Xelevia®
Sitagliptin is generally well tolerated both in monotherapy and in combination with other hypoglycemic drugs. In clinical studies, the overall incidence of adverse events and the incidence of drug discontinuation due to adverse events were similar to those observed with placebo.
According to 4 placebo-controlled studies (lasting 18-24 weeks) of sitagliptin at a daily dose of 100-200 mg as mono- or combination therapy with metformin or pioglitazone, no study-related adverse reactions were observed, the frequency of which exceeded 1% in the patient group who were taking sitagliptin. The safety profile of the 200 mg daily dose was comparable to that of the 100 mg daily dose.
Analysis of data obtained from the above clinical studies showed that the overall incidence of hypoglycemia in patients taking sitagliptin was similar to that when taking placebo (sitagliptin 100 mg - 1.2%, sitagliptin 200 mg - 0.9%, placebo - 0.9%). The incidence of monitored gastrointestinal adverse events with sitagliptin at both doses was similar to that with placebo (with the exception of more frequent nausea with sitagliptin 200 mg per day): abdominal pain (sitagliptin 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 of hypoglycemia were recorded based on all reports of clinically significant symptoms of hypoglycemia; parallel measurement of blood glucose concentration was not required.
Initial combination therapy with metformin
In a 24-week placebo-controlled factorial study of initial combination therapy with sitagliptin at 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) in the combination treatment group according to Compared with the metformin monotherapy group, the following adverse events were observed:
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the metformin monotherapy group: 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 sulfonylureas or sulfonylureas and metformin
In a 24-week placebo-controlled study of combination therapy with sitagliptin (100 mg daily dose) and glimepiride or glimepiride and metformin, the following adverse events were observed in the study drug group compared with the placebo and glimepiride or glimepiride and metformin group:
Drug-related adverse 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%).
Initial combination therapy with PPAR - γ
In a 24-week study of initial combination therapy with sitagliptin 100 mg daily and pioglitazone 30 mg daily, the following adverse events were observed in the combination treatment group compared with pioglitazone monotherapy:
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more often than in the pioglitazone monotherapy group: asymptomatic decrease in blood glucose concentration (sitagliptin + pioglitazone - 1.1%, pioglitazone - 0.0% ), symptomatic hypoglycemia (0.4%, 0.8%).
PPAR - y agonists and metformin
According to a placebo-controlled study, when treated with sitagliptin (daily dose 100 mg) in combination with rosiglitazone and metformin, the following adverse events were observed in the study drug group compared with a group of patients taking placebo with rosiglitazone and metformin:
At 18 weeks of observation:
drug-related adverse 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 54 weeks of observation:
drug-related adverse 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 infections (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 combination therapy with sitagliptin (at a daily dose of 100 mg) and constant-dose insulin (with or without metformin) in the study drug group compared with the placebo and insulin group (with or without metformin), observed the following undesirable effects:
Drug-related adverse 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%), flu (1.2%, 0.3%), headache (1.2%, 0.0%).
In another 24-week study in which patients received sitagliptin as adjunctive therapy to insulin therapy (with or without metformin), there were no drug-related adverse reactions with an incidence of >1% in the sitagliptin treatment group (at a dose of 100 mg), and more often than in the placebo group.
Pancreatitis
In a pooled analysis of 19 double-blind randomized clinical trials of sitagliptin at a daily dose of 100 mg or a corresponding control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 case per 100 patient-years of treatment in each group (see section " "Caution: Pancreatitis" and "Sitagliptin Cardiovascular Safety Study (TECOS)" below).
No clinically significant abnormalities in vital signs or ECG (including QTc interval) were observed during treatment with sitagliptin.
Study to evaluate the cardiovascular safety of sitagliptin ( TECOS )
The Study to Evaluate the Cardiovascular Safety of Sitagliptin (TECOS) enrolled 7332 patients who received sitagliptin 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min /1.73 m), and 7339 placebo patients in the overall intention-to-treat population. The study drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for selecting target HbA1C levels and controlling cardiovascular risk factors. The study included a total of 2004 patients aged 75 years or older (970 receiving sitagliptin and 1034 receiving placebo). The overall incidence of serious adverse events in patients taking sitagliptin was the same as in patients taking placebo. An assessment of previously identified complications associated with diabetes mellitus revealed comparable rates of adverse events between groups, including infections (18.4% in patients treated with sitagliptin and 17.7% in patients treated with placebo) and renal dysfunction ( 1.4% in patients taking sitagliptin and 1.5% in patients taking placebo). The adverse event profile in patients aged 75 years and older was generally similar to that of the general population.
In the intention-to-treat population, among those initially receiving insulin and/or sulfonylureas, the incidence of severe hypoglycemia was 2.7% in patients receiving sitagliptin and 2. 5% in patients taking placebo. Among patients not initially receiving 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 expertly confirmed pancreatitis was 0.3% in patients treated with sitagliptin and 0.2% in patients treated with placebo. The incidence of evidence-based malignancies was 3.7% in patients treated with sitagliptin and 4.0% in patients treated with placebo.
Post-registration observations
During post-marketing monitoring of the use of sitagliptin in monotherapy and/or in combination therapy with other hypoglycemic agents, additional adverse events were identified. Because these data were collected voluntarily from a population of undetermined size, the frequency and causal relationship to treatment of these adverse events cannot be determined. These include:
hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin diseases, including Stevens-Johnson syndrome; acute pancreatitis, including hemorrhagic and necrotizing forms with lethal and non-lethal outcomes; deterioration of kidney function, including acute renal failure (sometimes requiring dialysis); upper respiratory tract infections; nasopharyngitis; constipation; vomit; headache; arthralgia; myalgia; pain in the limb; backache; itching; pemphigoid.
Changes in laboratory parameters
The incidence of laboratory abnormalities in the sitagliptin treatment groups (at a daily dose of 100 mg) was comparable to that in the placebo groups. In most, but not all clinical studies, a small increase in white blood cell count was observed (approximately 200/μL compared with placebo; mean at baseline 6600/μL), due to an increase in neutrophil counts.
Analysis of data from clinical trials of the drug showed a slight increase in uric acid concentrations (approximately 0.2 mg/dL compared with placebo, average concentration before treatment 5-5.5 mg/dL) in patients receiving sitagliptin at a dose of 100 and 200 mg per day. day. No cases of gout were reported. There was a slight decrease in total alkaline phosphatase concentrations (approximately 5 IU/L compared with placebo, mean pre-treatment concentration 56-62 IU/L), partly due to a slight decrease in bone alkaline phosphatase fraction.
The listed changes in laboratory parameters are not considered clinically significant.
Xelevia tablet p o film 100 mg x28
Trade name: Xelevia
International name: Sitagliptin&, (Sitaglyptine)
Pharmacological group: hypoglycemic agent - dipeptidyl peptidase-4 inhibitor
Pharmacological group for ATC: A10BH01. Sitagliptin
Compound:
One film-coated tablet contains:
Active ingredient: sitagliptin phosphate monohydrate 128.5 mg (equivalent to 100 mg sitagliptin).
Excipients: microcrystalline cellulose 123.8 mg, unground calcium hydrogen phosphate 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%, dioxide titanium (E 171) 21.560%, macrogol 3350 (polyethylene glycol) 20.200%, talc 14.800%, iron yellow (e 172) 3.070 %, iron oxide red (E 172) 0.370%.
Description:
Round, biconvex, beige, film-coated tablets debossed with “277” on one side and plain on the other.
Pharmacodynamics:
Xelevia (sitagliptin) is an orally active, highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes mellitus. Sitagliptin differs in chemical structure and pharmacological action from glucarone-like peptide-1 (GLP-1) analogs, insulin, sulfonylureas, biguanides, peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists, alpha-glucosidase inhibitors, and amylin analogs. By inhibiting DPP-4, sitagliptin increases the concentration of two hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Hormones of the incretin family are secreted in the intestines throughout the day, their concentration increases in response to food intake. Incretins are part of the intrinsic physiological system for regulating glucose homeostasis. At normal or elevated blood glucose concentrations, hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion by pancreatic beta cells through intracellular signaling mechanisms associated with cyclic adenosine monophosphate (AMP).
GLP-1 also helps suppress increased glucagon secretion by alpha cells of the pancreas. A decrease in glucagon concentration against the background of an increase in insulin concentration helps to reduce the production of glucose by the liver, which ultimately leads to a decrease in glycemia. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin even at low concentrations of glucose in the blood, which is fraught with the development of sulfone-induced hypoglycemia not only in patients with type 2 diabetes mellitus, but also in healthy individuals.
At low blood glucose concentrations, the listed effects of incretins on insulin release and a decrease in glucagon secretion are not observed. GLP-1 and GIP do not affect glucagon release in response to hypoglycemia. Under physiological conditions, the activity of incretins is limited by the enzyme DPP-4, which rapidly hydrolyzes incretins to form inactive products.
Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing plasma concentrations of active forms of GLP-1 and GIP. By increasing the concentration of incretins, sitagliptin increases glucose-dependent insulin release and helps reduce glucagon secretion. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion 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 an exercise test.
In patients with type 2 diabetes mellitus, taking one dose of Xelevia leads to inhibition of the activity of the DPP-4 enzyme for 24 hours, which leads to an increase in the concentration of circulating incretins GLP-1 and GIP by 2-3 times, an increase in plasma concentrations of insulin and C- peptide, a decrease in the concentration of glucagon in the blood plasma, a decrease in fasting glycemia, as well as a decrease in glycemia after a glucose load or food load.
Pharmacokinetics:
The pharmacokinetics of sitagliptin have been extensively 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 observed with the maximum concentration (Cmax) being achieved within 1 to 4 hours from the moment of administration. Area under the “administration and dosage” curve).
Patients with liver failure
In patients with moderate hepatic impairment (Child-Pugh score 7-9), the mean AUC and Cmax of sitagliptin with a single 100 mg dose increase by approximately 21% and 13%, respectively. Thus, no dose adjustment is required for mild to moderate liver failure.
There are no clinical data on the use of sitagliptin in patients with severe liver failure (more than 9 points on the Child-Pugh scale). However, due to the fact that sitagliptin is primarily eliminated by the kidneys, a significant change in the pharmacokinetics of sitagliptin should not be expected in patients with severe hepatic impairment.
Elderly patients
The age of the patients did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared to younger patients, older patients (65-80 years) have approximately 19% higher concentrations of sitagliptin. No dose adjustment is required depending on age.
Indications for use:
MONOTHERAPY
Xelevia is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.
COMBINATION THERAPY
Combination with metformin
Xelevia in combination with metformin is indicated in patients with type 2 diabetes mellitus to improve glycemic control as initial therapy or when diet and exercise in combination with monotherapy with one of the listed drugs does not lead to adequate glycemic control.
Combination with sulfonylureas
Xelevia in combination with sulfonylurea derivatives is indicated for patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with monotherapy with one of these drugs do not lead to adequate glycemic control.
Combination with PPAR-gamma agonists
Xelevia in combination with PPAR-gamma agonists (thiazolidinediones) is indicated in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with monotherapy with one of these drugs do not lead to adequate glycemic control.
Combination with metformin and sulfonylureas
Xelevia in combination with metformin and sulfonylureas is indicated in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with therapy with two of these drugs do not lead to adequate glycemic control.
Combination with metformin and PPAR-gamma agonists
Xelevia in combination with metformin and PPAR-gamma agonists (thiazolidinediones) is indicated in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with therapy with two of these drugs do not lead to adequate glycemic control.
Combination with insulin
Xelevia is indicated in patients with type 2 diabetes mellitus as an adjunct to insulin (with or without metformin) in cases where diet, exercise and a stable dose of insulin do not lead to adequate glycemic control.
Contraindications:
- hypersensitivity to any of the components of the drug,
- pregnancy, breastfeeding period,
- type 1 diabetes mellitus,
- diabetic ketoacidosis,
- children under 18 years of age,
- renal failure of moderate and severe severity (for this dosage - see section "Method of administration and dosage").
Carefully:
Kidney failure
The main route of elimination of sitagliptin from the body is renal excretion. To achieve the same plasma concentrations as in patients with normal renal excretory function, patients with moderate to severe renal failure, as well as patients with end-stage chronic renal failure requiring hemodialysis or peritoneal dialysis, require a dose adjustment (reduction) of Xelevia (see section “Method of administration and dosage. Patients with renal failure”).
Pancreatitis
There have been reports of acute pancreatitis, including hemorrhagic or necrotizing with and without fatal outcome, in patients taking sitagliptin (see section "Side effects"). Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin. If pancreatitis is suspected, you should stop taking Xelevia and other potentially dangerous medications.
Dosage regimen:
The recommended dose of Xelevia is 100 mg orally once daily as monotherapy, or in combination with metformin, or sulfonylureas, or PPAR-gamma agonists (thiazolidinediones), or insulin (with or without metformin), or in combination with metformin and sulfonylurea derivatives, or metformin and PPAR-gamma agonists.
Xelevia can be taken with or without food. The dosage regimen for metformin, sulfonylureas and PPAR-gamma agonists should be selected based on the recommended doses for these drugs.
When combining Xelevia with sulfonylurea derivatives or insulin, it is advisable to reduce the traditionally recommended dose of the sulfonylurea derivative or insulin to reduce the risk of developing sulfone-induced or insulin-induced hypoglycemia (see section "Special instructions. Hypoglycemia").
If the patient misses a dose of Xelevia, the drug should be taken as soon as possible after the patient remembers the missed dose.
It is unacceptable to take a double dose of Xelevia on the same day.
Patients with kidney failure
Patients with mild renal failure (creatinine clearance (CC) >./=50 ml/min, approximately corresponding to serum creatinine concentration <./=1.7 mg/dL in men and <./=1.5 mg/dL in women), no dose adjustment of Xelevia is required.
Due to the need to adjust the dose of sitagliptin in patients with moderate and severe renal failure, the use of Xelevia in this category of patients is not indicated (the absence of risks on the 100 mg tablet and the absence of dosages of 25 mg and 50 mg does not allow for its dosage regimen in patients with renal failure). moderate to severe insufficiency).
Due to the need for dosage adjustments, it is recommended that patients with renal impairment have their renal function assessed before starting treatment with sitagliptin and periodically during treatment.
Patients with liver failure
No dose adjustment of Xelevia is required in patients with mild to moderate hepatic impairment. The drug has not been studied in patients with severe hepatic impairment.
Elderly patients
No dose adjustment of Xelevia is required in elderly patients.
Side effects:
Sitagliptin is generally well tolerated both in monotherapy and in combination with other hypoglycemic drugs. In clinical studies, the overall incidence of adverse events and the incidence of drug discontinuation due to adverse events were similar to those observed with placebo.
According to 4 placebo-controlled studies (lasting 18-24 weeks) of sitagliptin at a daily dose of 100-200 mg as mono- or combination therapy with metformin or pioglitazone, no study-related adverse reactions were observed, the frequency of which exceeded 1% in the patient group who were taking sitagliptin. The safety profile of the 200 mg daily dose was comparable to that of the 100 mg daily dose.
Analysis of data obtained from the above clinical studies showed that the overall incidence of hypoglycemia in patients taking sitagliptin was similar to that when taking placebo (sitagliptin 100 mg - 1.2%, sitagliptin 200 mg - 0.9%, placebo - 0.9%). The incidence of monitored gastrointestinal adverse events with sitagliptin at both doses was similar to that with placebo (with the exception of more frequent nausea with sitagliptin 200 mg per day): abdominal pain (sitagliptin 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 symptoms of hypoglycemia, and parallel measurement of blood glucose concentrations was not required.
Initial combination therapy with metformin
In a 24-week placebo-controlled factorial study of initial combination therapy with sitagliptin at 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) in the combination treatment group according to Compared with the metformin monotherapy group, the following adverse events were observed:
drug-related adverse reactions observed with a frequency of >./=1% in the sitagliptin treatment group and more often than in the metformin monotherapy treatment group: 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 sulfonylureas or sulfonylureas and metformin
In a 24-week placebo-controlled study of combination therapy with sitagliptin (100 mg daily dose) and glimepiride or glimepiride and metformin, the following adverse events were observed in the study drug group compared with the placebo and glimepiride or glimepiride and metformin group:
drug-related adverse 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%).
Initial combination therapy with PPAR-gamma agonists
In a 24-week study of initial combination therapy with sitagliptin 100 mg daily and pioglitazone 30 mg daily, the following adverse events were observed in the combination treatment group compared with pioglitazone monotherapy:
drug-related adverse reactions observed with a frequency of >/=1% in the sitagliptin treatment group and more often than in the pioglitazone monotherapy treatment group: asymptomatic decrease in blood glucose concentration (sitagliptin + pioglitazone - 1.1%, pioglitazone - 0 .0%), symptomatic hypoglycemia (0.4%, 0.8%).
Combination with PPAR-gamma agonists and metformin
According to a placebo-controlled study, when treated with sitagliptin (daily dose 100 mg) in combination with rosiglitazone and metformin, the following adverse events were observed in the study drug group compared with the group of patients taking placebo with rosiglitazone and metformin:
At 18 weeks of observation:
drug-related adverse 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 54 weeks of observation:
drug-related adverse 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 infections (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 combination therapy with sitagliptin (at a daily dose of 100 mg) and constant-dose insulin (with or without metformin) in the study drug group compared with the placebo and insulin group (with or without metformin), observed the following undesirable effects:
drug-related adverse 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%), flu (1.2%, 0.3%), headache (1.2%, 0.0%).
In another 24-week study in which patients received sitagliptin as adjunctive therapy to insulin therapy (with or without metformin), no drug-related adverse reactions were observed with an incidence of >/=1% in the sitagliptin treatment group ( at a dose of 100 mg), and more often than in the placebo group.
Pancreatitis
In a pooled analysis of 19 double-blind randomized clinical trials of sitagliptin at a daily dose of 100 mg or a corresponding control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 case per 100 patient-years of treatment in each group (see section " "Caution: Pancreatitis" and "Sitagliptin Cardiovascular Safety Study (TECOS)" below).
Clinically significant abnormalities in vital signs or ECG
(including the duration of the QTc interval) were not observed during treatment with sitagliptin.
Sitagliptin Cardiovascular Safety Study (TECOS)
The Study to Evaluate the Cardiovascular Safety of Sitagliptin (TECOS) enrolled 7332 patients who received sitagliptin 100 mg per day (or 50 mg per day if baseline estimated glomerular filtration rate (eGFR) was >/=30 and < 50 ml/min/1.73 m2), and 7339 placebo patients in the overall intention-to-treat population. The study drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for selecting target HbA1C levels and controlling cardiovascular risk factors. The study included a total of 2004 patients aged 75 years or older (970 receiving sitagliptin and 1034 receiving placebo). The overall incidence of serious adverse events in patients taking sitagliptin was the same as in patients taking placebo.
An assessment of previously identified complications associated with diabetes mellitus revealed comparable rates of adverse events between groups, including infections (18.4% in patients treated with sitagliptin and 17.7% in patients treated with placebo) and renal dysfunction ( 1.4% in patients taking sitagliptin and 1.5% in patients taking placebo). The adverse event profile in patients aged 75 years and older was generally similar to that of the general population.
In the intention-to-treat population, among those initially receiving insulin and/or sulfonylureas, the incidence of severe hypoglycemia was 2.7% in patients receiving sitagliptin and 2. 5% in patients taking placebo. Among patients not initially receiving 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 expertly confirmed pancreatitis was 0.3% in patients treated with sitagliptin and 0.2% in patients treated with placebo. The incidence of evidence-based malignancies was 3.7% in patients treated with sitagliptin and 4.0% in patients treated with placebo.
Post-registration observations
During post-marketing monitoring of the use of sitagliptin in monotherapy and/or in combination therapy with other hypoglycemic agents, additional adverse events were identified. Because these data were collected voluntarily from a population of undetermined size, the frequency and causal relationship to treatment of these adverse events cannot be determined.
These include:
hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin diseases, including Stevens-Johnson syndrome, acute pancreatitis, including hemorrhagic and necrotizing forms with and without fatal outcome, deterioration of kidney function, including acute renal failure (sometimes requiring dialysis), upper respiratory tract infections, nasopharyngitis, constipation, vomiting, headache, arthralgia, myalgia, limb pain, back pain, pruritus, pemphigoid.
Changes in laboratory parameters
The incidence of laboratory abnormalities in the sitagliptin treatment groups (at a daily dose of 100 mg) was comparable to that in the placebo groups. In most, but not all clinical studies, a small increase in white blood cell count was observed (approximately 200/μL compared with placebo; mean at baseline 6600/μL), due to an increase in neutrophil counts.
Analysis of data from clinical trials of the drug showed a slight increase in uric acid concentrations (approximately 0.2 mg/dL compared with placebo, average concentration before treatment 5-5.5 mg/dL) in patients receiving sitagliptin at a dose of 100 and 200 mg per day. day. No cases of gout were reported.
There was a slight decrease in total alkaline phosphatase concentrations (approximately 5 IU/L compared with placebo, mean pre-treatment concentration 56-62 IU/L), partly due to a slight decrease in bone alkaline phosphatase fraction.
The listed changes in laboratory parameters are not considered clinically significant.
Overdose:
During clinical studies in healthy volunteers, a single dose of 800 mg sitagliptin was generally well tolerated. Minimal changes in the QTc interval, not considered clinically significant, were observed in one study of sitagliptin at a dose of 800 mg per day. Doses above 800 mg per day have not been studied in humans.
In phase I clinical studies of repeated doses of any side effects associated with treatment with sitagliptin, no adverse reactions were observed when taking the drug in a daily dose of up to 400 mg for 28 days.
In case of overdose, standard supportive measures should be initiated: removing unabsorbed drug from the gastrointestinal tract, monitoring vital signs, including ECG, and prescribing supportive therapy if required.
Sitagliptin is poorly dialyzable. In clinical studies, only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session. Long-term dialysis may be prescribed if clinically necessary. There are no data on the effectiveness of peritoneal dialysis with sitagliptin.
Interaction:
In drug interaction studies, sitagliptin did not have a 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 CYP3A4, 2C8 or 2C9. Based on in vitro data, sitagliptin also does not inhibit the isoenzymes CYP2D6, 1A2, 2C19 and 2B6 and does not induce the CYP3A4 isoenzyme.
Repeated administration of metformin in combination with sitagliptin did not have a significant effect on the pharmacokinetic parameters of sitagliptin in patients with type 2 diabetes mellitus.
According to a population pharmacokinetic analysis of patients with type 2 diabetes mellitus, concomitant therapy did not have a clinically significant effect on the pharmacokinetics of sitagliptin. The study evaluated a number of drugs most commonly used for pain
