Kselevia® (Xelevia®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceSitagliptinSitagliptin
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  • Kselevia®
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    Berlin-Chemie, AG     Germany
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    Merck Sharp and Doum B.V.     Netherlands
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    • Dosage form: & nbspfilm-coated tablets
    Composition:

    One film-coated tablet contains:

    Active substance: sitagliptin phosphate monohydrate 128.5 mg (equivalent to 100 mg of sitagliptin).

    Excipients: cellulose microcrystalline 123.8 mg, calcium hydrophosphate unmilled 123.8 mg, croscarmellose sodium 8,000 mg, magnesium stearate 4,000 mg, sodium stearyl fumarate 12.00 mg;

    tablet shell Opadrai® II beige, 85F17438 (16.00 mg) contains: polyvinyl alcohol 40,000%, titanium dioxide (E 171) 21.560%, macrogol 3350 (polyethylene glycol) 20.200%, talc 14.800%, iron oxide yellow (E 172) 3.070%, iron oxide red (E 172) 0.370%.

    Description:

    Round biconvex tablets of beige color, covered with a film shell with engraving "277" on one side and smooth on the other.

    Pharmacotherapeutic group:Hypoglycemic agent - dipeptidyl peptidase-4 inhibitor
    ATX: & nbsp

    A.10.B.H   Inhibitors of dipeptidyl peptidase 4 (DPP-4)

    A.10.B.H.01   Sitagliptin

    Pharmacodynamics:

    The drug Kselevia® (sitagliptin) is active upon oral administration, a highly selective inhibitor enzyme dipeptidyl peptidase-4 (DPP-4), intended for the treatment of type 2 diabetes mellitus. Sitagliptin differs by chemical structure and pharmacological action from analogues of glucagon-like peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, gamma receptor agonists activated by peroxisome proliferator (PPAR-γ), inhibitors alpha-glucosidase, analogues of amylin. Inhibiting DPP-4, sitagliptin increases the concentration of two hormones of the incretin family: GLP-1 and a glucose-dependent insulinotropic polypeptide (GIP). Hormones of the family of incretins are secreted in the intestine within 24 hours, their concentration rises in response to food intake. Incretiny are part of the internal physiological system of regulation of glucose homeostasis. With a normal or elevated blood glucose concentration, the hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion by beta cells of the pancreas due to signaling intracellular mechanisms associated with cyclic adenosine monophosphate (AMP).

    GLP-1 also contributes to the suppression of increased secretion of glucagon by the alpha-cells of the pancreas.Reducing the concentration of glucagon on the background of increasing insulin concentration helps to reduce the production of glucose by the liver, which eventually leads to a decrease in glycemia. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives that stimulate the release of insulin and at low glucose concentration in the blood, which is fraught with the development of sulfone-induced hypoglycemia not only in patients with type 2 diabetes, but also in healthy individuals.

    At a low concentration of glucose in the blood, the listed effects of incretins on the release of insulin and a decrease in the secretion of glucagon are not observed. GLP-1 and HIP do not affect the release of glucagon in response to hypoglycemia. In physiological conditions, the activity of incretins is limited to DPP-4, which rapidly hydrolyses incretins with the formation of inactive products.

    Sitagliptin prevents the incretin hydrolysis by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and HIP. By increasing the concentration of incretin, sitagliptin increases the glucose-dependent release of insulin and helps to reduce the secretion of glucagon.In patients with type 2 diabetes mellitus with hyperglycemia, these changes in the secretion of insulin and glucagon lead to a decrease in the concentration of glycosylated hemoglobin HbA1C and a decrease in plasma glucose concentration, determined on an empty stomach and after a stress test.

    In patients with type 2 diabetes mellitus, taking one dose of Xlelevia® leads to inhibition of the activity of the DPP-4 enzyme within 24 hours, which leads to an increase in the concentration of circulating incretin GLP-1 and GIP by 2-3 times, an increase in the plasma concentration of insulin and C peptide, reducing the concentration glucagon in the blood plasma, a decrease in fasting glycemia, and a decrease glycemia after loading with glucose or food load.

    Pharmacokinetics:

    The pharmacokinetics of sitagliptin are comprehensively described in healthy individuals and patients with type 2 diabetes mellitus. In healthy individuals, after oral administration of 100 mg of sitagliptin, rapid absorption of the drug is achieved with a maximum concentration (CmOh) in the interval from 1 to 4 hours from the moment of reception. Area under the curve "concentration-time" (AUC) increases proportionally to the dose and is 8.52 μmol / L * hour in healthy subjects with 100 mg oral intake, CmOh was 950 nmol / l. Plasma AUC sitagliptin increased by approximately 14% after the next dose of 100 mg of the drug to achieve an equilibrium state after taking the first dose. Intra- and intersubjective coefficients of variation AUC sitagliptin were insignificant.

    Absorption

    The absolute bioavailability of sitagliptin is approximately 87%. Since the simultaneous reception of sitagliptin and fatty foods has no effect on the pharmacokinetics, the Xevlevi® preparation may be administered regardless of the meal.

    Distribution

    The average volume of distribution in the equilibrium state after a single dose of 100 mg of sitagliptin in healthy volunteers is approximately 198 liters. The fraction of sitagliptin binding to plasma proteins is relatively low and is 38%.

    Metabolism

    Approximately 79% of sitagliptin is excreted unchanged by the kidneys. Metabolized only an insignificant part of the drug received in the body.

    After the introduction 14C-labeled sitagliptin inside about 16% of the radioactive sitagliptin was excreted as its metabolites. Traces of six metabolites of sitagliptin, probably not possessing DPP-4 inhibitory activity, were found. In studies in vitro It was found that the primary isoenzymes involved in the restricted metabolism of sitagliptin are CYP3A4 and CYP2C8.

    Excretion

    After the introduction 14C-labeled sitagliptin inward to healthy volunteers approximately 100% of the administered sitagliptin was excreted: 13% through the intestine, 87% by the kidneys - within one week after taking the drug. The average half-life of sitagliptin for oral administration of 100 mg is approximately 12.4 hours; the renal clearance is approximately 330 ml / min.

    The excretion of sitagliptin is primarily by excretion by the kidneys the mechanism of active tubular secretion. Sitagliptin is a substrate for a transporter of organic human anions of the third type (hOAT-3), which can be involved in the process of releasing sitagliptin by the kidneys. Clinically Involvement hOAT-3 in the transport of sitagliptin has not been studied. Sitagliptin is also a substrate of the p-glycoprotein, which can also participate in the process of releasing sitagliptin by the kidneys. but ciclosporin, which is an inhibitor of p-glycoprotein, did not reduce the renal clearance of sitagliptin.

    Pharmacokinetics in selected patient groups

    Patients with renal insufficiency

    An open study of sitagliptin at a dose of 50 mg per day was conducted to study its pharmacokinetics in patients with varying degrees of severity of chronic renal failure. The patients included in the study were divided into groups of patients with mild renal insufficiency (creatinine clearance from 50 to 80 ml / min), mean (creatinine clearance from 30 to 50 ml / min) and severe renal insufficiency (creatinine clearance less than 30 ml / min) , as well as with the terminal stage of chronic renal failure, in need of dialysis.

    In patients with mild renal insufficiency, there was no clinically significant change in the plasma sitagliptin concentration compared to the control group of healthy volunteers.

    Increase AUC Sitagliptin was approximately twice as high as in the control group in patients with moderate renal insufficiency; approximately fourfold increase AUC was noted in patients with severe renal insufficiency, as well as in patients with terminal stage of chronic renal failure compared with the control group. Sitagliptin to a small extent was removed by hemodialysis: only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session.

    Thus, in order to achieve a therapeutic concentration of sitagliptin in the blood plasma (similar to that in patients with normal renal function), patients with renal insufficiency of moderate and severe severity require dose adjustment (see the section "Dosing and Administration").

    Patients with hepatic insufficiency

    In patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), the mean AUC and CmOh sitagliptin with a single admission of 100 mg increase by approximately 21% and 13%, respectively. Thus, the corrections dose of the drug for mild and moderate hepatic insufficiency is not required.

    There are no clinical data on the use of sitagliptin in patients with severe hepatic Insufficiency (more than 9 points on the Child-Pugh scale). However, due to the fact that sitagliptin is primarily excreted by the kidneys, there should not be a significant change in the pharmacokinetics of sitagliptin in patients with severe hepatic insufficiency.

    Elderly patients

    The age of the patients did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared with young patients, in elderly patients (65-80 years) the concentration of sitagliptin is approximately 19% higher. Correction of the dose of the drug according to age is not required.

    Indications:

    Monotherapy

    Kselevia® is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

    Combination Therapy

    Combination with metformin

    Xevlevia ® in combination with metformin is indicated in patients with type 2 diabetes to improve glycemic control as a starting therapy, or when diet and exercise combined with monotherapy with one of these drugs does not lead to adequate glycemic control.

    Combination with sulfonylurea derivatives

    Xevlevia® in combination with sulfonylureas is indicated in patients with type 2 diabetes to improve glycemic control when diet and exercise combined with monotherapy with one of these drugs do not lead to adequate glycemic control.

    Combination with agonists PPAR-γ

    Xevlevia® in combination with PPAR-γ agonists (thiazolidinediones) is indicated in patients with type 2 diabetes to improve glycemic control when diet and exercise combined with monotherapy with one of the listed drugs do not lead to adequate glycemic control.

    Combination with metformin and sulfonylurea derivatives

    Xevlevia ® in combination with metformin and sulfonylureas is indicated in patients with type 2 diabetes to improve glycemic control, when diet and exercise combined with therapy with two of these drugs do not lead to adequate glycemic control.

    Combination with metformin and PPAR-γ agonists

    The Xevlevia ® preparation in combination with metformin and PPAR-γ agonists (thiazolidinediones) is indicated in patients with type 2 diabetes to improve glycemic control, when diet and exercise combined with therapy with two of these drugs do not lead to adequate glycemic control.

    Combination with insulin

    Kselevia® is indicated for patients with type 2 diabetes mellitus as an adjunct to insulin (with or without metformin) in cases where a diet,physical activity and a stable dose of insulin do not lead to adequate glycemic control.

    Contraindications:

    - Hypersensitivity to any of the components of the drug;

    - pregnancy, the period of breastfeeding;

    - Type 1 diabetes mellitus;

    - diabetic ketoacidosis;

    - children's age till 18 years;

    - kidney failure secondary to severe (for a given dosage - see "Dosing and dose.").

    Carefully:

    Renal insufficiency

    The main way to remove sitagliptin from the body is renal excretion. To achieve the same plasma levels as in patients with normal excretory renal function in patients with renal failure secondary to severe, as well as patients with end stage renal disease requiring hemodialysis or peritoneal dialysis, it is required to carry out correction (reduction) dose Kseleviya preparation ® (see. the section "method of administration and dose. Patients with renal failure").

    Pancreatitis

    There have been reports of the development of acute pancreatitis, including hemorrhagic or necrotic with a lethal and non-lethal outcome, in patients taking sitagliptin (cm.section "Side effect"). Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of admission sitagliptin. In case of suspicion of pancreatitis it is necessary to stop taking Kselevia ® and other potentially dangerous drugs.

    Pregnancy and lactation:

    There have been no controlled trials of Xlelevia ® in pregnant women, therefore, there is no data on the safety of its use in pregnant women. Kselevia ®, like other oral hypoglycemic drugs, is not recommended for use during pregnancy. There is no data on the penetration of sitagliptin into breast milk. Therefore, Xevlevia® should not be given during breastfeeding.

    Dosing and Administration:

    The recommended dose of Xlelevia® is 100 mg once a day orally as a monotherapy, or in combination with metformin, or sulfonylurea derivatives, or agonists PPAR-γ (thiazolidinediones), or insulin (with or without metformin), or in combination with metformin and a sulfonylurea derivative,or metformin and agonists PPAR-γ.

    The drug Kselevia® can be taken regardless of food intake. The dosage regimen of metformin, sulfonylurea derivatives and agonists PPAR-γ should be selected on the basis of recommended doses for these drugs.

    When combining Kselevia ® with sulfonylureas or insulin derivatives, the traditionally recommended dose of a sulfonylurea or insulin derivative is advisable to reduce to reduce the risk of developing sulfon-induced or insulin-induced hypoglycemia (see section "Special instructions.").

    In the event that the patient misses the Xevlevia ® drug, the drug should be taken as soon as possible after the patient recalls the missed drug intake.

    Do not take a double dose of Kselevia ® on the same day.

    Patients with renal insufficiency

    Patients with mild renal insufficiency (creatinine clearance (CK) ≥50 ml / min, approximately equivalent to a serum creatinine concentration ≤1.7 mg / dl in males and ≤1.5 mg / dl in females) are not corrected for Xevlevia® it takes.

    Due to the need to correct the dose of sitagliptin in patients with renal insufficiency of moderate and severe severity, use of the drug Xevlevia® in this category of patients is not shown (the absence of risks on the pill 100 mg and the absence of dosages of 25 mg and 50 mg does not allow to provide its dosing regimen in patients with renal insufficiency of moderate and severe severity).

    In view of the need for dose adjustment in patients with renal insufficiency, it is recommended that renal function be assessed before treatment with sitagliptin and periodically during treatment.

    Patients with hepatic insufficiency

    It is not necessary to correct the dose of Xlelevia ® in patients with mild or moderate hepatic insufficiency. The drug was not studied in patients with severe hepatic impairment.

    Elderly patients

    It is not necessary to correct the dose of Xlelevia ® in elderly patients.

    Side effects:

    Sitagliptin is generally well tolerated both in monotherapy mode and in combination with other hypoglycemic drugs. In clinical trials, the overall incidence of undesired events, as well as the frequency of drug withdrawal due to adverse events, were similar to those observed with placebo.

    According to 4 placebo-controlled studies (duration 18-24 weeks) of sitagliptin in a daily dose of 100-200 mg as a monotherapy or combination therapy with metformin or pioglitazone, there were no adverse events associated with the study drug, the frequency of which exceeded 1% in the group of patients who took sitagliptin. The safety profile of the daily dose of 200 mg was comparable with the safety profile of a daily dose of 100 mg.

    Analysis of the data obtained in the above clinical studies showed that the overall incidence of hypoglycemia in patients taking sitagliptin, was similar to that of placebo (sitagliptin 100 mg - 1.2%, sitagliptin 200 mg - 0.9%, placebo - 0.9%). The frequency of monitored adverse events from the gastrointestinal tract when receiving sitagliptin in both doses was similar to that of placebo (except for the more frequent occurrence of nausea when taking sitagliptin at a dose of 200 mg per day): abdominal painsitagliptin 100 mg - 2.3%, sitagliptin 200 mg-1.3%, placebo-2.1%), nausea (1.4%, 2.9%, 0.6%), vomiting (0.8%, 0.7%, 0.9% ), diarrhea (3.0%, 2.6%, 2.3%).

    In all studies, adverse reactions in the form of hypoglycemia were recorded based on all reports of clinically significant symptomshypoglycemia; a parallel measurement of blood glucose concentration was not required.

    Start combination therapy with metformin

    In a 24-week placebo-controlled factorial study, the starting combined therapy with sitagliptin in a daily dose of 100 mg and metformin at a daily dose of 1000 mg or 2000 mg (sitagliptin 50 mg + metformin 500 mg or 1000 mg x 2 times a day), the following adverse events were observed in the combination treatment group compared with the metformin monotherapy group:

    adverse drug reactions observed with a frequency of ≥ 1% in the sitagliptin treatment group and more often than in the metformin treatment group in monotherapy: diarrhea (sitagliptin + metformin - 3,5%, metformin - 3,3%), dyspepsia (1.3%, 1.1%), headache (1.3%, 1.1%), flatulence (1.3%, 0.5%), hypoglycemia (1.1%, 0.5 %), vomiting (1.1%, 0.3%).

    Combination with derivatives of sulfonylurea or derivatives of sulfonylureas and metformin

    In a 24-week, placebo-controlled study of combined sitagliptin therapy (daily dose of 100 mg) and glimepiride or glimepiride and metformin in the study drug group compared to the placebo group and glimepiride or glimepiride and metformin, the following undesirable phenomena were observed:

    adverse drug reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the combination therapy group with placebo: hypoglycemia (sitagliptin - 9.5%, placebo - 0.9%).

    Start combination therapy with agonists PPAR-γ

    In a 24-week study of starting combination therapy with sitagliptin in a daily dose of 100 mg and pioglitazone at a daily dose of 30 mg, the following adverse events were observed in the combination treatment group compared to monotherapy with pioglitazone:

    adverse drug reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the pioglitazone treatment group in monotherapy: asymptomatic reduction in blood glucose (sitagliptin + pioglitazone - 1,1%, pioglitazone - 0,0%), symptomatic hypoglycaemia (0.4%, 0.8%).

    Combination with agonists PPAR-y and metformin

    According to a placebo-controlled study in the treatment of sitagliptin (daily dose of 100 mg) in combination with rosiglitazone and metformin in the study drug group compared with the group of patients taking placebo withrosiglitazone and metformin, the following adverse events were observed:

    At week 18 of observation:

    adverse drug reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the combination therapy group with placebo: headache (sitagliptin - 2.4%, placebo - 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0 %), vomiting (1.2%, 0.0%).

    At the 54th week of follow-up:

    adverse drug reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the combination therapy group with placebo: headache (sitagliptin - 2.4%, placebo - 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infection (1.8%, 0.0%), nausea (1.2% 1.1%), cough (1.2%, 0.0%), fungal skin infection (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), vomiting ( 1.2%, 0.0%).

    Combination with insulin

    In a 24-week, placebo-controlled study of combined sitagliptin therapy (at a daily dose of 100 mg) and a constant dose of insulin (with or without metformin) in the study drug group, compared to the placebo and insulin group (with or without metformin) the following undesirable phenomena:

    adverse drug reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the insulin treatment group (with or without metformin): hypoglycemia (sitagliptin + insulin (with or without metformin) - 9.6%, placebo + insulin (with or without metformin) - 5.3%), influenza (1.2%, 0.3%), headache (1.2% , 0.0%).

    In another 24-week study in which patients received sitagliptin as an additional therapy for insulin therapy (with or without metformin), there were no undesirable reactions associated with taking the drug, with a frequency> 1% in the sitagliptin group (100 mg dose), and more often than in the placebo group.

    Pancreatitis

    In a generalized analysis of 19 double-blind, randomized clinical trials of the use of sitagliptin in a daily dose of 100 mg or a corresponding control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 cases per 100 patient-years of treatment in each group (see " Precautions: Pancreatitis, and a Study on the Evaluation of Cardiovascular Safety of Sitagliptin (TECOS)" below).

    Clinically significant deviations in vital signs or ECG (including the duration of the interval QTc) on the background of treatment sitagliptin not observed.

    A study to assess the cardiovascular safety of sitagliptin (TECOS)

    In a study assessing the cardiovascular safety of sitagliptin (TECOS) 7332 patients were admitted who took sitagliptin 100 mg per day (or 50 mg per day, if the initial value of the calculated rate of glomerular filtration (eGFR) was ≥30 and <50 mL / min / 1.73 m), and 7,339 patients taking placebo in the general population of patients who were prescribed treatment. The test drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for target level selection HbA1C and control of cardiovascular risk factors. A total of 2004 patients were included in the study at the age of 75 years and older (970 took sitagliptin, and 1034 - placebo). The overall incidence of serious adverse events in patients taking sitagliptin, was the same as in patients taking placebo. Evaluation of previously identified complications associated with diabetes mellitus revealed a comparable incidence of adverse events between groups, including infections (18.4% in patients taking sitagliptin, and 17.7% in patients taking placebo) and renal dysfunction (1.4% in patients taking sitagliptin, and 1.5% in patients taking placebo). The profile of adverse events in patients aged 75 years and older was generally similar to that of the general population.

    In a population of patients who were prescribed treatment ("intention-to-treat"), among those who initially received insulin therapy and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 2.7% in patients taking sitagliptin, and 2.5% in patients taking placebo. Among patients who did not initially receive insulin and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 1.0% in patients taking sitagliptin, and 0.7% in patients taking placebo. The incidence of confirmed cases of pancreatitis was 0.3% in patients taking sitagliptin, and 0.2% in patients taking placebo. The incidence of confirmed cases of malignant neoplasms was 3.7% in patients taking sitagliptin, and 4.0% in patients taking placebo.

    Post-market observations

    In the course of post-marketing monitoring of the use of sitagliptin in monotherapy and / or in combination therapy with other hypoglycemic agents, additional adverse events have been identified. Since these data were received voluntarily from a population of undetermined size, the frequency and the causal relationship with the therapy of these undesirable phenomena can not be determined. These include:

    hypersensitivity reactions, including anaphylaxis, angioedema, rash, hives, skin vasculitis, exfoliative skin diseases, including Stevens-Johnson syndrome; acute pancreatitis, including hemorrhagic and necrotic forms with lethal and without lethal outcome; impairment of kidney function, including acute renal failure (sometimes dialysis is required); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in the limb; backache; itching; pemphigoid.

    Changes in laboratory indicators

    The frequency of deviations in laboratory parameters in the groups of treatment with sitagliptin (in a daily dose of 100 mg) was comparable with the frequency in the placebo groups.Most, but not all, of the clinical studies showed a slight increase in leukocyte count (approximately 200 / μL compared with placebo, with an average content of 6600 / μL at the beginning of treatment), due to an increase in the number of neutrophils.

    Analysis of the clinical trial data showed a slight increase in the concentration of uric acid (approximately 0.2 mg / dl versus placebo, mean concentration before treatment 5-5.5 mg / dl) in patients receiving sitagliptin in a dose of 100 and 200 mg per day. There were no cases of gout development. There was a slight decrease in the concentration of total alkaline phosphatase (approximately 5 IU / L compared with placebo, average concentration before treatment 56-62 IU / L), partially associated with a slight decrease in the bone fraction of alkaline phosphatase.

    The listed changes in laboratory indicators are not considered clinically significant.

    Overdose:

    During clinical studies on healthy volunteers, a single dose of 800 mg of sitagliptin was generally well tolerated. Minimum interval changes QTc, not considered clinically significant, were noted in one study of sitagliptin at a dose of 800 mg per day. A dose of more than 800 mg per day in humans has not been studied.

    In phase I clinical trials of multiple administration of any treatment-related sitagliptin adverse reactions when taking the drug in a daily dose up to 400 mg were not observed for 28 days.

    In case of an overdose, it is necessary to start the standard supporting measures: removal of unabsorbed drug from the gastrointestinal tract, exercise monitoring of vital signs, including ECG, as well as the appointment maintenance therapy, if required.

    Sitagliptin slightly dialyzed. In clinical trials, only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session. Prolonged dialysis may be prescribed in case of clinical necessity. There is no data on the efficacy of peritoneal dialysis of sitagliptin.

    Interaction:

    In studies on interactions with other drugs sitagliptin had no clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, sitagliptin does not inhibit isoenzymes CYP3A4, 2C8 or 2C9. Based on the data in vitro, sitagliptin also does not inhibit isoenzymes CYP2D6, 1A2, 2C19 and 2B6 and does not induce isoenzyme CYP3A4. Multiple administration of metformin in combination with sitagliptin had no significant effect on the pharmacokinetic parameters of sitagliptin in patients with type 2 diabetes mellitus.

    According to the population pharmacokinetic analysis of patients with type 2 diabetes, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin. The study evaluated a number of drugs most commonly used by patients with type 2 diabetes, including: hypolipidemic drugs (statins, fibrates, ezetimibe), antiplatelet agents (clopidogrel), antihypertensive drugs (ACE inhibitors, angiotensin II receptor antagonists, beta-adrenoblockers, slow calcium channel blockers, hydrochlorothiazide), non-steroidal anti-inflammatory drugs (naproxen, diclofenac, celecoxib), antidepressants (bupropion, fluoxetine, sertraline), antihistamines (cetirizine), proton pump inhibitors (omeprazole, lansoprazole) and drugs for the treatment of erectile dysfunction (sildenafil).

    A slight increase was noted AUC (11%), as well as the average CmOh (18%) digoxin when combined with sitagliptin. This increase is not considered clinically significant. It is not recommended to change the dose of either digoxin or sitagliptin when combined.

    An increase was noted AUC and CmOh sitagliptin on 29% and 68% respectively patients in the combined use of a single oral dose of 100 mg of sitagliptin and a single oral dose of 600 mg cyclosporine, a potent inhibitor of p-glycoprotein. The observed changes in pharmacokinetic characteristics of sitagliptin are not considered clinically significant. Not recommended dose change Kseleviya® drug when combined with cyclosporin and other inhibitors of p-glycoprotein (e.g., ketoconazole).

    Population pharmacokinetic analysis of patients and healthy volunteers (N=858) on a wide range of concomitant drugs (N=83, approximately half of which are excreted by the kidneys) did not reveal any clinically significant effect of these substances on the pharmacokinetics of sitagliptin.

    Special instructions:

    Hypoglycaemia

    According to clinical studies of sitagliptin, the incidence of hypoglycemia in monotherapy or combination therapy with drugs that do not cause hypoglycemiametformin, pioglitazone), was comparable to the incidence of hypoglycemia in the placebo group. As with other hypoglycemic drugs, hypoglycemia was observed with the use of sitagliptin in combination with insulin or sulfonylurea derivatives (see the "Side effect" section). In order to reduce the risk of development of sulfone-induced hypoglycemia, the dose of the sulfonylurea derivative should be reduced (see section "Method of administration and dose").

    Application the elderly people

    In clinical trials, the efficacy and safety of sitagliptin in elderly patients (≥65 years, 409 patients) were comparable to those in patients younger than 65 years of age. Dose adjustment according to age is not required. Older patients are more likely to develop kidney failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency (see section "Method of administration and dose").

    A study to assess the cardiovascular safety of sitagliptin (TECOS)

    In a study evaluating the cardiovascular safety of sitagliptin (TECOS) patients took sitagliptin 100 mg per day (or 50 mg per day, if the initial value of the calculated rate of glomerular filtration (eGFR) was ≥30 and <50 mL / min / 1.73 m2), or placebo, which were added to standard therapy according to existing national standards for determining target levels of HbA1C and control of cardiovascular risk factors. At the end of the average observation period of 3 years, in patients with type 2 diabetes mellitus In addition to standard treatment, sitagliptin did not increase the risk of serious cardiovascular adverse events (risk ratio 0.98, 95% confidence interval, 0.89-1.08, p <0.001 for evidence of lack of superiority), or hospitalization risk due to heart failure (risk ratio 1.00; 95% confidence interval, 0.83-1.20, p = 0.98 for difference in risk), compared with standard treatment without additional sitagliptin.

    Effect on the ability to drive transp. cf. and fur:

    No studies have been conducted to study the effect of Xevlevia® on the ability to drive vehicles and work with mechanisms. Nevertheless, it is not expected that Xlelevia ® will adversely affect the ability to drive vehicles and work with machinery.

    Form release / dosage:

    Film coated tablets 100 mg.

    Packaging:

    For 14 tablets in a blister of PVC / PE / PVDC film and aluminum foil. Two blisters are placed in a cardboard box together with instructions for use.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004456
    Date of registration:12.09.2017
    Expiration Date:12.09.2022
    The owner of the registration certificate:Berlin-Chemie, AGBerlin-Chemie, AG Germany
    Manufacturer: & nbsp
    Information update date: & nbsp03.10.2017
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