.

Metformin is a substrate of both OCT1 and OCT2 transporters. Concomitant use of metformin with: OCT1 inhibitors (verapamil) may reduce the effectiveness of metformin; with OCT1 inducers (rifampicin) may increase the absorption of metformin in the gastrointestinal tract and its effectiveness; with OCT2 inhibitors (cimetidine, dolutegravir, ranolazine, trimethoprim, crizotinib, olaparib, daclatasvir, vandetanib) may reduce the renal elimination of metformin and thus lead to an increase in the plasma concentration of metformin. In this regard, caution is recommended, especially in patients with renal failure, when these drugs are taken simultaneously with metformin, as an increase in the plasma concentration of metformin is possible. If necessary, the issue of adjusting the dose of metformin may be considered, as OCT inhibitors/inducers can change the effectiveness of metformin.

Some drugs can have a hyperglycemic effect and lead to a deterioration in glycemic control. Such drugs include phenothiazides, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, slow calcium channel blockers, thyroid hormones. When the above-mentioned drugs are used concomitantly in patients receiving metformin, a decrease in the effectiveness of the latter is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.