Pharmacological action Januvia 100 mg
Januvia Oral hypoglycemic drug, a highly selective inhibitor of dipeptidyl peptidase 4 (DPP-4).
Sitagliptin differs in chemical structure and pharmacological activity of analogues of glucagon-like peptide-1 (GLP-1), insulin, sulfonylureas, biguanides, γ-agonist receptors, peroxisome proliferator-activated (PPAR-γ), alpha-glycosidase inhibitors, amylin analogues. By inhibiting the DPP-4, sitagliptin increases the concentration of two known incretin hormone family: GLP-1 and glucose-dependent insulinotropic peptide (GIP). Hormones are secreted into the family of incretin gut during the day, its level rises in response to food intake. Incretins are part of the internal physiological systems of regulation of glucose homeostasis. At normal or elevated blood glucose incretin hormones contribute to the family increased synthesis of insulin and its secretion of β-cells of the pancreas due to signal intracellular mechanisms associated with cyclic AMP.
GLP-1 also contributes to the suppression of glucagon secretion increased α-cells of the pancreas. Reducing the concentration of glucagon, accompanied by increased levels of insulin reduces hepatic glucose production, which eventually leads to a decrease in glucose levels.
At low concentrations of blood glucose incretin effects listed on the release of insulin and glucagon secretion reduction is not observed. GLP-1 and GIP do not affect the release of glucagon response to hypoglycemia. Under physiological conditions, the enzyme activity of incretin limited DPP-4, which is rapidly hydrolyzed with the formation of incretins inactive products.
Sitagliptin prevents hydrolysis by the enzyme DPP incretin-4, thereby increasing plasma concentrations of active forms of GLP-1 and GIP. Increasing the level of incretins, sitagliptin increases insulin release glyukozozavisimy and reduces the secretion of glucagon. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin secretion and glucagon led to a decrease in the level of glycated hemoglobin and a decrease in plasma NbA1S glucose determined fasting and after exercise testing.
In patients with type 2 diabetes mellitus receiving a single dose Januvia inhibits activity of the enzyme DPP-4 for 24 h, which leads to increased levels of circulating incretin GLP-1 and GIP in 2-3 times, rise of plasma insulin and C- peptide, the decrease of concentration of glucagon in blood plasma, reduce fasting glucose and decrease blood glucose levels after glucose load or food load.
Pharmacokinetics Januvia 100 mg
The pharmacokinetics of sitagliptin was studied in healthy subjects and patients with type 2 diabetes.
Absorption
After ingestion of the drug at a dose of 100 mg in healthy subjects indicated rapid absorption of sitagliptin to achieve Cmax in 1-4 h. AUC increased in proportion to dose and is in healthy subjects 8.52 mmol × h when administered in doses of 100 mg, Cmax was 950 nM.
The absolute bioavailability of sitagliptin is approximately 87%. Intra-and interindividual variability in AUC of sitagliptin coefficients are insignificant.
Simultaneous treatment of fatty foods do not affect the pharmacokinetics of sitagliptin, so the drug can be prescribed Januvia , regardless of food intake.
Distribution
Plasma AUC of sitagliptin increased approximately 14% after the next administration of the drug at a dose of 100 mg to achieve an equilibrium state after the first dose.
After a single dose of the drug at a dose of 100 mg sitagliptin average Vd in healthy volunteers was approximately 198 liters. Binding of sitagliptin to plasma proteins is 38%.
Metabolism
Metabolized by only a small part of the body released to the drug. After the introduction of 14C-labeled sitagliptin into approximately 16% of the radioactive drug excreted in the form of its metabolites. There were traces of six metabolites of sitagliptin, probably do not have the DPP-4 inhibitory activity. In in vitro studies revealed that the primary enzymes involved in metabolism of sitagliptin limited, is a CYP3A4 with CYP2C8.
Breeding
Approximately 79% of sitagliptin is excreted unchanged in the urine.
1 week after taking the drug to healthy volunteers 14C-labeled sitagliptin Conclusion: urine – 87% -13% and feces.
T1 / 2 when administered with sitagliptin 100 mg was approximately 12.4 h. Renal clearance is approximately 350 ml / min.
Excretion of sitagliptin is primarily carried out through excretion by the kidneys by active tubular secretion mechanism. Sitagliptin is a substrate for the transporter of organic anions of human type III (hOAT-3), which may be involved in the process of removing the kidney of sitagliptin. Clinical involvement hOAT-3 in sitagliptin transport has not been studied. Sitagliptin is also a substrate of P-glycoprotein, which may also participate in the renal elimination of sitagliptin. However, cyclosporine, which is an inhibitor of P-glycoprotein, did not reduce the renal clearance of sitagliptin.
Pharmacokinetics in special clinical situations
Patients with renal insufficiency
Open-label study drug Januvia at 50 mg / was conducted to study its pharmacokinetics in patients with varying severity of chronic renal failure. Included in the study, patients were divided into groups of mild renal insufficiency (creatinine clearance 50-80 ml / min), moderate (creatinine clearance 30-50 ml / min) and severe renal insufficiency (creatinine clearance below 30 ml / min), and patients with end-stage renal disease requiring dialysis.
In patients with mild renal insufficiency were no clinically significant changes in the concentration of sitagliptin in plasma compared with a control group of healthy volunteers.
The increase in AUC of sitagliptin is approximately 2-fold compared with the control group was observed in patients with renal insufficiency moderately, approximately 4-fold increase in AUC observed in patients with severe renal insufficiency and in patients with end-stage renal disease compared with the control group . Sitagliptin to a lesser degree removed from the systemic circulation by hemodialysis: only 13.5% of the dose was removed from the body within 3-4 hours of dialysis.
Thus, to achieve therapeutic drug concentrations in blood plasma (similar to that in patients with normal renal function) in patients with renal failure and moderate to severe correction is required dose.
Patients with liver failure
In patients with moderate hepatic impairment (7-9 points in Child-Pugh), the mean AUC and Cmax of sitagliptin at 100 mg once daily increased by approximately 21% and 13% respectively. Thus, the correct dose of the drug in mild to moderate hepatic insufficiency is not required.
No clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh). However, due to the fact that the drug is primarily excreted by the kidneys, you should not expect significant changes in the pharmacokinetics of sitagliptin in patients with severe hepatic impairment.
Elderly patients
Age of the patients had no clinically significant effect on pharmacokinetic parameters of sitagliptin. Compared with younger patients in elderly patients (65-80 years), the concentration of sitagliptin by approximately 19% higher. Correct dose of the drug, depending on age is not required.
Indications for use of the drug Januvia 100 mg
- Monotherapy: as an adjunct to diet and exercise to improve glycemic control in diabetes mellitus type 2;
- Combination therapy: type 2 diabetes mellitus to improve glycemic control in combination with metformin or agonists of PPAR-γ (eg, thiazolidinedione) when diet and exercise in combination with monotherapy listed funds do not result in adequate glycemic control.
Dosage regimen Januvia 100 mg
When used as monotherapy or in combination with metformin or an agonist of PPAR-γ (eg, thiazolidinediones), recommended dose is 100 mg Januvia 1 time /
Januvia can be taken irrespective of food intake. If the patient misses Januvia , the drug should be taken as soon as possible. Unacceptable reception double dose Januvia .
In renal insufficiency, mild (creatinine clearance ≥ 50 ml / min, approximately corresponding to the content of serum creatinine ≤ 1.7 mg / dl in men, ≤ 1.5 mg / dl in women), the dose correction is required.
In renal insufficiency, moderate (creatinine clearance ≥ 30 ml / min but1.7 mg / dL, but ≤ 3 mg / dl in men,> 1.5 mg / dL, but ≤ 2.5 mg / dl in women), Januvia dose of 50 mg 1 time /
In renal failure, severe (creatinine clearance3 mg / dl in men,> 2.5 mg / dl in women), for patients with end-stage renal failure and need dialysis dose is Januvia 25 mg 1 time / Januvia can be applied regardless of the schedule of hemodialysis.
Side effect Januvia 100 mg
Presented adverse reactions occur without a causal relationship with drug intake Januvia in doses of 100 mg and 200 mg per day, but more often than with placebo.
The respiratory system: upper respiratory tract infection (100 mg – 6.8%, 200 mg – 6.1%, placebo – 6.7%), nasopharyngitis (100 mg – 4.5%, 200 mg – 4.4%, placebo – 3.3%).
CNS: headache (100 mg – 3.6%, 200 mg – 3.9%, placebo – 3.6%).
Part of the digestive system: diarrhea (100 mg – 3%, 200 mg – 2.6%, placebo – 2.3%), abdominal pain (100 mg – 2.3%, 200 mg – 1.3%, placebo – 2.1%), nausea (100 mg – 1.4%, 200 mg – 2.9%, placebo – 0.6%), vomiting (100 mg – 0.8%, 200 mg – 0.7%, placebo – 0.9%), diarrhea (100 mg – 3%, 200 mg – 2.6% placebo – 2.3%).
With the Musculoskeletal System: arthralgia (100 mg – 2.1%, 200 mg – 3.3%, placebo – 1.8%).
From the Endocrine: hypoglycemia (100 mg – 1.2%, 200 mg – 0.9%, placebo – 0.9%).
From the laboratory parameters: at doses of 100 mg / 200 mg and / – increase in uric acid of approximately 0.2 mg / dL compared with placebo (average 5-5.5 mg / dl) in patients treated with a dose of 100 mg / and 200 mg / cases of gout have been reported.
A slight decrease in total alkaline phosphatase concentrations (approximately 5 IU / l compared with placebo, the average level of 56-62 IU / L), partly associated with a slight decrease in bone-specific alkaline phosphatase.
A small increase in white blood cells (approximately 200/mkl compared with placebo, the average 6600/mkl) due to an increase in the number of neutrophils. This observation was noted in most but not all studies.
These changes in laboratory parameters are not considered clinically significant.
Against the background of the drug were noted Januvia clinically relevant changes in vital signs and ECG (including interval QTc).
Januvia is generally well tolerated both as monotherapy and in combination with other hypoglycemic agents. In clinical trials, the overall incidence of side effects, as well as the frequency of withdrawal Januvia because of side effects were similar to those on placebo.
Contraindications to the use of the drug Januvia 100 mg
- Diabetes mellitus type 1;
- Diabetic ketoacidosis;
- Pregnancy
- Lactation (breastfeeding);
- Hypersensitivity to the drug.
The drug is not recommended in Januvia children and adolescents under 18 years (data on the use of the drug in pediatric patients have not).
With caution in patients with renal insufficiency. In renal insufficiency, moderate and severe, and patients with end-stage renal failure requiring hemodialysis, the required adjustment of dosing regimen.
Use of the drug Januvia 100 mg of pregnancy and breast-feeding
Adequate and well controlled clinical trials of drug safety in pregnant women Januvia was conducted. The use of the drug during pregnancy is contraindicated.
Is not known whether sitagliptin in breast milk in humans. If needed, use during lactation should decide on the termination of breastfeeding.
Use in hepatic dysfunction Januvia 100 mg
Patients with mild to moderate hepatic impairment dose adjustment is required Januvia . The drug has not been studied in patients with severe hepatic impairment.
Use in renal impairment Januvia 100 mg
Patients with renal impairment is mild (creatinine clearance ≥ 50 ml / min, approximately corresponding to the content of serum creatinine ≤ 1.7 mg / dl in men, ≤ 1.5 mg / dl in women), the dose correction is required.
For patients with renal insufficiency moderate (creatinine clearance ≥ 30 ml / min but1.7 mg / dL, but ≤ 3 mg / dl in men,> 1.5 mg / dL, but ≤ 2.5 mg / dl in women), Januvia dose of 50 mg 1 time /
For patients with severe renal insufficiency (creatinine clearance3 mg / dl in men,> 2.5 mg / dl in women), for patients with end-stage renal disease and need dialysis dose Januvia is 25 mg 1 time / Januvia can be applied regardless of the schedule of hemodialysis.
Cautions Januvia 100 mg
In clinical trials, drug Januvia as monotherapy or as part of combination therapy with metformin or pioglitazone, the incidence of hypoglycemia when using the drug Januvia was similar to the frequency of hypoglycemia with placebo. The combined use of the drug in combination with Januvia drugs that can cause hypoglycemia, such as insulin, sulfonylureas, has not been investigated.
Patients with mild to moderate hepatic impairment dose adjustment is required Januvia . The drug has not been studied in patients with severe hepatic impairment.
In clinical trials, the efficacy and safety of the drug Januvia in elderly patients (≥ 65 years, 409 patients) were comparable to those indicators in patients younger than 65 years. No dose adjustment for age is not required. Elderly patients are more likely to develop kidney failure. Accordingly, as in other age groups need a dosage adjustment in patients with severe renal insufficiency.
Effects on ability to drive and control mechanisms
Not conducted studies on the effect of the drug Januvia ‘s ability to drive vehicles. Nevertheless, is not expected to adversely affect the drug’s ability to drive or complex mechanisms.
Overdose Januvia 100 mg
Symptoms: During clinical trials on healthy volunteers, there was well tolerated when receiving a single dose of Januvia 800 mg. Minimal change interval QTc, are not considered clinically significant, were observed in one study, the dose of the drug. Clinical trials of the drug at a dose of 800 mg / not done.
Treatment: removal of unabsorbed drug from the gastrointestinal tract, monitoring vital signs, including ECG, if necessary – the holding of symptomatic and supportive therapy.
Sitagliptin poorly dialyzed. In clinical trials, only 13.5% of the dose was removed from the body within 3-4 hours of dialysis. Prolonged dialysis can naznachits if clinically necessary. Data on the effectiveness of peritoneal dialysis, sitagliptin does not.
Drug Interactions Januvia 100 mg
In studies of interactions with other medicines, 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 isozymes CYP3A4, 2C9 or 2S8. Based on data obtained in vitro, sitagliptin did not inhibit also likely CYP2D6, 1A2, 2C19 or 2V6, and does not induce SYP3A4.
It was noted a slight increase in AUC (11%) and average C max (18%) of digoxin or combined with sitagliptin. This increase is not considered clinically significant. We do not recommend any change in the dose of digoxin, the drug or when they are simultaneously Januvia application.
Was an increase in AUC and Cmax of sitagliptin by 29% and 68% respectively in patients with joint application Januvia in a single dose of 100 mg and cyclosporine (a potent inhibitor of P-glycoprotein) in a single dose of 600 mg. These changes of pharmacokinetic parameters of sitagliptin is not considered clinically significant. We do not recommend changing the dose Januvia or combined with cyclosporine and other inhibitors of P-glycoprotein (eg, ketoconazole).
Population pharmacokinetic analysis in patients and healthy volunteers (n = 858) treated with a wide range of concomitant medications (n = 83, approximately half of which are excreted by the kidneys) did not reveal any clinically significant effects of drugs on the pharmacokinetics of sitagliptin.
