Instructions for use JANUVIA
The pharmacokinetics of sitagliptin have been extensively characterized in healthy individuals and in 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 plasma Cmax achieved 1-4 hours after taking the drug. The AUC value of sitagliptin in blood plasma increases in proportion to the dose. When the drug was administered orally at a single dose of 100 mg in healthy people, the AUC of sitagliptin in blood plasma was 8.52 µmol x h, Cmax was 950 nmol, apparent terminal T1/2 was 12.4 h. AUC of sitagliptin in plasma increased by approximately 14% after dosing 100 mg at steady state, compared to the first dose. Intra- and intersubject coefficients of variation for sitagliptin AUC were negligible (5.8% and 15.1%). The pharmacokinetics of sitagliptin are generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Absorption
The absolute bioavailability of sitagliptin is approximately 87%. Since the simultaneous intake of a high-fat meal and the drug Januvia does not affect the pharmacokinetics, the drug Januvia can be taken regardless of food intake.
Distribution
The mean steady-state volume of distribution following a single 100 mg intravenous dose of sitagliptin in healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is insignificant (38%).
Metabolism
Sitagliptin is excreted primarily unchanged in the urine and metabolism is negligible. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Following oral administration of [14C]sitagliptin, approximately 16% of the radioactive drug was excreted as sitagliptin metabolites. Trace levels of 6 metabolites were detected that are not expected to have the DPP-4 inhibitory activity of sitagliptin in plasma. In vitro studies revealed that the main enzyme responsible for the limited metabolism of sitagliptin is CYP3A4 with the participation of CYP2C8.
Removal
Following oral administration of [14C]sitagliptin to healthy subjects, approximately 100% of the ingested radioactive drug was excreted in feces (13%) and urine (87%) within one week of dosing. The apparent terminal half-life following oral administration of sitagliptin 100 mg is approximately 12.4 hours; renal clearance is approximately 350 ml/min.
Excretion of sitagliptin is carried out mainly by excretion by the kidneys via the mechanism of active tubular secretion. Sitagliptin is a substrate for human organic anion transporter type 3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical significance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a p-glycoprotein substrate, which may also be involved in the renal excretion of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Pharmacokinetics in selected patient groups
Kidney failure. An open-label, single-dose study was conducted to examine the pharmacokinetics of Januvia (50 mg) in patients with chronic renal failure of varying severity compared with a healthy control group. The study included patients with renal failure, classified according to creatinine clearance into mild (50 to 80 ml/min), moderate (30 to 50 ml/min) and severe (less than 30 ml/min) forms, as well as patients with end-stage renal failure undergoing dialysis. Creatinine clearance was determined by renal creatinine clearance per day or using serum creatinine concentrations using the Cockcroft-Gault formula:
- CC = ([140 - age (in years)] x body weight (in kg) x 0.85 for women) / [72 x serum creatinine (mg/dl)]
In patients with mild renal failure, there was no clinically significant increase in plasma sitagliptin concentrations compared to a control group of healthy volunteers. An approximately 2-fold increase in sitagliptin plasma AUC was observed in patients with moderate renal impairment, and an approximately 4-fold increase in sitagliptin plasma AUC was observed in patients with severe renal impairment and in patients with end-stage renal disease undergoing hemodialysis, compared with a control group of healthy volunteers. Sitagliptin is excreted to a weak extent during hemodialysis (13.5% during a 3-4 hour dialysis session, which began 4 hours after taking the drug). Because the drug is not available in the dosage required to achieve sitagliptin plasma concentrations similar to those in patients with normal renal function, Januvia is not recommended for patients with moderate to severe renal impairment or patients with end-stage renal disease undergoing hemodialysis.
Liver failure. In patients with moderate hepatic impairment (Child-Pugh score 7-9), the mean AUC and Cmax of sitagliptin increased by approximately 21% and 13%, respectively, compared with healthy controls, after a single dose of Januvia 100 mg. Such differences are not considered clinically significant. There is no need to adjust the dose of the drug in patients with mild to moderate hepatic impairment.
There is no clinical experience with the use of the drug in patients with severe liver failure (more than 9 points on the Child-Pugh scale). However, due to the fact that sitagliptin is excreted primarily by the kidneys, a significant effect on the pharmacokinetics of sitagliptin in severe hepatic impairment is not expected.
Elderly patients. There is no need to adjust the dose of the drug depending on age. Patient age does not have a clinically significant effect on the pharmacokinetics of sitagliptin based on population pharmacokinetic analysis of Phase I and Phase II data. In elderly patients (65-80 years), sitagliptin plasma concentrations were approximately 19% higher than in younger patients.
Children
Studies on the use of Januvia in children have not been conducted.
Floor
There is no need to adjust the dose of the drug depending on gender. Gender does not have a clinically significant effect on the pharmacokinetics of sitagliptin based on a comprehensive analysis of Phase I pharmacokinetic data and from a population pharmacokinetic analysis of Phase I and Phase II data.
Race
There is no need to adjust the dose of the drug depending on race. Race does not have a clinically significant effect on the pharmacokinetics of sitagliptin based on a comprehensive analysis of Phase I pharmacokinetic data and a population pharmacokinetic analysis of Phase I and Phase II data, including patients of white, Hispanic, black, Asian, and other racial groups.
Body Mass Index (BMI)
There is no need to adjust the dose of the drug depending on BMI. Body mass index does not have a clinically significant effect on the pharmacokinetics of sitagliptin, based on a comprehensive analysis of Phase I pharmacokinetic data and population pharmacokinetic analysis of Phase I and Phase II data.
Diabetes mellitus type 2
The pharmacokinetics of sitagliptin in patients with type 2 diabetes mellitus are generally similar to those in healthy subjects.
YANUVIA film-coated tablets 100 mg No. 28
Januvia is an oral hypoglycemic drug, a highly selective inhibitor of dipeptidyl peptidase 4 (DPP-4). Sitagliptin differs in chemical structure and pharmacological action from glucagon-like peptide-1 (GLP-1) analogs, insulin, sulfonylureas, biguanides, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, alpha-glycosidase inhibitors, and amylin analogs. By inhibiting DPP-4, sitagliptin increases the concentration of 2 known hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic peptide (GIP). Hormones of the incretin family are secreted in the intestines throughout the day, and their levels increase in response to food intake. Incretins are part of the intrinsic physiological system for regulating glucose homeostasis. With normal or elevated blood glucose levels, hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion by pancreatic β-cells due to intracellular signaling mechanisms associated with cyclic AMP. GLP-1 also helps suppress increased glucagon secretion by pancreatic α-cells. A decrease in glucagon concentration against the background of an increase in insulin levels helps to reduce the production of glucose by the liver, which ultimately leads to a decrease in glycemia. 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 level 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 level of glycated hemoglobin HbA1C and a decrease in plasma glucose concentrations determined on an empty stomach and after an exercise test. In patients with type 2 diabetes mellitus, taking one dose of Januvia leads to inhibition of the activity of the DPP-4 enzyme for 24 hours, which leads to an increase in the level 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.
Content
- Characteristics of Januvia (tablet p/o 100 mg No. 28)
Composition: Active ingredient: Sitagliptin.
Pharmacological Action: Sitagliptin is an orally active, highly selective inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4), intended for the treatment of type 2 diabetes mellitus.
By inhibiting DPP-4, sitagliptin increases the concentrations of two known hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic peptide (GIP).
Incretins are part of the intrinsic physiological system for regulating glucose homeostasis.
With normal or elevated blood glucose levels, hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion by beta cells of the pancreas due to intracellular signaling mechanisms associated with cyclic 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 levels helps to reduce the production of glucose by the liver, which ultimately leads to a decrease in glycemia.
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 level 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 level of glycosylated hemoglobin HbA1C and a decrease in plasma glucose concentrations determined on an empty stomach and after an exercise test.
In patients with type 2 diabetes mellitus, taking one dose of Januvia leads to inhibition of the activity of the DPP-4 enzyme for 24 hours, which leads to an increase in the level 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.
The absolute bioavailability of sitagliptin is approximately 87%.
Protein binding – 38%.
Approximately 79% of sitagliptin is excreted unchanged in the urine.
The mean half-life of sitagliptin when administered orally at 100 mg is approximately 12.4 hours; renal clearance – 350 ml/min.
Excretion of sitagliptin is carried out primarily by excretion by the kidneys through the mechanism of active tubular secretion.
Indications for Use: • Monotherapy.
Januvia is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
• Combination therapy.
Is Januvia also indicated in patients with type 2 diabetes to improve glycemic control in combination with metformin or PPAR agonists? (for example, thiazolidinedione), when diet and physical activity in combination with monotherapy with the listed drugs do not lead to adequate glycemic control.
Method of Administration: The recommended dosage of Januvia is 100 mg 1 time per day as monotherapy or in combination with metformin or a PPAR agonist? (for example, thiazolidinedione).
The drug can be taken regardless of meals.
If the patient misses a dose, he should take it as soon as possible after he remembers the missed dose.
It is not permissible to take a double dose of Januvia.
In patients with mild renal failure, no dose adjustment is required.
For patients with moderate renal failure, the dosage of the drug is 50 mg 1 time per day.
For patients with severe renal failure, as well as with end-stage renal disease requiring hemodialysis, the dosage of the drug is 25 mg once a day.
The drug can be used regardless of the schedule of the hemodialysis procedure.
No dose adjustment is required in elderly patients.
Interaction: Sitagliptin does not have a clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives.
It is not recommended to change the dose of either digoxin or Januvia when used together.
It is not recommended to change the dose of Januvia when used together with cyclosporine and other p-glycoprotein inhibitors (for example, ketoconazole).
Side Effects: The drug is generally well tolerated.
Side effects that occurred without a causal relationship with taking the drug at a dose of 100 mg and 200 mg per day: upper respiratory tract infections, nasopharyngitis, headache, diarrhea, arthralgia.
The overall incidence of hypoglycemia in patients receiving Januvia was similar to that observed when taking placebo.
The incidence of some side effects from the gastrointestinal tract when taking the drug at both dosages was similar to that when taking placebo, with the exception of more frequent nausea when taking the drug at a dose of 200 mg per day: abdominal pain, nausea, vomiting, diarrhea.
Contraindications: Hypersensitivity to any of the components of the drug, pregnancy, breastfeeding, type 1 diabetes, diabetic ketoacidosis.
The use of Januvia in pediatric practice in patients under 18 years of age is not recommended.
With caution: renal failure.
In patients with moderate and severe renal failure, as well as in patients with end-stage renal disease requiring hemodialysis, dosage adjustment of the drug is required.
Overdose: No data available.
Special Instructions: The combined use of Januvia in combination with drugs that can cause hypoglycemia, such as insulin, sulfonylurea derivatives, has not been studied.
Elderly patients are more likely to develop kidney failure.
Accordingly, as in other age groups, dosage adjustment is necessary in patients with severe renal failure.
During treatment with Januvia, there were no clinically significant changes in vital signs and ECG (including the QTc interval).
No studies have been conducted to study the effect of the drug Januvia on the ability to drive vehicles.
However, Januvia is not expected to have a negative effect on the ability to drive a car or operate complex machinery.
