SITOLA 1000/50 [Metformin hydrochloride + Sitagliptin phosphate] 1000 + 50 mg Tablets
SITOLA
instructions for medical use of the medicinal product
Tradename
Sitola, Ситола
International non-proprietary name
Metformin hydrochloride + Sitagliptin phosphate,
Compound
Each film-coated tablet contains:
active substances: metformin hydrochloride 500 mg, sitagliptin phosphate 50 mg
excipients: starch, dextrin, microcrystalline cellulose, sodium carboxymethyl starch, hydroxypropyl methylcellulose, silicon dioxide, magnesium stearate, talc
Each film-coated tablet contains:
active substances: metformin hydrochloride 850 mg, sitagliptin phosphate 50 mg
excipients: starch, dextrin, microcrystalline cellulose, sodium carboxymethyl starch, hydroxypropyl methylcellulose, silicon dioxide, magnesium stearate, talc
Each film-coated tablet contains:
active substances: metformin hydrochloride 1000 mg, sitagliptin phosphate 50 mg
excipients: starch, dextrin, microcrystalline cellulose, sodium carboxymethyl starch, hydroxypropyl methylcellulose, silicon dioxide, magnesium stearate, talc
Dosage form
Tablets.
Pharmacotherapeutic group
Combined oral hypoglycemic agent (dipeptidyl peptidase-4 inhibitor + biguanide) .
Pharmacological properties
The drug is a combination of two hypoglycemic drugs with a complementary mechanism of action, designed to improve glycemic control in patients with type II diabetes mellitus : sitagliptin phosphate, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), and metformin hydrochloride, a member of the biguanide class.
Pharmacodynamics
metformin hydrochloride
It is a hypoglycemic drug that increases glucose tolerance in patients with type II diabetes mellitus , reducing basal and postprandial blood glucose levels. Its pharmacological mechanisms of action differ from those of other oral hypoglycemic classes.
Reduces the synthesis of glucose in the liver, reduces the absorption of glucose in the intestine and increases insulin sensitivity by enhancing the peripheral uptake and utilization of glucose. Unlike sulfonylurea derivatives, metformin hydrochloride does not cause hypoglycemia in either patients with type II diabetes mellitus or in healthy people (except in certain circumstances) and does not cause hyperinsulinemia. During treatment, insulin secretion does not change, while fasting insulin concentration and daily plasma insulin concentration may decrease.
Sitagliptin phosphate
It is an orally active, highly selective inhibitor of the DPP-4 enzyme, indicated for the treatment of diabetes mellitus II. type. The pharmacological effects of the DPP-4 inhibitor class of drugs are mediated by the activation of incretins. By inhibiting DPP-4, sitagliptin phosphate increases the concentration of two known active hormones of the incretin family: glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are part of the internal physiological system for the regulation of glucose homeostasis. At normal or elevated blood glucose concentrations, GLP-1 and GIP contribute to an increase in the synthesis and secretion of insulin by pancreatic β-cells. GLP-1 also inhibits the secretion of glucagon by pancreatic α-cells, thus reducing hepatic glucose synthesis. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin at low blood glucose concentrations, which is fraught with the development of sulfonyl-induced hypoglycemia not only in patients with type II diabetes mellitus, but also in healthy individuals. Sitagliptin phosphate at therapeutic concentrations does not inhibit the activity of related enzymes DPP-8 or DPP-9. Sitagliptin phosphate differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylurea derivatives or meglitinides, biguanides, peroxisome proliferator-activated receptor γ-agonists (PPARγ), alpha-glucosidase inhibitors, and amylin analogues.
Pharmacokinetics
The results of a bioequivalence study in healthy volunteers demonstrated that the combined metformin hydrochloride + sitagliptin phosphate 500 mg + 50 mg and 1000 mg + 50 mg tablets are bioequivalent to taking metformin hydrochloride and sitagliptin phosphate separately at appropriate doses.
Taking into account the proven bioequivalence of tablets with the lowest and highest doses of metformin hydrochloride, tablets with an intermediate dose (metformin hydrochloride + sitagliptin phosphate) 850 mg + 50 mg were also assigned bioequivalence, provided that fixed doses of drugs were combined in a tablet.
metformin hydrochloride
The absolute bioavailability of metformin hydrochloride when taken on an empty stomach at a dose of 500 mg is 50-60%. Results from single-dose studies with tablets ranging from 500 mg to 1500 mg and from 850 mg to 2550 mg indicate a dose-proportionality disorder with increasing dose, which is due to reduced absorption rather than accelerated excretion. Simultaneous administration of the drug with food reduces the rate and amount of absorbed metformin hydrochloride, as evidenced by a decrease in plasma C max by about 40%, a decrease in AUC by about 25%, and a 35-minute delay in reaching C max after a single dose of metformin hydrochloride in a dose of 850 mg simultaneously with food compared with the values of the corresponding parameters after taking a similar dose of the drug on an empty stomach. The clinical significance of the decrease in the values of pharmacokinetic parameters has not been established.
Vd metformin hydrochloride after a single oral dose of 850 mg averaged 654±358 liters. Metformin hydrochloride is only very slightly bound to plasma proteins. Partially and temporarily distributed in erythrocytes. When using metformin hydrochloride at recommended doses, plasma concentrations of the equilibrium state (usually <1 µg / ml) are reached after about 24-48 hours. According to controlled studies, Cmax in the plasma of the drug did not exceed 5 µg / ml even after taking the drug at maximum doses .
After a single intravenous administration of metformin hydrochloride to healthy volunteers, almost the entire administered dose was excreted unchanged by the kidneys. Metabolic transformations of the drug in the liver and its excretion with bile does not occur.
Renal clearance of metformin hydrochloride exceeds CC by 3.5 times, indicating active renal secretion as the main route of excretion. After taking metformin hydrochloride, about 90% of the absorbed drug is excreted by the kidneys during the first 24 hours with a plasma half-life of approximately 6.2 hours, in the blood this value is extended to 17.6 hours, indicating the possible participation of erythrocytes as a potential distribution compartment.
Sitagliptin phosphate
The absolute bioavailability of sitagliptin phosphate is approximately 87%. Simultaneous administration with fatty foods does not affect the pharmacokinetics of the drug.
The average V d at steady state after a single intravenous injection of 100 mg of sitagliptin phosphate in healthy volunteers is approximately 198 liters. The fraction of sitagliptin phosphate reversibly binding to plasma proteins is relatively small (38%).
Approximately 79% of sitagliptin phosphate is excreted unchanged by the kidneys, the metabolic transformation of the drug is minimal.
After oral administration of 14 C-labeled sitagliptin phosphate, approximately 16% of the administered radioactivity was excreted as metabolites. Trace concentrations of 6 sitagliptin phosphate metabolites have been identified that do not contribute in any way to the plasma DPP-4 inhibitory activity of sitagliptin phosphate. In in vitro studies, the isoenzymes of the cytochrome system CYP3A4 and CYP2C8 have been identified as the main enzymes involved in the limited metabolism of sitagliptin phosphate.
After ingestion of 14 C-labeled sitagliptin phosphate by healthy volunteers, almost all of the administered radioactivity was eliminated from the body within a week, incl. 13% - through the intestines and 87% - by the kidneys; the average T 1/2 of sitagliptin phosphate when taken orally at a dose of 100 mg is approximately 12.4 hours, renal clearance is approximately 350 ml / min.
Excretion is carried out mainly by renal excretion by the mechanism of active tubular secretion. Sitagliptin phosphate is a substrate for the human organic anion transporter type 3 (hOAT-3), which is involved in the elimination of sitagliptin phosphate by the kidneys. The clinical significance of the involvement of hOAT-3 in the transport of sitagliptin phosphate has not been established. It is possible that P-glycoprotein is involved in the renal elimination of sitagliptin phosphate (as a substrate), but the P-glycoprotein inhibitor cyclosporine does not reduce the renal clearance of sitagliptin phosphate.
Indications for use
Sitol tablets are indicated for patients with type II diabetes mellitus, both at the initial stage of treatment and for regular glycemic control. It can be used as monotherapy if the appropriate diet and physical activity does not bring significant results. Combination therapy in combination with other drugs of similar action, which include sulfonylurea derivatives, thiazolidinediones or insulin, may also be an indication. In any case, Sitol tablets must be combined with an adequate diet and balanced physical activity, so a preliminary consultation with a doctor is necessary. He must select an individual dose, based on the history of the disease and the characteristics of the patient's condition.
Contraindications
Type I diabetes mellitus ; kidney disease or decreased kidney function (with serum creatinine concentration> 1.5 mg / dl and> 1.4 mg / dl in men and women, respectively, or a decrease in CC (<60 ml / min), including due to cardiovascular collapse (shock), acute myocardial infarction or septicemia; acute conditions that occur with a risk of developing renal dysfunction, such as dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases) acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma), clinical manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including heart or respiratory failure, acute myocardial infarction), extensive surgical operations and injuries, when insulin therapy is indicated, liver failure, impaired liver function, chronic alcoholism, acute alcohol poisoning; pregnancy, lactation; lactic acidosis (including history); use for at least 48 hours before and within 48 hours after radioisotope or X-ray studies with the introduction of an iodine-containing contrast agent; compliance with a hypocaloric diet (less than 1000 kcal / day); children and adolescents up to 18 years of age; hypersensitivity to metformin hydrochloride, sitagliptin phosphate or any of the components of the drug.
Dosage and administration
Taken orally, during meals. Tablets are swallowed whole, without chewing, drinking plenty of water.
The dosage regimen of the drug is selected individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of metformin hydrochloride 2000 mg and sitagliptin phosphate 100 mg.
Sitola is produced in the following dosages: 500 mg metformin hydrochloride + 50 mg sitogliptin phosphate, 850 mg metformin hydrochloride + 50 mg sitogliptin phosphate and 1000 mg metformin hydrochloride + 50 mg sitogliptin phosphate.
The drug is taken 2 times a day, morning and evening.
The initial dose of the drug depends on the current hypoglycemic therapy.
In patients with type II diabetes mellitus with inadequate glycemic control against the background of diet and exercise, the recommended starting dose is 500 mg metformin hydrochloride + 50 mg sitagliptin phosphate 2 times / day. Subsequently, the dose can be increased to 1000 mg metformin hydrochloride + 50 mg sitagliptin phosphate 2 times / day.
The dose of the drug should be increased gradually to reduce adverse reactions from the gastrointestinal tract due to the action of metformin hydrochloride.
For patients who have not achieved adequate glycemic control on monotherapy with the maximum tolerated dose of metformin hydrochloride
The recommended initial dose of the drug for patients who have not achieved adequate control on metformin hydrochloride monotherapy should provide the recommended therapeutic daily dose of sitagliptin phosphate 100 mg, i.e. 50 mg sitagliptin phosphate 2 times / day plus the current dose of metformin hydrochloride.
For patients who have not achieved adequate glycemic control on the background of monotherapy with sitaglintin phosphate
The recommended initial dose of the drug for patients who have not achieved adequate control on monotherapy with sitagliptin phosphate is 500 mg of metformin hydrochloride + 50 mg of sitagliptin phosphate 2 times / day. In the future, the dose can be increased to 1000 mg of metformin hydrochloride + 50 mg of sitagliptin phosphate 2 times / day to achieve glycemic control. Patients taking an adjusted dose of sitagliptin phosphate due to impaired renal function should not be treated with Sitola.
For patients who have previously received combination therapy with metformin hydrochloride and sitaglintin phosphate in the form of monodrugs
When switching from combination therapy of metformin hydrochloride and sitagliptin phosphate in the form of monodrugs, the initial dose of Sitol should correspond to the doses of metformin hydrochloride and sitagliptin phosphate monodrugs taken.
For patients who have not achieved adequate glycemic control when using a combination of a sulfonylurea derivative and metformin hydrochloride
The initial dose of the drug should provide the recommended therapeutic daily dose of sitagliptin phosphate 100 mg, i.e. 50 mg sitagliptin phosphate 2 times / day. The initial dose of metformin hydrochloride is determined based on the level of glycemic control and the current (if the patient is taking this drug) dose of metformin hydrochloride. Increasing the dose of metformin hydrochloride should be gradual in order to minimize adverse reactions from the gastrointestinal tract.
In patients taking a sulfonylurea derivative, it would be rational to reduce the current dose to reduce the risk of sulfonylurea-induced hypoglycemia.
For patients who have not achieved adequate glycemic control when using a combination of metformin hydrochloride and thiazolidinedione
The initial dose should correspond to the daily dose of sitagliptin phosphate 100 mg, i.e. 50 mg of sitagliptin phosphate 2 times / day and the previously taken dose of metformin hydrochloride. If it is necessary to increase the dose of metformin hydrochloride, a gradual titration of the drug is recommended in order to minimize adverse reactions from the gastrointestinal tract.
For patients who have not achieved adequate glycemic control when using a combination of insulin and metformin hydrochloride as monotherapy
The initial dose should correspond to the daily dose of sitagliptin phosphate 100 mg, i.e. 50 mg of sitagliptin phosphate 2 times / day and the previously taken dose of metformin hydrochloride. If it is necessary to increase the dose of metformin hydrochloride, a gradual titration of the drug is recommended in order to minimize adverse reactions from the gastrointestinal tract. Patients may need to reduce their insulin dose to prevent the risk of hypoglycemia.
Special instructions and precautions
There have been reports of cases of acute pancreatitis, including hemorrhagic or necrotizing with and without fatal outcome, in patients taking sitagliptin phosphate. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin phosphate. If pancreatitis is suspected, it is necessary to stop taking the drug and other potentially dangerous drugs. Metformin hydrochloride and sitagliptin phosphate are excreted primarily by the kidneys. The risk of accumulation of metformin hydrochloride and the development of lactic acidosis increases in proportion to the degree of impaired renal function, so the drug should not be prescribed to patients with a serum creatinine concentration above the upper age limit of normal. In elderly patients, due to age-related decline in kidney function, a minimum dose of the drug should be used to achieve adequate glycemic control. In elderly patients, especially those aged -80 years, regular monitoring of renal function is carried out. Before starting therapy with the drug, as well as at least 1 time per year after the start of treatment, normal kidney function should be confirmed using appropriate tests. In patients at risk of developing renal dysfunction, monitoring of renal function should be carried out more often, and if symptoms of renal dysfunction are detected, the drug should be discontinued.
Influence on the ability to drive vehicles and mechanisms
Use during pregnancy and during breastfeeding
The drug, like other oral hypoglycemic drugs, is not recommended for use during pregnancy and during breastfeeding.
Interaction with other drugs
Studies of the effect of drug-drug interactions on the pharmacokinetic parameters of the drug have not been conducted, however, there are a sufficient number of such studies for each of the components of the drug.
metformin hydrochloride
Glibenclamide: In a single dose drug interaction study of metformin hydrochloride and glibenclamide in patients with type II diabetes mellitus, no changes were observed in the pharmacokinetic and pharmacodynamic parameters of metformin hydrochloride. The decrease in AUC and C max values of glibenclamide was highly variable.
Insufficient information (single dose) and inconsistency in the blood concentration of glibenclamide to the observed pharmacodynamic effects call into question the clinical significance of this interaction.
Furosemide : In a drug-drug interaction study, changes in the pharmacokinetic parameters of both drugs were observed when taking single doses of metformin hydrochloride and furosemide in healthy volunteers. Furosemide increased the Cmax value of metformin hydrochloride in plasma and whole blood by 22%, the AUC value in whole blood by 15% without a significant change in renal clearance. With the simultaneous administration of metformin hydrochloride and furosemide, the values of C max and AUC of furosemide decreased by 31% and 12%, respectively, compared with taking only furosemide, and T 1/2 decreased by 32% without a significant change in the renal clearance of furosemide. There is no information on drug-drug interactions of metformin hydrochloride and furosemide with long-term simultaneous use.
Nifedipine: A single dose drug-drug interaction study of nifedipine and metformin hydrochloride in healthy volunteers showed an increase in plasma metformin hydrochloride C max and AUC of 20% and 9%, respectively, and an increase in the amount of metformin hydrochloride excreted by the kidneys. The values of T max and T 1/2 metformin hydrochloride have not changed. Nifedipine increases the absorption of metformin hydrochloride. The effect of metformin hydrochloride on the pharmacokinetics of nifedipine is minimal.
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin ) excreted by tubular secretion could theoretically interact with metformin hydrochloride as they are excreted via the common renal tubular transport system. A similar interaction between metformin hydrochloride and cimetidine was observed with simultaneous oral administration of metformin hydrochloride and cimetidine in healthy volunteers in single and multiple dose interaction studies in which Cmax and AUC of metformin hydrochloride in plasma and whole blood increased by 60% and 40% respectively. In a single dose study, T 1/2 of metformin hydrochloride did not change, nor did it affect the pharmacokinetics of cimetidine.
Others: Some drugs have hyperglycemic potential and may impair glycemic control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers, and isoniazid. When prescribing these drugs to a patient receiving a combination of metformin hydrochloride + sitagliptin phosphate, careful monitoring of glycemic control parameters is recommended.
In interaction studies involving healthy volunteers, while taking single doses of metformin hydrochloride and propranolol or metformin hydrochloride and ibuprofen, no change in the pharmacokinetic parameters of these drugs was observed.
Sitagliptin phosphate
According to a drug interaction study, sitagliptin phosphate did not have a clinically significant effect on the pharmacokinetics of the following drugs: metformin hydrochloride, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, it can be assumed that sitagliptin phosphate does not inhibit the CYP isoenzymes of the cytochrome CYP3A4, 2C8 or 2C9 system. In vitro data indicate that sitagliptin phosphate also does not inhibit CYP2D6, 1A2, 2C19 or 2B6 isoenzymes and does not induce CYP3A4 isoenzyme.
According to a population pharmacokinetic analysis in patients with type 2 diabetes mellitus, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin phosphate. The study evaluated a number of drugs most commonly used by patients with type II diabetes , incl. lipid-lowering drugs (eg, statins, fibrates, ezetimibe), antiplatelet agents (eg, clopidogrel), antihypertensive drugs (eg, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics, and NSAIDs (eg, naproxen, diclofenac, celecoxib), antidepressants (eg bupropion, fluoxetine, sertraline), antihistamines (eg cetirizine), proton pump inhibitors (eg omeprazole, lansoprazole) and erectile dysfunction drugs (eg sildenafil).
There was a slight increase in the AUC value (by 11%), as well as the average C max (by 18%) of digoxin when used simultaneously with sitagliptin phosphate. This increase was not considered clinically significant. With the simultaneous use of digoxin and sitagliptin phosphate, monitoring of the patient is recommended.
There was an increase in the AUC and C max values of sitagliptin phosphate by approximately 29% and 68%, respectively, with simultaneous single oral administration of sitagliptin phosphate at a dose of 100 mg and cyclosporine (a strong P-glycoprotein inhibitor) at a dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin phosphate were not considered clinically significant.
Side effect
Combined treatment of metformin hydrochloride and sitagliptin phosphate: skin rash, urticaria, cutaneous vasculitis and exfoliative skin diseases, including Stevens-Johnson syndrome, acute pancreatitis, nausea, vomiting, abdominal pain, dyspepsia, flatulence, diarrhoea, headache, upper respiratory tract infections, deterioration of kidney function arthralgia, myalgia, pain in extremities, back pain, hypoglycemia.
Combined treatment with metformin hydrochloride, sitagliptin phosphate and a sulfonylurea derivative: constipation, hypoglycemia.
Combination therapy with metformin hydrochloride, sitagliptin phosphate and thiazolidinediones: headache, diarrhea, nausea, vomiting, peripheral edema, hypoglycemia.
Combination therapy with metformin hydrochloride, sitagliptin phosphate and insulin: vomiting.
If any of the side effects listed in the instructions get worse, or if you notice any other side effects not listed in the instructions, tell your doctor.
Overdose
Overdose for each of the components of the drug.
metformin hydrochloride
Symptoms: d hypoglycemia, lactic acidosis.
Treatment: symptomatic therapy, emergency hemodialysis.
Sitagliptin phosphate
Symptoms: