Januvia film-coated tablets 100 mg No. 28

Instructions for Januvia film-coated tablets 100 mg No. 28

Composition

active ingredient: sitagliptin;

1 film-coated tablet contains sitagliptin phosphate hydrate equivalent to 100 mg sitagliptin;

excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate;

tablet shell: Opadry® II beige dye.

Dosage form

Film-coated tablets.

Main physicochemical properties:

round, biconvex, film-coated tablets, beige in color, with "277" on one side and smooth on the other.

Pharmacotherapeutic group

Hypoglycemic agents, except insulins Dipeptidyl peptidase 4 inhibitors.

ATX code A10V H01.

Pharmacological properties

Pharmacodynamics.

Januvia (sitagliptin) is an orally active, highly selective inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4) that is indicated for the treatment of type 2 diabetes mellitus. Sitagliptin differs in chemical structure and pharmacological action from glucagon-like peptide-1 (GLP-1) analogues, insulin, sulfonylureas, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glycosidase inhibitors, and amylin analogues. By inhibiting DPP-4, sitagliptin increases the concentration of two known hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic peptide (GIP). Incretin hormones are secreted in the intestine throughout the day and their levels increase in response to food intake. Incretins are part of the intrinsic physiological system for regulating glucose homeostasis. At normal or elevated blood glucose levels, hormones of the incretin family contribute to increased insulin synthesis and secretion by pancreatic beta cells through intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also helps to suppress the increased secretion of glucagon by pancreatic alpha cells. A decrease in glucagon concentration with an increase in insulin levels contributes to a decrease in glucose production by the liver, which ultimately leads to a decrease in glycemia.

At low blood glucose concentrations, the effects of incretins on insulin release and decreased 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 enzyme DPP-4, which rapidly hydrolyzes incretins to form inactive products.

Sitagliptin prevents the hydrolysis of incretins by the enzyme DPP-4, thereby increasing the plasma concentrations of the active forms of GLP-1 and GIP. By increasing the level of incretins, sitagliptin increases glucose-dependent insulin release and contributes to a decrease in glucagon secretion. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in the level of glycosylated hemoglobin A1c (HbA1c) and a decrease in plasma glucose concentrations in fasting and after a stress test.

The glucose-dependent mechanism of action of sitagliptin differs from that of sulfonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycemia in patients with type 2 diabetes and in healthy volunteers. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

In a 2-day study in healthy volunteers, sitagliptin administered alone increased active GLP-1 concentrations, while metformin administered alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.

Clinical efficacy and safety

Sitagliptin improved glycaemic control when used as monotherapy or as part of combination therapy in adult patients with type 2 diabetes (see Table 1).

Table 1.

HbA1c results from placebo-controlled monotherapy and combination therapy studies*.

*All population of patients who received treatment (analysis of patients who started treatment).

†Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.

‡p < 0.001 compared to placebo or placebo + combination treatment.

§HbA1c (%) at week 18.

||HbA1c (%) at week 24.

#HbA1c (%) at week 26.

¶Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (premixed vs. unmixed [intermediate- or long-acting]), and baseline value. The treatment interactions (metformin and insulin use) were not significant (p > 0.10).

The TECOS Cardiovascular Safety Study of Sitagliptin was a randomized study of 14,671 patients with HbA1c ≥ 6.5 to 8.0% and established cardiovascular disease who received sitagliptin (7,332) 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate (eGFR) was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7,339) in addition to standard therapy guided by regional standards for HbA1c and cardiovascular risk factors. Patients with eGFR < 30 mL/min/1.73 m2 were not included in the study. The study included 2,004 patients ≥ 75 years of age and 3,324 patients with renal insufficiency (eGFR < 60 mL/min/1.73 m2).

During the study, the estimated mean (SD) difference in HbA1c between sitagliptin and placebo was 0.29% (0.01), 95% CI (-0.32, -0.27); p < 0.001.

The primary cardiovascular endpoint was: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints were: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; first occurrence of individual components of the primary endpoint; all-cause mortality; and hospitalization for congestive heart failure.

After a median follow-up of 3 years, sitagliptin added to standard therapy did not increase the risk of serious adverse cardiovascular events or the risk of hospitalization for heart failure compared with standard therapy without sitagliptin in patients with type 2 diabetes (Table 2).

Table 2.

Incidence of composite and major secondary cardiovascular endpoints.

†Based on Cox model stratified by region. For composite endpoints, p-values meet the criterion for non-inferiority to demonstrate a hazard ratio of less than 1.3. For all other endpoints, p-values meet the criterion for differences in risk ratios.

‡The analysis of hospitalization for heart failure was adjusted for history of heart failure.

Children

A 54-week, double-blind study was conducted to evaluate the efficacy and safety of sitagliptin 100 mg once daily in children (aged 10 to 17 years) with type 2 diabetes mellitus who were not on antihyperglycemic therapy for at least 12 weeks (with HbA1c 6.5-10%) or who were on a stable dose of insulin for at least 12 weeks (with HbA1c 7-10%). Patients were randomized to receive sitagliptin 100 mg once daily or placebo for 20 weeks.

The mean baseline HbA1c was 7.5%. Treatment with sitagliptin 100 mg did not significantly improve HbA1c over 20 weeks. The reduction in HbA1c in patients treated with sitagliptin (N = 95) was 0.0% compared with 0.2% in patients treated with placebo (N = 95), a difference of -0.2% (95% CI: -0.7, 0.3) (see Paediatric population).

Pharmacokinetics.

The pharmacokinetics of sitagliptin were generally similar in healthy volunteers and patients with type 2 diabetes. In healthy volunteers, after oral administration of 100 mg of sitagliptin, rapid absorption of the drug is observed, with maximum concentration (Cmax) achieved within 1 to 4 hours after administration. The area under the concentration-time curve (AUC) increases proportionally to the dose and is 8.52 μM h in healthy volunteers when administered 100 mg orally, Cmax was 950 nM, and the mean half-life was 12.4 hours.

Absorption

The absolute bioavailability of sitagliptin is approximately 87%. Since the combined administration of Januvia and fatty food does not affect the pharmacokinetics, Januvia can be administered regardless of food intake.

Distribution

The mean volume of distribution at steady state after a single 100 mg dose of sitagliptin in healthy volunteers is approximately 198 L. The fraction of sitagliptin bound to plasma proteins is relatively low and is 38%.

Metabolism

Approximately 79% of sitagliptin is excreted unchanged in the urine. Only a small portion of the administered drug is metabolized.

Following an oral dose of [14C] sitagliptin, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the DPP-4 inhibitory activity of sitagliptin in plasma. In vitro studies have shown that the major enzyme responsible for the limited metabolism of sitagliptin is CYP3A4 and, to some extent, CYP2C8.

In vitro data have shown that sitagliptin is not an inhibitor of CYP isozymes such as CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6, and is not an inducer of CYP3A4 and CYP1A2.

Breeding

Following oral administration of [14C]-labeled sitagliptin to healthy volunteers, approximately 100% of the administered drug was excreted within one week of dosing: 13% via the intestines and 87% via the kidneys. The mean elimination half-life of sitagliptin following oral administration of 100 mg is approximately 12.4 hours; renal clearance is approximately 350 mL/min.

Sitagliptin is eliminated primarily by renal excretion via a mechanism of active tubular secretion.

Pharmacokinetics in specific patient groups

Patients with renal insufficiency

An open-label, single-dose study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50 mg) in patients with varying degrees of chronic renal failure compared with healthy control subjects. The study included patients with mild, moderate, and severe renal failure, as well as patients with end-stage chronic renal failure (ESRD) undergoing hemodialysis. In addition, the effect of renal impairment on the pharmacokinetics of sitagliptin in patients with type 2 diabetes and mild, moderate, or severe renal failure (including ESRD) was evaluated using a population pharmacokinetic analysis.

Compared with healthy control subjects, plasma AUC values of sitagliptin were approximately 1.2-fold and 1.6-fold higher in patients with mild renal impairment (GFR ≥ 60 to <90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to <60 mL/min), respectively. Since this increase is not clinically relevant, no dose adjustment is required in these patients.

Plasma AUC values of sitagliptin were approximately 2-fold higher in patients with moderate renal impairment (GFR ≥ 30 to < 45 mL/min) and approximately 4-fold higher in patients with severe renal impairment (GFR < 30 mL/min), including patients with CKD on hemodialysis. Sitagliptin was moderately removed by hemodialysis (13.5% during a 3-4 hour hemodialysis session, which was started 4 hours after dosing). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower doses are recommended in patients with GFR < 45 mL/min (see section 4.2).

No dose adjustment of Januvia is required in patients with mild or moderate hepatic impairment (≤ 9 points on the Child-Pugh scale). There are no clinical data on the use of sitagliptin in patients with severe hepatic impairment (> 9 points on the Child-Pugh scale). However, due to the primary renal excretion of the drug, severe hepatic impairment does not affect the pharmacokinetics of sitagliptin.

Elderly patients

Age of patients has no clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared with young patients, elderly patients (65-80 years) have an approximately 19% higher concentration of sitagliptin. No dose adjustment is required based on patient age.

Children

The pharmacokinetics of sitagliptin (single doses of 50 mg, 100 mg, or 200 mg) have been studied in children (aged 10 to 17 years) with type 2 diabetes. In this population, the AUC of sitagliptin at the adjusted dose was approximately 18% lower compared to that in adult patients with type 2 diabetes at the 100 mg dose. This is not considered a clinically meaningful difference given the direct pharmacokinetic/pharmacodynamic relationship between the 50 mg and 100 mg doses. Sitagliptin has not been studied in children under 10 years of age.

Other patients

No dose adjustment is necessary based on gender, race, or body mass index, as these characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin.

Indication

In adult patients with type 2 diabetes, Januvia is indicated to improve glycemic control:

as monotherapy:

when the patient's condition is not adequately controlled with diet and exercise alone and when metformin cannot be used due to contraindications or intolerance;

as dual oral therapy in combination with:

metformin, when diet and exercise combined with metformin alone do not provide adequate glycemic control;

sulfonylurea, when diet and exercise combined with the maximum tolerated dose of sulfonylurea alone do not provide adequate glycemic control and when metformin cannot be used due to contraindications or intolerance;

a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) when the use of a PPARγ agonist is appropriate and when diet and exercise combined with a PPARγ agonist alone do not provide adequate glycaemic control;

as triple oral therapy in combination with:

sulfonylurea and metformin, when diet and exercise combined with dual therapy with these drugs do not provide adequate glycemic control;

PPARγ agonist and metformin, when the use of a PPARγ agonist is appropriate and when diet and exercise combined with dual therapy with these medicinal products do not provide adequate glycaemic control.

Januvia is also indicated as an adjunct to insulin (with or without metformin) when diet and exercise combined with a stable dose of insulin do not provide adequate glycemic control.

Contraindication

Hypersensitivity to any of the components of the drug.

Type 1 diabetes.

Diabetic ketoacidosis.

Interaction with other medicinal products and other types of interactions

Metformin.

Coadministration of metformin 1000 mg and sitagliptin 50 mg twice daily for a long period of time did not significantly alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Cyclosporine.

A study was conducted to investigate the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single oral dose of 100 mg sitagliptin and a single oral dose of 600 mg cyclosporine increased the area under the concentration-time curve (AUC) and Cmax of sitagliptin by approximately 29% and 68%, respectively. No clinically significant drug interactions were observed with cyclosporine and other p-glycoprotein inhibitors.

CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin).

In vitro studies have shown that the main enzyme responsible for the limited metabolism of sitagliptin is CYP3A4 and, to a lesser extent, CYP2C8. In patients with normal renal function, metabolism, including CYP3A4 metabolism, plays a minor role in the clearance of sitagliptin. Metabolism may play a greater role in the elimination of sitagliptin in patients with severe renal impairment or end-stage chronic renal failure (ESRD). Therefore, CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) may alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD.

In vitro transport studies have shown that sitagliptin is a substrate for organic anion transporter 3 (OAT3) and p-glycoprotein. OAT3-mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically significant interactions is considered low. Concomitant use of OAT3 inhibitors has not been evaluated in vivo.

In vitro data suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical studies, sitagliptin did not significantly alter the pharmacokinetics of metformin, glibenclamide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of low potential for interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and the organic cation transporter (OCT). Sitagliptin may be a weak inhibitor of p-glycoprotein in vivo.

Digoxin.

Sitagliptin has a small effect on the plasma concentration of digoxin. After concomitant administration of 0.25 mg of digoxin with 100 mg of Januvia per day for 10 days, the area under the plasma concentration-time curve for digoxin increased by an average of 11% and plasma Cmax by an average of 18%. No dose adjustment of digoxin is recommended.

However, patients at risk of developing digoxin toxicity should be carefully monitored if sitagliptin and digoxin are taken concomitantly.

Application features

Acute pancreatitis

DPP-4 inhibitors are associated with a risk of acute pancreatitis. Acute pancreatitis, such as necrotizing or hemorrhagic pancreatitis, and/or death have been reported (see section 4.8). Patients should be informed of the characteristic symptom of acute pancreatitis, persistent, severe abdominal pain. Symptoms of pancreatitis resolved after discontinuation of sitagliptin (with or without maintenance therapy). If pancreatitis is suspected, Januvia should be discontinued; if acute pancreatitis is confirmed, Januvia should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Hypoglycemia

In clinical trials of Januvia as monotherapy or in combination with metformin or a PPARγ agonist (thiazolidinedione), the incidence of hypoglycemia was similar to that seen with placebo. As with other antihyperglycemic agents, hypoglycemic episodes have been observed with Januvia when used in combination with insulin or a sulfonylurea. Therefore, a lower dose of sulfonylurea or insulin should be used to reduce the risk of hypoglycemia (see section 4.8).

Kidney failure

Januvia is excreted by the kidneys. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower doses are recommended for patients with GFR < 45 ml/min and for patients with CKD requiring hemodialysis or peritoneal dialysis (see sections 4.2 and 5.1).

When considering the use of sitagliptin in combination with another antidiabetic drug, the specifics of its use in patients with renal insufficiency should be checked.

Hypersensitivity reactions

Serious allergic reactions have been reported in the post-marketing setting with Januvia. These reactions include anaphylaxis, angioedema, and exfoliative skin reactions, including Stevens-Johnson syndrome (see Adverse Reactions). These reactions have occurred within the first 3 months of treatment with Januvia, and sometimes after the first dose. If an allergic reaction is suspected, Januvia should be discontinued, other potential causes of the reaction evaluated, and alternative diabetes treatment should be considered.

Bullous pemphigoid

During post-marketing surveillance, cases of bullous pemphigoid have been reported in patients receiving DPP-4 inhibitors, including sitagliptin. If bullous pemphigoid is suspected, Januvia should be discontinued.

Sodium

This medicine contains less than 1 mmol (23 mg) sodium per tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Controlled clinical studies of Januvia have not been conducted in pregnant women, therefore the drug is not recommended for use during pregnancy.

There is no data on the excretion of sitagliptin into breast milk, therefore the drug is not prescribed during breastfeeding.

Animal studies have shown reproductive toxicity when the drug is used in high doses.

Animal studies do not indicate a potential effect of sitagliptin treatment on male or female fertility. The potential risk for humans is unknown.

There are no data from studies involving humans.

The ability to influence the reaction speed when driving or working with other mechanisms

When driving or working with other mechanisms, it is recommended to exercise special caution, taking into account the possibility of developing undesirable reactions from the nervous system (dizziness, drowsiness).

Patients should be warned about the risk of hypoglycemia when using Januvia as part of combination therapy.

Method of administration and doses

When Januvia is prescribed in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin is considered to reduce the risk of hypoglycemia (see section 4.4).

If a patient misses a dose, the dose should be taken as soon as possible after the patient remembers. It is not permissible to take a double dose of Januvia on the same day.

Januvia can be taken regardless of meals.

Patients with renal impairment

Since the dose depends on renal function, it is recommended to assess renal function before starting the drug and periodically during treatment.

Patients with mild renal impairment (glomerular filtration rate [GFR] ≥ 60 to < 90 mL/min) do not require dose adjustment of Januvia.

Patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min) do not require dose adjustment of Januvia.

Lower doses of sitagliptin are recommended for patients with moderate renal impairment (GFR ≥ 30 to < 45 mL/min) or severe renal impairment (GFR ≥ 15 to < 30 mL/min), or end-stage renal disease (GFR < 15 mL/min), including those requiring hemodialysis or peritoneal dialysis.

Patients with hepatic insufficiency

No dosage adjustment of Januvia is required for patients with mild to moderate hepatic impairment. The drug has not been studied in patients with severe hepatic impairment and caution should be exercised (see section 5.1).

Elderly patients

No dosage adjustment of the drug is required for elderly patients.

Children

Sitagliptin should not be used in children and adolescents aged 10 to 17 years due to insufficient efficacy. Currently available data are described in sections “Adverse reactions”, “Pharmacological properties: Pharmacodynamics and Pharmacokinetics”. Sitagliptin has not been studied in children under 10 years of age.

Overdose

In clinical studies in healthy volunteers, a single dose of 800 mg of Januvia was generally well tolerated. Minimal changes in QTc interval, not considered clinically significant, were observed in one study of Januvia at a dose of 800 mg per day. Doses above 800 mg per day have not been studied.

In case of overdose, standard supportive measures are necessary: removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including ECG, and supportive therapy, if necessary.

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

Side effects

Serious adverse reactions, including pancreatitis and allergic reactions, have been reported. Hypoglycemia has been reported when used in combination with sulfonylureas (4.7-13.8%) and insulin (9.6%) (see section 4.4).

Adverse reactions are listed by system organ class and absolute frequency (Table 3). The frequency of occurrence is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

Table 3.

The frequency of adverse reactions is determined based on the results of placebo-controlled clinical trials and post-marketing surveillance.

*Adverse reactions were identified during post-marketing surveillance.

†See section “Special instructions for use”.

‡See “TECOS Cardiovascular Safety Study” below.

Description of selected adverse reactions

The following adverse reactions, regardless of causal relationship to drug use, were observed in at least 5% of patients and more frequently: upper respiratory tract infection and nasopharyngitis. In addition, osteoarthritis and pain in extremity were reported uncommonly (0.5% more in subjects taking sitagliptin compared to control).

Some adverse reactions were observed more frequently with the combined use of sitagliptin with other antidiabetic drugs than with sitagliptin monotherapy:

hypoglycemia (very common) – in combination with sulfonylurea and metformin;

flu (often) – with insulin (with or without metformin);

nausea or vomiting (often) – with metformin;

flatulence (often) – with metformin or pioglitazone;

constipation (often) – in combination with sulfonylurea and metformin;

peripheral edema (often) – with pioglitazone or in combination with pioglitazone and metformin;

drowsiness and diarrhea (uncommon) – with metformin;

dry mouth (uncommon) – with insulin (with or without metformin).

Children

In clinical studies of sitagliptin in children aged 10 to 17 years with type 2 diabetes, the adverse reaction profile was comparable to that in adults.

TECOS cardiovascular safety study.

The TECOS cardiovascular safety study of sitagliptin included 7,332 patients treated with Januvia 100 mg daily (or 50 mg daily if estimated glomerular filtration rate (eGFR) ≥ 30 and < 50 mL/min/1.73 m2) and 7,339 patients treated with placebo in the all-treatment population. Both drugs were added to background therapy, according to regional standards and taking into account HbA1c levels and cardiovascular risk factors. A total of 2,004 patients ≥ 75 years of age were enrolled in the study (970 treated with Januvia and 1,034 with placebo). The overall incidence of serious adverse reactions in patients treated with Januvia was similar to that in patients treated with placebo.

In the population of all patients who started treatment, among patients receiving insulin and/or a sulfonylurea, the incidence of severe hypoglycemic episodes at the first examination was 2.7% in patients receiving Januvia and 2.5% in patients receiving placebo; among patients not receiving insulin and/or a sulfonylurea, the incidence of severe hypoglycemic episodes at the first examination was 1.0% in patients receiving Januvia and 0.7% in the placebo group.

Post-marketing experience

During post-marketing use of Januvia as monotherapy and/or in combination with other hypoglycemic agents, the following adverse reactions have been identified: