Universal reference book for medicines
Product name: JANUVIA (JANUVIA)

Active substance: sitagliptin

Type: Oral hypoglycemic drug

Manufacturer: MERCK SHARP & DOHME (The Netherlands)
Composition, form of production and packaging
The tablets covered with a film cover of
beige color, round, biconcave, with engraving "277" on one side and smooth - on the other.

1 tab.

sitagliptin (in the form of phosphate monohydrate) 100 mg

Excipients: microcrystalline cellulose, calcium hydrophosphate, sodium croscarmellose, magnesium stearate, sodium stearyl fumarate.

Sheath composition: Opadry II beige 85 F17438, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol) 3350, talc, iron oxide, yellow, iron oxide red.

14 pcs.
- packings cellular planimetric (2) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

The product description was approved by the manufacturer for the 2009 print edition.

PHARMACHOLOGIC EFFECT

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

Sitagliptin differs in chemical structure and pharmacological effect from analogues of glucagon-like peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, β-receptor-activated receptor agonists (PPAR-?), Alpha-glycosidase inhibitors, amylin analogs.
Inhibiting DPP-4, sitagliptin increases the concentration of 2 known hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic peptide (HIP). Hormones of the family of incretins are secreted in the intestine within 24 hours, their level rises in response to food intake. Incretiny are part of the internal physiological system of regulation of glucose homeostasis. At normal or elevated blood glucose levels, the hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion of β-cells of the pancreas due to signaling intracellular mechanisms associated with cyclic AMP.
GLP-1 also promotes suppression of increased secretion of glucagon-β-cells of the pancreas.
Reducing the concentration of glucagon on the background of increasing insulin levels helps to reduce the production of glucose by the liver, which eventually leads to a decrease in glycemia.
At a low blood glucose concentration, the listed effects of incretins on the release of insulin and the decrease in glucagon secretion are not observed.
GLP-1 and HIP do not affect the release of glucagon in response to hypoglycemia. In physiological conditions, the activity of incretins is limited to DPP-4, which rapidly hydrolyses incretins with the formation of inactive products.
Sitagliptin prevents the incretin hydrolysis by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and HIP.
Increasing the level of incretin, sitagliptin increases the glucose-dependent release of insulin and helps to reduce the secretion of glucagon. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in the secretion of insulin and glucagon lead to a decrease in the level of glycated hemoglobin HbA 1C and a decrease in plasma glucose concentration determined on an empty stomach and after a loading test.
In patients with type 2 diabetes mellitus, taking one dose of Yanuvia leads to inhibition of the activity of the DPP-4 enzyme within 24 hours, which leads to an increase in the level of circulating incretin GLP-1 and GIP by 2-3 times, an increase in the plasma concentration 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 has been studied in healthy individuals and patients with type 2 diabetes mellitus.

Suction

After ingestion of the drug in a dose of 100 mg in healthy individuals, rapid absorption of sitagliptin is achieved with the achievement of C max in 1-4 hours. AUC increases proportionally to the dose and is 8.52 μmol in healthy subjects.
h when taken in a dose of 100 mg, C max was 950 nmol.
The absolute bioavailability of sitagliptin is approximately 87%.
The intra- and interindividual coefficients of the variability of the sitagliptin AUC are insignificant.
Simultaneous reception of fatty foods does not affect the pharmacokinetics of sitagliptin, therefore the preparation of Yanuvia can be administered regardless of the meal.

Distribution

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

After a single dose of 100 mg, the average V d of sitagliptin in healthy volunteers was approximately 198 liters.
The binding of sitagliptin to plasma proteins is 38%.
Metabolism

Metabolized only a small part of the drug received in the body.
After the administration of 14 C-labeled sitagliptin, approximately 16% of the radioactive preparation was excreted inside its metabolites. Traces of six metabolites of sitagliptin, probably not possessing DPP-4 inhibitory activity, were found. In vitro studies, it was found that the primary enzyme involved in the restricted metabolism of sitagliptin is CYP3A4 with the participation of CYP2C8.
Excretion

Approximately 79% of sitagliptin is excreted unchanged in urine.

Within 1 week after receiving the drug with healthy volunteers, 14 C-labeled sitagliptin was excreted: with urine 87% and feces -13%.

T 1/2 sitagliptin for oral administration at a dose of 100 mg is approximately 12.4 hours. The renal clearance is approximately 350 ml / min.

The excretion of sitagliptin is carried out primarily by excretion by the kidneys according to the mechanism of active tubular secretion.
Sitagliptin is a substrate for the transporter of organic human anions of the third type (hOAT-3), which can be involved in the process of releasing sitagliptin by the kidneys. Clinically, the involvement of hOAT-3 in the transport of sitagliptin has not been studied. Sitagliptin is also a substrate of p-glycoprotein, which can also participate in the process of renal elimination of sitagliptin. However, cyclosporine, an inhibitor of p-glycoprotein, did not reduce renal clearance of sitagliptin.
Pharmacokinetics in special clinical cases

Patients with renal insufficiency

An open study of the drug Januvia in a dose of 50 mg / day was conducted to study its pharmacokinetics in patients with varying degrees of severity of chronic renal failure.
The patients included in the study were divided into groups of mild renal insufficiency (CK 50-80 ml / min), moderate (CK 30-50 ml / min) and severe renal failure (CK less than 30 ml / min), as well as patients with terminal stage renal pathology requiring dialysis.
In patients with mild renal insufficiency, there was no clinically significant change in the plasma sitagliptin concentration compared to the control group of healthy volunteers.

An increase in the AUC of sitagliptin was approximately 2-fold compared to the control group in patients with moderate-grade renal failure, approximately 4-fold increased AUC in patients with severe renal insufficiency, as well as in patients with end-stage renal disease compared with the control group .
Sitagliptin was slightly removed from the systemic blood flow by hemodialysis: only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session.
Thus, in order to achieve a therapeutic drug concentration in the blood plasma (similar to that in patients with normal renal function), patients with moderate and severe renal insufficiency require dose adjustment.

Patients with hepatic insufficiency

In patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), the average AUC and C max of sitagliptin with a single admission of 100 mg increase by approximately 21% and 13%, respectively.
Thus, correction of the dose of the drug with mild and moderate hepatic insufficiency is not required.
There are no clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale).
However, due to the fact that the drug is primarily excreted by the kidneys, there should not be a significant change in the pharmacokinetics of sitagliptin in patients with severe hepatic insufficiency.
Elderly patients

The age of the patients did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin.
In comparison with young patients, in elderly patients (65-80 years) the concentration of sitagliptin is approximately 19% higher. Correction of the dose of the drug according to age is not required.
INDICATIONS

- monotherapy: as a supplement to the diet and exercise to improve control of glycemia in type 2 diabetes mellitus;

- combination therapy: Type 2 diabetes mellitus to improve control of glycemia in combination with metformin or PPAR- agonists?
(eg, thiazolidinedione), when diet and exercise combined with monotherapy with the listed agents do not lead to adequate control of glycemia.
DOSING MODE

When used as a monotherapy or in combination with metformin or a PPAR- agonist?
(eg, thiazolidinedione), the recommended dose of Yanuvia is 100 mg 1 time / day.
Yanuvia can be taken regardless of food intake.
In case the patient missed the intake of Yanuvia, the drug should be taken as soon as possible. It is unacceptable to take a double dose of Yanuvia.
For renal insufficiency of mild severity (CK 50 ml / min , approximately corresponding to a serum creatinine content of 1.7 mg / dl in males, ≤ 1.5 mg / dl in women ), dose adjustment is not required.

For renal insufficiency of moderate severity (CK ≤ 30 mL / min, but <50 mL / min , approximately equivalent to a serum creatinine content of 1.7 mg / dL , but ≤ 3 mg / dl in men,> 1.5 mg / dL, but ≥ 2.5 mg / dL in women ), the dose of Yanuvia is 50 mg 1 time / day.

For severe renal insufficiency (CC <30 mL / min , approximately equivalent to 3 mg / dl serum creatinine in men,> 2.5 mg / dl in women ), for patients withterminal renal failure and the need for hemodialysis, the dose of Januvia is 25 mg once a day.
Yanuvia can be used regardless of the schedule of the procedure for hemodialysis.
SIDE EFFECT

There are side reactions that occurred without a causal relationship with taking Yanuvia in doses of 100 mg and 200 mg per day, but more often than with placebo.

On the part of the respiratory system: infections of the upper respiratory tract (100 mg - 6.8%, 200 mg - 6.1%, placebo - 6.7%), nasopharyngitis (100 mg - 4.5%, 200 mg - 4.4%, placebo - 3.3%).

From the side of the central nervous system: headache (100 mg - 3.6%, 200 mg - 3.9%, placebo - 3.6%).

From 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 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%).

From the musculoskeletal system: arthralgia (100 mg - 2.1%, 200 mg - 3.3%, placebo - 1.8%).

On the part of the endocrine system: hypoglycemia (100 mg - 1.2%, 200 mg - 0.9%, placebo - 0.9%).

From the laboratory parameters: at doses of 100 mg / day and 200 mg / day - an increase in uric acid by about 0.2 mg / dl compared with placebo (average level of 5-5.5 mg / dl) in patients receiving the drug at a dose of 100 mg / day and 200 mg / day.
No cases of gout development have been reported.
A slight decrease in the concentration of total APF (approximately 5 IU / L compared with placebo, an average level of 56-62 IU / L), partially associated with a small decrease in bone fraction of AP.

A slight increase in leukocyte count (approximately 200 / μL compared with placebo, an average level of 6600 / μL), caused by an increase in the number of neutrophils.
This observation was noted in the majority, but not in all studies.
The listed changes in laboratory indicators are not considered clinically significant.

Against the backdrop of Yanuvia, there were no clinically significant changes in vital signs and ECG (including the QTc interval).

Januvia as a whole is well tolerated both as a monotherapy and in combination with other hypoglycemic drugs.
In clinical trials, the overall incidence of side effects, as well as the frequency of cancellation of Yanuvia due to side effects, were similar to those observed with placebo.
CONTRAINDICATIONS

- Type 1 diabetes mellitus;

- diabetic ketoacidosis;

- Pregnancy;

- the period of lactation (breastfeeding);

- Hypersensitivity to the components of the drug.

It is not recommended to prescribe Januvia to children and adolescents under the age of 18 (there is no data on the use of the drug in pediatric practice).

With caution appoint to patients with renal insufficiency.
For renal insufficiency of moderate and severe severity, as well as for patients with terminal stage of renal failure who need hemodialysis, correction of the dosing regimen is required.
PREGNANCY AND LACTATION

Adequate and strictly controlled clinical safety studies of the drug Yanuvia in pregnant women have not been conducted.
The use of the drug during pregnancy is contraindicated.
It is not known whether sitagliptin is excreted in human breast milk.
If you need to use the drug during lactation, you should decide whether to stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with mild renal insufficiency (KK ≤50 mL / min, approximately equivalent to a serum creatinine content of 1.7 mg / dl in men, ≤ 1.5 mg / dL in women) are not required to correct the dose.

For patients with moderate-stage renal insufficiency (QC-30 mL / min, but <50 mL / min, approximately equivalent to a serum creatinine content of 1.7 mg / dL, but ≥3 mg / dl in men,> 1.5 mg / dL, but? 2.5 mg / dl in women), the dose of Yanuvia is 50 mg 1 time / day.

For patients with severe renal insufficiency (CK <30 mL / min, approximately equivalent to 3 mg / dl serum creatinine in men,> 2.5 mg / dl in women), for patients with terminal kidney disease and the need for hemodialysis, the dose of the drug Yanuvia is 25 mg 1 time / day.
Yanuvia can be used regardless of the schedule of the procedure for hemodialysis.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Patients with mild and moderate hepatic insufficiency do not need to adjust the dose of Januvia.
The drug has not been studied in patients with severe hepatic insufficiency.
APPLICATION FOR CHILDREN

It is not recommended to prescribe Januvia to children and adolescents under the age of 18 (there is no data on the use of the drug in pediatric practice).

APPLICATION IN ELDERLY PATIENTS

In clinical trials, the efficacy and safety of Januvia in elderly patients (≥65 years of age, 409 patients) were comparable to those in patients younger than 65 years of age.
Dose adjustment by age is not required. Older patients are more likely to develop kidney failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency.
SPECIAL INSTRUCTIONS

In clinical studies of Januvia as a monotherapy or as part of a combination therapy with metformin or pioglitazone, the incidence of hypoglycemia with Yanuvia was similar to the incidence of hypoglycemia with placebo.
The combined use of the drug Januvia in combination with drugs that can cause hypoglycemia, such as insulin, sulfonylureas, has not been investigated.
Patients with mild and moderate hepatic insufficiency do not need to adjust the dose of Januvia.
The drug has not been studied in patients with severe hepatic insufficiency.
In clinical trials, the efficacy and safety of Januvia in elderly patients (≥65 years of age, 409 patients) were comparable to those in patients younger than 65 years of age.
Dose adjustment by age is not required. Older patients are more likely to develop kidney failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency.
Impact on the ability to drive vehicles and manage mechanisms

There have been no studies to study the effect of the drug Yanuvia on the ability to drive vehicles.
However, the drug is not expected to have a negative effect on the ability to drive or complex machinery.
OVERDOSE

Symptoms: during clinical trials in healthy volunteers, there was good tolerability when taking Yanuvia in a single dose of 800 mg.
Minimal changes in the QTc interval, not considered clinically significant, were noted in one study of the drug at the indicated dose. Clinical studies of the drug in a dose of more than 800 mg / day were not carried out.
Treatment: removal of unabsorbed preparation from the digestive tract, monitoring of vital signs, including ECG, if necessary - conducting symptomatic and maintenance therapy.

Sitagliptin slightly dialyzed.
In clinical trials, only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session. Prolonged dialysis can be prescribed in the case of clinical necessity. There is no data on the efficacy of peritoneal dialysis of sitagliptin.
DRUG INTERACTION

In studies of interactions with other drugs, 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 the isoenzymes CYP3A4, 2C8 or 2C9. Based on the data obtained in vitro, sitagliptin also probably does not inhibit CYP2D6, 1A2, 2C19 or 2B6, nor does it induce CYP3A4.
There was a slight increase in AUC (11%), as well as in mean C max (18%) digoxin when combined with sitagliptin.
This increase is not considered clinically significant. We do not recommend any change in the dose of digoxin or drug Janow at their simultaneous application.
It was noted an increase in AUC and C max of sitagliptin at 29% and 68% respectively in patients with joint application Janow a single dose of 100 mg cyclosporin (a potent inhibitor of p-glycoprotein) in a single dose of 600 mg. These changes in sitagliptin pharmacokinetics parameters are not considered clinically significant. Not recommended dose change Janow drug when combined with cyclosporin and other inhibitors of p-glycoprotein (e.g., ketoconazole).
Population pharmacokinetic analysis in patients and healthy volunteers (n = 858) treated with a wide range of related formulations (n ​​= 83, approximately half of which are excreted by the kidneys) did not reveal any clinically significant effect of drugs on the pharmacokinetics of sitagliptin.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
Shelf life - 2 years.
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