Expiration date: 07/2025

The composition and form of issue: 

Tablets, film-coated. 1 tablet contains:

sitagliptin (as phosphate monohydrate) 100 mg

other ingredients: microcrystalline calcium hydrogen phosphate croscarmellose sodium magnesium stearate sodium fumarate 

the shell: Opadry II beige 85 F17438 polyvinyl alcohol titanium dioxide macrogol (polyethylene glycol) 3350 talc iron oxide yellow iron oxide red 

in a contour cells packing 14 PCs. in cardboard pack 2 packs.

Description pharmaceutical form:

Tablets are beige, round, biconvex, engraved with "277" on one side and smooth on the other.

Feature:

Oral hypoglycemic drug, a highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4).

Pharmacokinetics:

The pharmacokinetics of sitagliptin was studied in healthy persons and patients with diabetes mellitus type 2.

Suction

After ingestion of the drug in a dose of 100 mg in healthy individuals there has been a rapid absorption of sitagliptin with the achievement of Cmax 1-4 hours AUC increased proportionally with dose and is in healthy subjects of 8.52 µmol × h when administered at a dose of 100 mg, Cmax — 950 nmol.

The absolute bioavailability of sitagliptin is approximately 87%. Intra - and interindividual coefficients of variation in AUC of sitagliptin is insignificant.

Simultaneous reception fatty foods does not affect the pharmacokinetics of sitagliptin, and the drug of Januvia can be assigned regardless of the meal.

Distribution

Plasma AUC of sitagliptin increased approximately 14% after the next dose of the drug in a dose of 100 mg to achieve equilibrium after the first dose.

After a single dose of the drug in the dose 100 mg average apparent volume of distribution of sitagliptin in healthy volunteers was approximately 198 L. Linking sitagliptin to plasma proteins — 38%.

Metabolism

Metabolized only a small portion of ingested drug. After administration of 14C-labeled sitagliptin inside approximately 16% of radioactive drug ekskretiruetsja in the form of its metabolites. Showed traces of 6 of the metabolites of sitagliptin, perhaps non-DPP-4-inhibiting activity. In vitro studies revealed that the primary enzyme involved in the limited metabolism of sitagliptin is CYP3A4, with the participation of CYP2C8.

Excretion

Approximately 79% of sitagliptin is excreted unchanged in the urine.

Within 1 week of ingestion of healthy volunteers with 14C-labeled sitagliptin output: urine — 87% and feces 13%.

T1/2 of sitagliptin when administered at a dose of 100 mg is approximately 12.4 h. Renal Cl is approximately 350 ml/min.

Excretion sitagliptin is primarily by excretion by the kidneys in the mechanism of active tubular secretion. Sitagliptin is a substrate for the Transporter of organic anions of the person of the third type (hOAT-3), which may be involved in the process of removing sitagliptin kidneys. Clinically, the involvement of hOAT-3 in sitagliptin transport has not been studied. Sitagliptin is also a substrate for 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 cases

Patients with renal insufficiency

An open study of drug Januvia at a dose of 50 mg/day was performed to study its pharmacokinetics in patients with varying severity of chronic renal failure. Included in the study patients were divided into 4 groups: patients with mild renal insufficiency (Cl creatinine 50-80 ml/min), moderate (Cl creatinine 30-50 ml/min) and severe (creatinine Cl <30 ml/min) and end-stage of renal disease requiring dialysis.

In patients with mild renal insufficiency were not observed clinically significant changes in the concentration of sitagliptin in plasma compared with the control group of healthy volunteers.

The increase in AUC of sitagliptin by approximately 2 times in comparison with the control group was observed in patients with renal insufficiency of moderate extent, approximately in 4 times — with renal insufficiency, severe, and in patients with end-stage of renal disease compared with the control group. Sitagliptin to a lesser degree, was removed from systemic blood flow by hemodialysis: only 13.5% the dose was removed from the body within 3-4 hour dialysis session.

Thus, to achieve therapeutic concentrations of drug in plasma (similar to that in patients with normal renal function) in patients with renal insufficiency moderate and severe dose adjustment is required.

Patients with hepatic insufficiency

In patients with moderate hepatic impairment (7-9 points on a scale child-Pugh) mean AUC and Cmax of sitagliptin in single dose 100 mg increase of approximately 21% and 13% respectively. Thus, the correction of the dose in mild and moderate hepatic insufficiency is not required.

No clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (more 9 points on a scale child-Pugh). However, due to the fact that the drug is primarily excreted by the kidneys, we should not expect significant changes in the pharmacokinetics of sitagliptin in patients with severe hepatic insufficiency.

Elderly patients

The age of patients had no clinically significant effects on pharmacokinetic parameters of sitagliptin. Compared to younger patients elderly patients (65-80 years) the concentration of sitagliptin by approximately 19% above. Correction of the dose according to age is not required.

Description pharmacological action:

Sitagliptin differs in chemical structure and pharmacological action from analogues glucagonoma peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, agonists &gamma-receptors, peroxisome proliferator-activated (PPAR-&gamma), inhibitors of alpha-glycosidase, analogues Amelina. By inhibiting DPP-4, sitagliptin increases the concentration of 2 hormones known family of incretins: GLP-1 and glukagonovykh insulinotropic peptide (GIP). Hormones the family of incretins secreted in the gut during the day, their level is increased in response to food intake. Incretins are part of the internal physiological regulation of glucose homeostasis. When normal or elevated blood glucose levels hormones the family of incretins contribute to increase of insulin synthesis and its secretion &beta-pancreatic cells due to intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also suppresses the increased secretion of glucagon &alpha-cells of the pancreas. The decrease in the concentration of glucagon on the background of increasing insulin levels promotes a decrease in hepatic glucose production, which ultimately leads to the reduction of glycemia.

At low concentrations of blood glucose of these effects of incretin on insulin release and decrease glucagon secretion are not observed. GLP-1 and GIP did not affect the release of glucagon in response to hypoglycemia. Under physiological conditions, the activity of incretins is limited by the enzyme DPP-4, which rapidly hydrolyzes incretins into inactive products.

Sitagliptin prevents the hydrolysis of incretin enzyme DPP-4, thereby increasing plasma concentrations of the active form of GLP-1 and GIP. Increasing the level of incretin, glucosetoxicity sitagliptin increases insulin release and reduces secretion of glucagon. In patients with diabetes mellitus type 2 with hyperglycemia, these changes in insulin secretion and glucagon lead to reduction in level of glycated hemoglobin HbA1c and reduce plasma concentrations of glucose, defined on an empty stomach and after loading samples.

In patients with diabetes type 2 taking one dose of Januvia leads to inhibition of the enzyme activity of DPP-4 for 24 h, which leads to increased levels of circulating incretins GLP-1 and GIP by 2-3 times, increasing the plasma concentrations of insulin and C-peptide, a decrease in the concentration of glucagon in plasma, reduction of fasting glycemia, and reduction of glycaemia after glucose load or food load.

Indications:

Monotherapy:

as an adjunct to diet and exercise to improve glycemia control in diabetes type 2.

Combination therapy:

diabetes mellitus type 2 to improve control of blood glucose in combination with Metformin or agonist of PPAR-&gamma (e.g. thiazolidinedione) when diet and exercise in combination with monotherapy of the means listed do not result in adequate control of glycemia.

Contraindications:

• hypersensitivity to the drug
  
• diabetes mellitus type 1
  
• diabetic ketoacidosis
  
• pregnancy
  
• lactation (breastfeeding).
  
• childhood and adolescence to 18 years (data on the use of drugs in pediatric patients are not available).
  

Caution — renal failure. In renal insufficiency, moderate and severe and patients with end-stage renal disease requiring hemodialysis requires correction dosing regimen.

Application of pregnancy and breast-feeding:

Adequate and well-controlled clinical studies safety of the drug Januvia in pregnant women have not been conducted. The use of the drug during pregnancy is contraindicated.

Unknown, selects whether sitagliptin in breast milk in humans. If necessary, use of the drug during lactation should decide the issue of termination of breastfeeding.

Side effects:

Submitted adverse reactions encountered when taking the drug of Januvia in doses of 100 and 200 mg/day more than when taking a placebo (a causal relationship to drug intake is not installed).

The respiratory system: infections of the upper respiratory tract (100 mg to 6.8%, 200 mg and 6.1%, placebo — 6.7 percent), nasopharyngitis (100 mg — 4,5%, 200 mg — 4,4%, placebo 3.3 percent).

CNS: headache (100 mg — 3,6%, 200 mg and 3.9%, placebo 3.6% respectively).

From the digestive system: diarrhea (100 mg — 3%, 200 mg and 2.6% with placebo and 2.3%), abdominal pain (100 mg and 2.3%, 200 mg and 1.3%, placebo 2.1 percent), nausea (100 mg and 1.4%, 200 mg% and 2.9%, placebo 0.6 percent), vomiting (100 mg is 0.8% of 200 mg, or 0.7%, placebo — 0.9 percent), diarrhea (100 mg — 3%, 200 mg is 2.6%, placebo and 2.3%).

From the side of musculoskeletal system: arthralgia (100 mg and 2.1%, 200 mg and 3.3%, placebo 1.8 percent).

From the endocrine system: hypoglycemia (100 mg — 1,2%, 200 mg and 0.9%, placebo — 0.9 percent).

From the laboratory parameters: at doses of 100 and 200 mg/day — increase uric acid levels of approximately 0.2 mg/DL compared with placebo (average rate of 5 to 5.5 mg/DL) in patients receiving the drug in a dose of 100 and 200 mg/day. Cases of gout is not registered.

A small reduction in the concentration of total alkaline phosphatase (approximately 5 IU/l compared with placebo, the average level 56-62 IU/l), partly associated with a small decrease in bone-alkaline phosphatase.

A small increase in the content of leukocytes (approximately 200/µl, compared with placebo, the average 6600/µl), due to the increase in the number of neutrophils. This observation was noted in most, but not all studies.

These changes in laboratory parameters is not considered clinically significant.

On the background of the drug of Januvia not observed clinically significant changes in vital signs and ECG (including QTc interval).

Januvia generally well tolerated both as monotherapy and in combination with other hypoglycemic drugs. In clinical studies, the overall incidence of side effects, as well as the frequency of cancellation of Januvia due to side effects were similar to those when receiving a placebo.

Drug interactions:

In studies of interaction with other drugs sitagliptin had no clinically significant effect on farmakokinetiku following preparations: Metformin, rosiglitazona, glibenclamide, simvastatin, warfarin, oral contraceptives. Therefore, sitagliptin does not inhibit isozymes CYP3A4, 2C9, or 2C8. Based on data obtained in vitro, sitagliptin is also not likely to inhibit CYP2D6, 1A2, 2C19 or 2B6 and does not induce CYP3A4.

There has been a slight increase in AUC (11%), and average Cmax (18%) of digoxin when used together with sitagliptin. This increase is not considered clinically significant. Not recommended dose change no digoxin, no drug Januvia in their simultaneous application.

There was an increase in AUC and Cmax of sitagliptin on 29% and 68% respectively in patients with joint application of Januvia at a dose of 100 mg and cyclosporine (a potent inhibitor of P-glycoprotein) in a dose of 600 mg. the changes of pharmacokinetic parameters of sitagliptin are not considered clinically significant. Not recommended changing the dose of Januvia when used together with cyclosporine and other inhibitors of P-glycoprotein (e.g. ketoconazole).

Population pharmacokinetic analysis in patients and healthy volunteers (n=858) receiving a wide range of concomitant medications (n=83, approximately half of which is excreted by the kidneys) did not reveal any clinically significant effects of drugs on the pharmacokinetics of sitagliptin.

Method of application and dose:

Inside. When used as monotherapy or in combination with Metformin or agonist of PPAR-&gamma (e.g. thiazolidinediones) recommended dose of 100 mg 1 time per day.

Januvia can be taken with or without food. If the patient missed receiving Januvia, the drug should be taken as soon as possible. Invalid receiving a double dose of Januvia.

In renal insufficiency, mild (creatinine Cl &ge50 ml/min, approximately corresponding to serum creatinine &le1,7 mg/DL in men, &le1. 5 mg/DL in women) correction dose is not required.

When kidney failure of moderate severity (creatinine Cl &ge30 ml/min but <50 ml/min, approximately corresponding to serum creatinine >1.7 mg/DL but &le3 mg/DL in males, >1.5 mg/DL but &le2. 5 mg/DL in women) dose — 50 mg 1 time a day.

In renal insufficiency, severe (creatinine Cl <30 ml/min, approximately corresponding to serum creatinine >3 mg/DL in men, >2.5 mg/DL in women), for patients with end-stage renal failure and needed hemodialysis dose 25 mg 1 times per day. Januvia can be applied regardless of the scheduling procedure of hemodialysis.

Overdose:

Symptoms: during clinical studies in healthy volunteers there was a good tolerability when taking Januvia at a dose of 800 mg. Minimal changes in QTc, not considered to be clinically significant, was noted in one study of the drug in the dose. Clinical studies of the drug in a dose of 800 mg/day was conducted.

Treatment: removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including ECG, if necessary, — symptomatic and supportive therapy.

Sitagliptin poorly cialisinuaecy. In clinical studies, only 13.5% the dose was removed from the body within 3-4 hour dialysis session. Prolonged dialysis can be administered in case of clinical necessity. Data about the effectiveness of peritoneal dialysis sitagliptin no.

Special instructions:

In clinical studies of the drug Januvia as monotherapy or as part of combination therapy with Metformin or pioglitazone, the incidence of hypoglycemia when using the drug of Januvia was similar to the frequency of hypoglycemia with placebo. The combined use of the drug Januvia in combination with drugs that can cause hypoglycemia, such as insulin, sulfonylureas, were not studied.

Patients with mild to moderate hepatic insufficiency dose adjustment of the drug Januvia not required. The drug has not been investigated in patients with severe hepatic insufficiency.

In clinical studies, the efficacy and safety of drug Januvia from elderly patients (&ge65 years, 409 patients) was comparable with these indices in patients younger than 65 years. Dose adjustment for age is required. Elderly patients are more likely to develop kidney failure. Accordingly, as in other age groups require dose adjustment in patients with renal insufficiency.

Effects on ability to drive vehicles and management mechanisms

There were no studies on the effects of the drug Januvia on the ability to drive vehicles. However, it is not expected negative impact of the drug on the ability to drive or complex mechanisms.