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Januvia

Januvia
Januvia is prescribed both as monotherapy and in combination with other drugs that improve glycemic control.

Brand: Sitagliptin

Availability: In Stock
Average Delivery Time: 9 Days
Exp. Date: December 2023
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Januvia 100 mg
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Januvia 50 mg
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10 pills - 50 mg $55.25 $5.53 No Add to cart

Product description

Pharmacodynamics of the Januvia

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Januvia® (sitagliptin) is an active, orally administered, highly selective inhibitor of the DPP-4 enzyme, intended for the treatment of type 2 diabetes mellitus. peroxisome proliferator-activated gamma receptors (PPAR-γ), alpha-glucosidase inhibitors, amylin analogs. By inhibiting DPP-4, sitagliptin increases the concentration of two hormones of the incretin family: GLP-1 and GIP. Hormones of the incretin family are secreted in the intestine during the day, their concentration increases in response to food intake. Incretins are part of the internal physiological system of glucose homeostasis regulation. At normal or increased blood glucose concentration, hormones of the incretin family promote an increase in insulin synthesis, as well as its secretion by beta cells of the pancreas due to signaling intracellular mechanisms associated with cAMP.

GLP-1 also helps to suppress the increased secretion of glucagon by alpha cells in the pancreas. A decrease in glucagon concentration against the background of an increase in insulin concentration contributes to a decrease in the production of glucose by the liver, which ultimately leads to a decrease in glycemia. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin even at low blood glucose concentrations, which is fraught with the development of sulfonated hypoglycemia not only in patients with type 2 diabetes mellitus, but also in healthy individuals.

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 DPP-4 enzyme, which rapidly hydrolyzes incretins to form inactive products.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and GIP. By increasing the concentration of incretins, sitagliptin increases the glucose-dependent release of insulin and helps to reduce the secretion of glucagon. Patients with type 2 diabetes with hyperglycemia such changes insulin and glucagon secretion lead to lower concentrations HbA1c and decrease in plasma glucose concentration, determined by fasting and after loading the sample.

Patients with type 2 diabetes receiving a single dose of the drug Januvia® leads to inhibition of the enzyme DPP-4 for 24 hours, resulting in an increase in concentration of circulating incretins GLP-1 and GIP 2-3 times, rise of 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 after glucose load or food load.

Effect on blood pressure. In a randomized, placebo-controlled crossover study of patients with arterial hypertension sochetannyj antihypertensive drugs (one or more from the list of: ACE inhibitors, ARA II, CCB, beta-blockers, diuretics) with Januvia drug® was generally well tolerated by patients. In these patients the drug Januvia® demonstrated negligible hypotensive effect: in a daily dose of 100 mg sitagliptin lowered the average daily value outpatient Sad 2 mmHg compared to the placebo group. In patients with normal blood pressure, no hypotensive effect was observed.

Influence on the electrophysiology of the heart. In a randomized, placebo-controlled crossover study in healthy volunteers Januviaformulation® taken once at a dose of 100 or 800 mg of (8-fold excess of the recommended dose) or placebo. After taking the recommended therapeutic dose of 100 mg, no effect of the drug on the duration of the QT interval, both at the time of its plasma Cmax, and at other points of verification, was not observed throughout the study. After dosing with 800 mg, the maximum increase in placebo-corrected mean change in QT interval duration from baseline 3 hours after dosing was 8 ms. This slight increase was judged to be clinically insignificant. After taking a dose of 800 mg, the plasma Cmax of sitagliptin was approximately 11 times higher than the corresponding value after taking a therapeutic dose of 100 mg.

Study to evaluate the cardiovascular safety of sitagliptin (TECOS). Thestudy TECOS patients received drug Januvia® 100 mg per day (or 50 mg per day if the baseline of estimated GFR (eGFR) was ≥30 and <50 mL / min / 1.73 m2)or placebo, are added to the standard therapy according to existing national standards to determine the target levels HbA1c and control of cardiovascular risk factors. Upon completion of the average observation period is 3 years, patients with type 2 diabetes receiving Januviapreparation® in addition to standard therapy is not increased risk of serious adverse effects from the CAS (hazard ratio - 0.98; 95% CI: 0.89 –1.08; p <0.001 to prove no superiority) or the risk of hospitalization due to heart failure (hazard ratio - 1; 95% CI: 0.83–1.2; p = 0.98 for the difference in risk frequency), according to compared with standard treatment without additional administration of Januvia®.

Pharmacokinetics

The pharmacokinetics of sitagliptin have been comprehensively described in healthy individuals and patients with type 2 diabetes mellitus. In healthy individuals, after oral administration of 100 mg sitagliptin, rapid absorption of the drug is noted, reaching Cmax in the interval from 1 to 4 hours from the moment of administration. AUC increases in proportion to the dose and in healthy subjects is 8.52 μmol / l · h when taken orally 100 mg, Cmax was 950 nmol / l. The plasma AUC of sitagliptin increased by approximately 14% after the next dose of 100 mg of the drug, after reaching equilibrium after the first dose. The intra- and intersubjective coefficients of variation in sitagliptin AUC were insignificant.

Absorption. The absolute bioavailability of sitagliptin is approximately 87%. Because the co-administration of the drug Januvia ® and greasy food has no effect on the pharmacokinetics, the preparation Januvia® may be assigned regardless of the meal.

Distribution. The average Vss after a single dose of 100 mg sitagliptin in healthy volunteers is approximately 198 liters. The fraction of sitagliptin that binds to plasma proteins is relatively low and amounts to 38%.

Metabolism. Approximately 79% of sitagliptin is excreted unchanged by the kidneys. Only a small part of the drug that has entered the body is metabolized. Afteradministration of 14oralC-labeled sitagliptin, approximately 16% of the radioactive sitagliptin was excreted as its metabolites. Traces of 6 sitagliptin metabolites were found, probably lacking DPP-4 inhibitory activity. In vitro studies have shown that the primary isoenzymes involved in the limited metabolism of sitagliptin are CYP3A4 and CYP2C8.

Excretion. Afteradministration of 14oralC-labeled sitagliptin to healthy volunteers, approximately 100% of the administered sitagliptin was excreted as follows: 13% through the intestines, 87% by the kidneys within one week after taking the drug. The average T1/2 of sitagliptin with oral administration of 100 mg is approximately 12.4 hours; renal clearance is approximately 350 ml / min.

Excretion of sitagliptin is carried out primarily by excretion by the kidneys through the mechanism of active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter of the third type (hOAT-3), which may be involved in the process of excretion of sitagliptin by the kidneys. The clinical involvement of hOAT-3 in sitagliptin transport has not been studied. Sitagliptin is also a P-gp substrate that may be involved in the process of excretion of sitagliptin by the kidneys. However, cyclosporine, which is a P-gp inhibitor, did not decrease the renal clearance of sitagliptin.

Separate groups of patients

Renal dysfunction. Open study drug Januvia® dose of 50 mg / day was conducted to study its pharmacokinetics in patients with varying severity of chronic renal impairment as compared to the control group of healthy volunteers. The study included patients with mild, moderate, and severe renal impairment, as well as patients with end-stage CKD requiring dialysis. In addition, the effect of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (including those with end-stage CKD) was assessed using population pharmacokinetic analyzes.

An increase in the plasma AUC of sitagliptin approximately 1.2 and 1.6 times compared with the control group was observed in patients with impaired renal function of mild (eGFR from ≥60 to <90 ml / min / 1.73 m2) and average (eGFR from ≥45 to <60 ml / min / 1.73 m2) severity, respectively. Since an increase in this value is not clinically significant, dose adjustment in these patients is not required. Approximately two-fold increase in the plasma AUC of sitagliptin was observed in patients with impaired renal function moderate severity (eGFR of ≥30 to <60 mL / min / 1.73 m2)and about a four-fold - in patients with impaired renal function, severe (eGFR <30 ml / min / 1.73 m2), including patients with end-stage CKD requiring dialysis. An insignificant amount of sitagliptin was removed during the hemodialysis procedure: only 13.5% of the administered dose was excreted from the body during a 3-4-hour dialysis session started 4 hours after drug administration. Thus, to achieve a therapeutic concentration of sitagliptin in blood plasma (similar to that in patients with normal renal function) in patients with eGFR <45 ml / min / 1.73 mDosage and Administration2 , lower doses are recommended (see "" ).

Liver dysfunction. In patients with moderate liver dysfunction (7-9 points on the Child-Pugh scale), the average AUC and Cmax of sitagliptin after a single dose of 100 mg increase by approximately 21 and 13%, respectively, compared with the control group of healthy volunteers. Thus, dose adjustment for mild and moderate liver dysfunctions is not required.

There are no clinical data on the use of sitagliptin in patients with severe liver dysfunction (> 9 points on the Child-Pugh scale). However, due to the fact that sitagliptin is primarily excreted by the kidneys, one should not expect a significant change in the pharmacokinetics of sitagliptin in patients with severe liver dysfunction.

Elderly patients. Patient age did not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared with young patients, in elderly patients (65–80 years), the concentration of sitagliptin is approximately 19% higher. No dose adjustment depending on age is required.

Indications preparation Januvia®

Januvia for the treatment of diabetes

monotherapy

Januvia® shown as an adjunct to diet and exercise to improve glycemic control in patients with diabetes mellitus type 2.

Combination therapy

Kombirirovaniewith metformin. Januvia® in combination with metformin in patients with type 2 diabetes mellitus to improve glycemic control as a starting therapy or when diet and exercise in combination with monotherapy with one of the listed drugs do not lead to adequate glycemic control.

Combination with sulfonylurea derivatives. Januvia® in combination with sulfonylurea derivatives in patients with type 2 diabetes mellitus to improve glycemic control, when diet and exercise in combination with monotherapy with one of the listed drugs do not lead to adequate glycemic control.

Combination with PPAR-γ agonists. Januvia® in combination with PPAR-γ agonists (thiazolidinediones) in patients with type 2 diabetes mellitus to improve glycemic control, when diet and exercise in combination with monotherapy with one of the listed drugs do not lead to adequate glycemic control;

Combination with metformin and sulfonylurea derivatives. Januvia® in combination with metformin and sulfonylurea derivatives in patients with type 2 diabetes mellitus to improve glycemic control, when diet and exercise in combination with therapy with two of the listed drugs do not lead to adequate glycemic control;

Combination with metformin and PPAR-γ agonists. Januvia formulation® in combination with metformin and agonists of PPAR-γ (thiazolidinediones) in patients with type 2 diabetes mellitus to improve glycemic control as diet and physical activity in combination therapy with two of these preparations does not lead to adequate glycemic control;

Combination with insulin. Januvia® as an insulin supplement (with or without metformin) in patients with type 2 diabetes mellitus in cases where diet, exercise and a stable dose of insulin do not lead to adequate glycemic control.

Method of administration and dosage of the Januvia

 Januvia drug packaging

Is taken orally. The recommended dose of Januvia® is 100 mg once a day as monotherapy or in combination with metformin, or sulfonylurea derivatives, or PPAR-γ agonists (thiazolidinediones), or insulin (with or without metformin), or in combination with metformin and a derivative sulfonylureas; or metformin and PPAR-γ agonists.

Januvia® can be taken with or without food. The dosage regimen of metformin, sulfonylurea derivatives and PPAR-γ agonists should be selected based on the recommended doses for these drugs.

When combining Januvia® with sulfonylurea derivatives or insulin, it is advisable to reduce the traditionally recommended dose of a sulfonylurea or insulin derivative to reduce the risk of sulfone-induced or insulin-induced hypoglycemia (see "Special instructions", Hypoglycemia).

If the patient missed taking Januvia®, the drug should be taken as soon as possible after the patient remembers about the missed dose.

It is unacceptable to take a double dose of Januvia® on the same day.

Special groups of patients

Renal dysfunction. Given the need to dose adjustment for patients with impaired renal function is recommended to assess renal function prior to initiation of treatment Januvia® and periodically during treatment.

Patients with impaired mild renal function (eGFR of ≥60 to <90 mL / min / 1.73 m2)dose correction Januvia® not required.

Patients with impaired moderate renal function (eGFR of ≥45 to <60 mL / min / 1.73 m2)dose correction Januvia® not required.

Patients with impaired renal function, moderate (eGFR of ≥30 to <45 mL / min / 1.73 m2)Dose preparation Januvia® 50 mg 1 time per day.

Patients with impaired renal function, severe (eGFR of ≥15 to <30 mL / min / 1.73 m2)or end-stage CKD (eGFR <15 mL / min / 1.73 m2)requiring hemodialysis or peritoneal dialysis, the dose of Januvia® is 25 mg once a day. Januvia® can be used regardless of the dialysis schedule.

Liver dysfunction. Not required drug dose Januvia correction® in patients with impaired liver mild to moderate severity function. The drug has not been studied in patients with severe liver dysfunction.

Elderly patients. No dose adjustment of Januviarequired® is in elderly patients.

Overdose

During clinical studies in healthy volunteers, a single dose of 800 mg drug Januvia® was generally well tolerated. Minimal changes QTc interval not considered clinically significant, were recorded in one study drug Januvia® in a dose of 800 mg / day. Doses over 800 mg / day have not been studied in humans.

In phase I clinical studies multiple receiving any drug treatment-related Januvia® adverse reactionswhile taking the drug in a daily dose of 400 mg for 28 days did not observed.

Treatment: in case of an overdose, it is necessary to start standard supportive measures - removing the unabsorbed drug from the gastrointestinal tract, monitoring vital signs, including ECG, and prescribing supportive therapy, if required.

Sitagliptin is poorly dialyzed. In clinical studies, only 13.5% of the dose was removed from the body during a 3–4 hour dialysis session. Prolonged dialysis can be prescribed if clinically necessary. There are no data on the effectiveness of sitagliptin peritoneal dialysis.

Special instructions

Pancreatitis. There have been reports of the development of acute pancreatitis, including hemorrhagic or necrotic with fatal and non-fatal outcome, in patients taking sitagliptin (see "Side effects"). Patients should be informed about the characteristic symptoms of acute pancreatitis - persistent, severe abdominal pain. The clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin. If you suspect pancreatitis, you should stop taking Januvia® and other potentially dangerous drugs.

Hypoglycemia. According to clinical studies of the drug Januvia®,incidence of hypoglycemia in monotherapy and combination therapy with drugs that do not cause hypoglycemia (metformin, pioglitazone), was comparable to the incidence of hypoglycemia in the placebo group. As in the case of taking other hypoglycemic drugs in conjunction with sulfonylurea or insulin, the incidence of hypoglycemia when using sitagliptin in combination with insulin or sulfonylurea derivatives was higher than when taking placebo (see "Side Effects"). In order to reduce the risk of insulin- or sulfone-induced hypoglycemia, the dose of insulin or a sulfonylurea derivative should be reduced (see "Dosage and Administration").

Hypersensitivity reactions. In the course of post-marketing monitoring of the use of Januvia® , serious hypersensitivity reactions were identified. These reactions included anaphylaxis, angioedema, exfoliative skin diseases, including Stevens-Johnson syndrome. Since these data were obtained voluntarily from a population of uncertain size, the frequency and causality of these reactions with therapy cannot be determined. These reactions occurred within the first 3 months after beginning treatment with Januvia®,some were observed after the first dose. If the development of a hypersensitivity reaction is suspected, it is necessary to stop taking Januvia®, evaluate other possible causes of the adverse event and prescribe another drug therapy for the treatment of diabetes mellitus (see "Contraindications", "Side effects").

Use in the elderly. The efficacy and safety of the drug JanuviaIn clinical trials® in elderly patients (≥65 years, 409 patients) were comparable to those indicators in patients younger than 65 years. No dose adjustment depending on age is required. Elderly patients are more likely to develop renal impairment. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal impairment (see "Dosage and Administration").

Bullous pemphigoid. There have been reports of post-registration cases of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. In the reported cases, patients recovered from either topical or systemic immunosuppressive therapy and discontinuation of the DPP-4 inhibitor. Patients should be informed of the need to report on the development of blisters or ulcers during treatment with Januvia®.In case of suspicion of bullous pemphigoid, it is necessary to stop taking Januvia® and consult a dermatologist for diagnosis and appropriate treatment.

Influence on the ability to drive vehicles and work with mechanisms. No studies have been conducted to study the effect of Januvia® on the ability to drive vehicles and work with mechanisms. Nevertheless, the negative effect of Januviais not expected® on the ability to drive vehicles and work with mechanisms.

Contraindications

Hypersensitivity to any of the components of the drug;

  • type 1 diabetes mellitus;
  • diabetic ketoacidosis;
  • pregnancy;
  • period of breastfeeding;
  • children under 18 years of age.

With caution: impaired renal function (the main route of excretion of sitagliptin from the body is renal excretion. To achieve the same plasma concentrations as in patients with normal renal function, patients with eGFR <45 ml / min / 1.73 m2, as well as patients with end-stage chronic kidney disease requiring hemodialysis or peritoneal dialysis should adjust (reduce) the dose of JanuviaDosage and Administration® (see "", Renal dysfunction); pancreatitis (see "Special instructions", Pancreatitis) .

Pregnancy and breast-feeding

there have been no controlled studies of Januviadrug® in pregnant women, therefore, no safety data of its use in pregnant women. The drug Januvia®,as well as other oral hypoglycemic agents are not recommended for use during pregnancy.

no data on the penetration of sitagliptin into breast milk.Consequently, Januvia® should not be prescribed during breastfeeding feeding.


Side effects

Overview of the safety profile

Serious adverse events have been reported, including pancreatitis and hypersensitivity reactions. Hypoglycemia was recorded when the drug was taken in combination with sulfonylurea (4.7-13.8%) and insulin (9.6%) (see “Special instructions”).

The incidence of adverse events identified in placebo-controlled clinical trials of sitagliptin in monotherapy and during post-registration observation.

Adverse events are listed below by system organ classes and frequency. Frequencies are defined as: very often (≥1 / 10); often (≥1 / 100 - <1/10); infrequently (≥1 / 1000 - <1/100); rarely (≥1 / 10000 - <1/1000); very rare (<1/10000); frequency not set (cannot be set based on available data).

On the part of the blood and lymphatic system: rarely - thrombocytopenia.

From the side of the immune system: the frequency has not been established - hypersensitivity reactions, incl. anaphylaxis *, **.

From the side of metabolism and nutrition: often - hypoglycemia **.

From the nervous system: often - headache; infrequently - dizziness.

From the respiratory system, chest and mediastinal organs: frequency not established - interstitial lung disease *.

From the gastrointestinal tract: infrequently - constipation; frequency not established - vomiting *, acute pancreatitis *, **, ***, fatal and non-fatal hemorrhagic and necrotizing pancreatitis *, **.

From the skin and subcutaneous tissues: infrequently - itching *; frequency not established - angioedema *, **, rash *, **, urticaria *, **, cutaneous vasculitis *, **, exfoliative skin diseases, including Stevens-Johnson syndrome *, **, bullous pemphigoid *.

From the musculoskeletal system and connective tissue: the frequency has not been established - arthralgia *, myalgia *, back pain *, arthropathy *.

From the side of the kidneys and urinary tract: the frequency has not been established - impaired renal function *, acute renal failure *.

Description of selected adverse events

In addition to the drug-related adverse events described above, adverse events were recorded regardless of the presence of a drug-related relationship if they developed in at least 5% or more of patients receiving sitagliptin, incl. upper respiratory tract infections and nasopharyngitis. Adverse events that were subject to registration additionally, regardless of the presence of a connection with the drug, were reactions that developed more often in patients receiving sitagliptin (the frequency did not reach the 5% level, but was more than 0.5% higher in the sitagliptin groups compared with control group); these included osteoarthritis and limb pain.

Some adverse events were reported more often in studies with the combined use of sitagliptin and other antihyperglycemic drugs than in studies of sitagliptin monotherapy. These included hypoglycemia (frequency: very often in combination with sulfonylureas and metformin), influenza (often with insulin (with and without metformin), nausea and vomiting (often in combination with metformin), bloating (often when used together) with metformin or pioglitazone), constipation (often when used in combination with sulfonylureas and metformin), peripheral edema (often when used in combination with pioglitazone or a combination of pioglitazone and metformin), drowsiness and diarrhea (rarely in combination with metformin), and dryness during mouth (infrequently in combination with insulin (with and without metformin)

TECOS Sitagliptin Cardiovascular Safety Study The TECOS

study enrolled 7,332 patients who took sitagliptin 100 mg daily (or 50 mg daily if baseline eGFR was ≥30 and <50 mL / min / 1.73 m2)and 7339 patients receiving placebo in the general population of patients who received treatment(intention-to-treat). The study drug (sitagliptin or placebo) was added to standard therapy according to existing national standards for choosing HbA1target levelc and control of cardiovascular risk factors. The overall incidence of serious adverse events in patients taking sitagliptin was the same as in patients taking placebo.

In the population of patients who were prescribed treatment (intention-to-treat), among those who initially received insulin therapy and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 2.7% in patients taking sitagliptin, and 2.5% in patients taking placebo. Among patients initially not receiving insulin and / or sulfonylureas, the incidence of episodes of severe hypoglycemia was 1% in patients taking sitagliptin and 0.7% in patients taking placebo. The incidence of expert-confirmed cases of pancreatitis was 0.3% in patients taking sitagliptin and 0.2% in patients taking placebo.