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.
Januvia, 28 pcs., 100 mg, film-coated tablets
The drug Januvia® 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 (duration: 18–24 weeks) of the drug Januvia® at a daily dose of 100–200 mg as mono- or combination therapy with metformin or pioglitazone, there were no adverse reactions associated with the study drug, the frequency of which exceeded 1 % in the group of patients taking Januvia®. 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 Januvia® was similar to that when taking placebo (Januvia® 100 mg - 1.2%, Januvia® 200 mg - 0 .9%, placebo - 0.9%). The incidence of monitored gastrointestinal adverse events with Januvia® at both doses was similar to that with placebo (with the exception of more frequent nausea with Januvia® at a dose of 200 mg/day): abdominal pain (Januvia® 100 mg - 2.3%, Januvia® 200 mg - 1.3%, placebo - 2.1%), nausea (1.4; 2.9; 0.6%), vomiting (0.8; 0.7; 0.9%), diarrhea (3; 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 Januvia® 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 × 2 times a day) in the combination group treatment compared with the metformin monotherapy group, the following drug-related adverse events were observed with a frequency of ≥1% in the Januvia® treatment group and more often than in the metformin monotherapy group: diarrhea (Januvia® + 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 Januvia® (daily dose 100 mg) and glimepiride or glimepiride and metformin, the following adverse events were observed in the study drug group compared with the group of patients taking placebo and glimepiride or glimepiride and metformin: with taking the drug, with a frequency of ≥1% in the Januvia® treatment group and more often than in the combination therapy group with placebo: hypoglycemia (Januvia® - 9.5%, placebo - 0.9%).
Initial combination therapy with PPAR-γ agonists
In a 24-week study of initial combination therapy with Januvia® at a daily dose of 100 mg and pioglitazone at a daily dose of 30 mg in the combination treatment group compared with pioglitazone monotherapy, the following drug-related adverse events were observed, observed with an incidence of ≥1% in the group treatment with Januvia® and more often than in the pioglitazone treatment group in monotherapy: asymptomatic decrease in blood glucose concentration (Januvia® + pioglitazone - 1.1%, pioglitazone - 0%), symptomatic hypoglycemia (0.4; 0.8%) .
Combination with PPAR-γ agonists and metformin
According to a placebo-controlled study, when treated with Januvia® (daily dose 100 mg) in combination with rosiglitazone and metformin, the following drug-related adverse events were observed in the study drug group compared with the group of patients taking placebo with rosiglitazone and metformin, with a frequency of ≥1% in the Januvia® treatment group and more often than in the combination therapy group with placebo: at 18 weeks of observation - headache (Januvia® - 2.4%, placebo - 0%), diarrhea (1.8; 1.1%), nausea (1.2; 1.1%), hypoglycemia (1.2; 0%), vomiting (1.2; 0%); at 54 weeks of observation - headache (Januvia® - 2.4%, placebo - 0%), hypoglycemia (2.4; 0%), upper respiratory tract infections (1.8; 0%), nausea (1.2 ; 1.1%), cough (1.2; 0%), fungal skin infection (1.2; 0%), peripheral edema (1.2; 0%), vomiting (1.2; 0%).
Combination with insulin
In a 24-week placebo-controlled study of combination therapy with Januvia® (at a daily dose of 100 mg) and constant dose insulin (with or without metformin) in the study drug group compared with a group of patients taking placebo and insulin (with or without metformin) , the following drug-related adverse events were observed with a frequency of ≥1% in the Januvia® treatment group and more often than in the insulin treatment group (with or without metformin): hypoglycemia (Januvia® + insulin (with or without metformin) - 9.6%, placebo + insulin (with or without metformin) - 5.3%), flu (1.2; 0.3%), headache (1.2; 0%).
In another 24-week study in which patients received Januvia® as an add-on therapy to insulin therapy (with or without metformin), there were no drug-related adverse reactions with an incidence of ≥1% in the Januvia® 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 cases per 100 patient-years of treatment in each group (see "Special Instructions" ", Pancreatitis
, as well as the Study to Evaluate the Cardiovascular Safety of Sitagliptin (
TECOS
) below).
No clinically significant deviations in vital signs or ECG (including QTc interval) were observed during treatment with Januvia®.
Sitagliptin Cardiovascular Safety Study (TECOS)
The study evaluating the cardiovascular safety of sitagliptin ( TECOS
) included 7332 patients with type 2 diabetes mellitus who took Januvia® 100 mg per day (or 50 mg per day if baseline eGFR was ≥30 and <50 ml/min/1.73 m2), and 7339 patients , taking placebo, in the general population of patients assigned to treatment. The study drug (Januvia® or placebo) was added to standard therapy according to existing national standards for selecting target HbA1C levels and controlling cardiovascular risk factors. A total of 2,004 patients 75 years of age and older were included in the study (970 received Januvia® and 1,034 received placebo). The overall incidence of serious adverse events in patients treated with Januvia® was the same as in patients treated with placebo. An evaluation of previously identified complications associated with diabetes mellitus revealed comparable rates of adverse events between groups, including infections (18.4% in patients treated with Januvia® and 17.7% in patients treated with placebo) and dysfunction. kidneys (1.4% in patients taking Januvia® and 1.5% in patients taking placebo). The adverse event profile in patients 75 years of age and older was generally similar to that of the general population.
an intention-to-treat patient population
(patients who took at least one dose of study drug), among those who initially received insulin therapy and/or sulfonylureas, the incidence of episodes of severe hypoglycemia was 2.7% in patients taking Januvia® 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% in patients taking Januvia® and 0.7% in patients taking placebo. The incidence of expertly confirmed cases of pancreatitis was 0.3% in patients taking Januvia® and 0.2% in patients taking placebo. The incidence of expertly confirmed cases of malignant neoplasms was 3.7% in patients taking Januvia® and 4% in patients taking placebo.
Post-registration observations
During post-registration monitoring of the use of Januvia® 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, incl. 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 frequency of laboratory abnormalities in the treatment groups with Januvia® (at a daily dose of 100 mg) was comparable to the frequency 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 Januvia® at a dose of 100 and 200 mg/day No cases of gout were reported.
There was a small decrease in total ALP concentrations (approximately 5 IU/L compared with placebo, mean pre-treatment concentration 56–62 IU/L), partly due to a small decrease in bone ALP fraction.
The listed changes in laboratory parameters are not considered clinically significant.
Januvia: high efficiency, physiological effect
A.S. Ametov, Doctor of Medical Sciences, Professor, RMAPO
Despite the availability of a wide range of oral drugs targeting various aspects of the pathogenesis of diabetes mellitus, publicly available treatment paradigms are considered unsatisfactory because in many patients they do not achieve adequate glycemic control even when using a combination of several, which ultimately forces resort to insulin therapy to control hyperglycemia. Thus, there is a need for truly effective drugs aimed not only at treatment, but also at preventing the disease, its progression and combating associated conditions.
In 2007, a new drug YANUVIA (sitagliptin) produced by , the first DPP-4 inhibitor, was registered in Russia
The main place of Januvia in the treatment of type 2 diabetes mellitus is a combination with metformin, which has been proven to be highly effective. In patients receiving initial combination therapy with Januvia at a dose of 100 mg and metformin at a dose of 2000 mg per day, by the 54th week of combination therapy, a decrease in HbA1c was achieved by an average of 1.9% (initial HbA1c level 8.8%) . At the same time, in the subgroup with a high initial level of HbA1c (average 10.4%), a decrease was achieved by 3,1%.
Impressive treatment success rate: 77% of patients achieved target HbA1c values.
Januvia has confirmed its high effectiveness when used as monotherapy. Thus, in a study in patients who did not receive any therapy before the appointment of sitagliptin, by the end of the 1st year of treatment, a decrease in HbA1c by an average of 1.4% was achieved. At the same time, in the subgroup with a high initial HbA1c level, a reduction of 2.0% was achieved. By week 54, 41% of patients who completed the study achieved target HbA1c values
The studies also demonstrated significant improvements in β-cell function, expressed as a decrease in the proinsulin-to-insulin ratio and an increase in the HOMA-β ratio.
In a number of numerous studies, it has been proven that the action of Januvia is aimed at restoring the natural physiology of glucose homeostasis, correcting impaired insulin secretion and inadequate glucagon secretion. Januvia acts by preserving the body's own incretins. The effect of the drug is glucose-dependent, i.e. Stimulation of insulin secretion and suppression of glucagon secretion occurs only when glucose levels are elevated. Consequently, there is no reason for hypoglycemia, which is inherent, for example, in sulfonylurea drugs. This has been proven in studies: the overall incidence of hypoglycemia was low and similar to placebo (1.2% versus 0.9%). In addition, given the mechanism of action of sitagliptin, there is no reason to expect any negative effects on the cardiovascular system, because sitagliptin has no effect on ATP-dependent potassium channels.
Januvia is aimed at maintaining both fasting and postprandial plasma glucose levels, deviations in which are considered to be the cause of many diabetic complications.
Januvia does not cause weight gain, which is very important for overweight patients.
Sitagliptin has a positive effect on pancreatic beta cell mass and function in vivo,
thus allowing the progression of the disease to be slowed.
Which patients should I prescribe Januvia? At the moment, we can recommend both the addition of Januvia to metformin in all patients with an HbA1c level of more than 7% (or fasting glycemia more than 6.5 mmol/l), and the initial combination therapy of Januvia and metformin in patients with newly diagnosed type 2 diabetes mellitus. By initiating therapy this early, the physician can be confident that the patient will live longer with an acceptable glycemic level.
The drug sitagliptin (Januvia) is included in the “Algorithms for specialized medical care for patients with diabetes mellitus” (3rd edition, updated) ed. I.I. Dedova, M.V. Shestakova by letter dated March 11, 2008. Sitagliptin is also included in the joint EASD (European Association for the Study of Diabetes) and ADA (American Diabetes Association) Consensus on the treatment algorithm for patients with diabetes mellitus.
Thus, Januvia (sitagliptin) is an effective drug with a physiological mechanism of action and impressive potential for the treatment of type 2 diabetes.
