Sytene®-pharmak

Ukraine
Brand name Sytene®-pharmak
Form tablets, film-coated
Active substance / Dosage
sitagliptin · 100 mg
Prescription type prescription only
ATC code
A10BH01
Registration number UA/17815/01/02
Manufacturer Farmak JSC

Table of Contents

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SYTENA-FARMAK (SYTENA-FARMAK)

Composition:

Active substance: sitagliptin;

One film-coated tablet contains 64.24 mg or 128.48 mg of sitagliptin phosphate monohydrate, equivalent to 50 mg or 100 mg of sitagliptin;

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

50 mg: Opadry II 85F17498 light beige (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172));

100 mg: Opadry II 85F17438 beige (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: round, biconvex, film-coated tablets of light beige color;

100 mg tablets: round, biconvex, film-coated tablets of beige to dark beige color.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Dipeptidyl peptidase-4 inhibitors. ATC code A10BH01.

Pharmacological Properties

Pharmacodynamics

Sitagliptin is an orally active, highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), indicated for the treatment of type 2 diabetes mellitus. Sitagliptin differs chemically and pharmacologically from glucagon-like peptide-1 (GLP-1) analogs, insulin, sulfonylureas, biguanides, gamma-activated receptor agonists proliferated by peroxisomes (PPARγ), alpha-glucosidase inhibitors, and amylin analogs. By inhibiting DPP-4, sitagliptin increases the concentrations of two known incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin hormones are secreted by the intestine throughout the day, and their levels rise in response to food intake. Incretins are part of the body's intrinsic physiological system regulating glucose homeostasis.

At normal or elevated blood glucose levels, incretin hormones promote increased insulin synthesis and its secretion from pancreatic beta cells via intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also promotes suppression of elevated glucagon secretion from pancreatic alpha cells. Reduced glucagon concentration, together with increased insulin levels, leads to decreased hepatic glucose production, ultimately resulting in reduced glycemia.

When blood glucose concentration is low, these effects of incretins on insulin release and glucagon suppression 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 into inactive metabolites.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing plasma concentrations of active forms of GLP-1 and GIP. By increasing incretin levels, sitagliptin enhances glucose-dependent insulin release and reduces glucagon secretion. In patients with type 2 diabetes and hyperglycemia, these changes in insulin and glucagon secretion lead to reductions in glycated hemoglobin A1c (HbA1c) levels and decreased fasting and postprandial plasma glucose concentrations.

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

In a two-day study involving healthy volunteers, sitagliptin administered alone increased concentrations of active GLP-1, while metformin administered alone increased both active and total GLP-1 concentrations to a similar extent. Concomitant administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active concentrations of GIP.

Clinical Efficacy and Safety

Sitagliptin improved glycemic control when used as monotherapy or as part of combination therapy (see Table 1).

Table 1

Results of HbA1c in placebo-controlled studies of monotherapy and combination therapy*

Study

Mean baseline HbA1c (%)

Mean change in HbA1c from baseline (%)†

Placebo-adjusted mean change in HbA1c (%)† (95% CI)

Monotherapy studies

Sitagliptin 100 mg once daily§ (N=193)

8.0
  • 0.5
  • 0.6‡

(-0.8; -0.4)

Sitagliptin 100 mg once daily|| (N=229)

8.0
  • 0.6
  • 0.8‡

(-1.0; -0.6)

Combination therapy studies

Sitagliptin 100 mg once daily as add-on to ongoing metformin therapy|| (N=453)

8.0
  • 0.7
  • 0.7‡

(-0.8; -0.5)

Sitagliptin 100 mg once daily as add-on to ongoing pioglitazone therapy|| (N=163)

8.1
  • 0.9
  • 0.7‡

(-0.9; -0.5)

Sitagliptin 100 mg once daily as add-on to ongoing glimepiride therapy|| (N=102)

8.4
  • 0.3
  • 0.6‡

(-0.8; -0.3)

Sitagliptin 100 mg once daily as add-on to ongoing glimepiride + metformin therapy|| (N=115)

8.3
  • 0.6
  • 0.9‡

(-1.1; -0.7)

Sitagliptin 100 mg once daily as add-on to ongoing pioglitazone + metformin therapy# (N=152)

8.8
  • 1.2
  • 0.7‡

(-1.0; -0.5)

Initial combination therapy (twice daily)||: sitagliptin 50 mg + metformin 500 mg (N=183)

8.8
  • 1.4
  • 1.6‡

(-1.8; -1.3)

Initial combination therapy (twice daily)||: sitagliptin 50 mg + metformin 1000 mg (N=178)

8.8
  • 1.9
  • 2.1‡

(-2.3; -1.8)

Sitagliptin 100 mg once daily as add-on to ongoing insulin therapy (+/- metformin)|| (N=305)

8.7
  • 0.61¶
  • 0.6‡,¶

(-0.7; -0.4)

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

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

‡p < 0.001 compared with placebo or placebo + combination therapy.

§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 (prior mixed vs. prior unmixed [intermediate- or long-acting]) and baseline value. Treatment interactions (metformin and insulin use) were not significant (p > 0.10).

TECOS – a randomized trial involving 14,671 patients with HbA1c from ≥6.5 to 8.0% and established cardiovascular disease, who received sitagliptin (7,332) 100 mg once daily (or 50 mg once 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 directed toward 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 aged ≥75 years and 3,324 patients with renal impairment (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.

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

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

Table 2.

Incidence of composite and key secondary cardiovascular endpoints

Sitagliptin 100 mg

Placebo

N (%)

Event rate per 100 patient-years*

N (%)

Event rate per 100 patient-years*

Relative risk (95% CI)

p-value†

Population analysis – all patients who initiated treatment

Number of patients

7332

7339

Primary composite endpoint

(cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina)

839 (11.4)

4.1

851 (11.6)

4.2

0.98 (0.89–1.08)

<0.001

Secondary composite endpoint

(cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke)

745 (10.2)

3.6

746 (10.2)

3.6

0.99 (0.89–1.10)

<0.001

Secondary endpoint

Cardiovascular death

380 (5.2)

1.7

366 (5.0)

1.7

1.03 (0.89–1.19)

0.711

All myocardial infarction events (fatal and non-fatal)

300 (4.1)

1.4

316 (4.3)

1.5

0.95 (0.81–1.11)

0.487

All stroke events (fatal and non-fatal)

178 (2.4)

0.8

183 (2.5)

0.9

0.97 (0.79–1.19)

0.760

Hospitalization for unstable angina

116 (1.6)

0.5

129 (1.8)

0.6

0.90 (0.70–1.16)

0.419

Death from any cause

547 (7.5)

2.5

537 (7.3)

2.5

1.01 (0.90–1.14)

0.875

Hospitalization for heart failure‡

228 (3.1)

1.1

229 (3.1)

1.1

1.00 (0.83–1.20)

0.983

*Incidence per 100 patient-years is calculated as 100 × (total number of patients with ≥1 event during the on-treatment period divided by the total number of patient-years of follow-up).

†Based on a Cox model stratified by region. For composite endpoints, the p-value corresponds to a criterion of non-inferiority to demonstrate that the hazard ratio is less than 1.3. For all other endpoints, the p-value corresponds to a criterion of differences in hazard rates.

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

Pharmacokinetics.

The pharmacokinetics of sitagliptin have been extensively characterized in healthy volunteers and patients with type 2 diabetes mellitus. In healthy volunteers, after oral administration of 100 mg sitagliptin, rapid absorption of the drug is observed, with peak concentrations (Cmax) reached within 1 to 4 hours post-dose. The area under the plasma concentration-time curve (AUC) increases proportionally with dose and amounts to 8.52 µM·h in healthy volunteers after a single 100 mg oral dose, with a Cmax of 950 nM and a mean elimination half-life of 12.4 hours.

Absorption

The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of sitagliptin with a high-fat meal does not affect its pharmacokinetics, sitagliptin can be administered regardless of food intake.

Distribution

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

Metabolism

Approximately 79% of sitagliptin is excreted unchanged in urine. Only a minor portion of the administered drug undergoes metabolism.

Following administration of an oral dose of [14C]sitagliptin, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected only at trace levels, which are expected not to influence the DPP-4 inhibitory activity of sitagliptin in plasma. In vitro studies have shown that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with partial contribution from CYP2C8.

In vitro data indicate that sitagliptin is not an inhibitor of the CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6, and is not an inducer of CYP3A4 or CYP1A2.

Excretion

After administration of an oral dose of 14C-labeled sitagliptin to healthy volunteers, approximately 100% of the administered radioactivity was recovered within one week: 13% via feces and 87% via kidneys. The mean elimination half-life of sitagliptin after a 100 mg oral dose is approximately 12.4 hours, and renal clearance is approximately 350 mL/min.

Sitagliptin is primarily eliminated via renal excretion through active tubular secretion.

Pharmacokinetics in specific patient populations

Patients with renal impairment

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 impairment compared to healthy control volunteers. The study included patients with mild, moderate, and severe renal impairment, as well as patients with end-stage renal disease (ESRD) on hemodialysis. Additionally, the impact of renal impairment on the pharmacokinetics of sitagliptin in patients with type 2 diabetes and mild, moderate, or severe renal impairment (including ESRD) was evaluated using population pharmacokinetic analysis.

Compared to healthy control volunteers, plasma AUC values for sitagliptin were approximately 1.2-fold and 1.6-fold higher in patients with mild renal impairment (eGFR ≥60 to <90 mL/min) and moderate renal impairment (eGFR ≥45 to <60 mL/min), respectively. Since this increase is not considered clinically significant, dose adjustment is not required in these patients.

Plasma AUC values for sitagliptin were approximately 2-fold higher in patients with moderate renal impairment (eGFR ≥30 to <45 mL/min) and approximately 4-fold higher in patients with severe renal impairment (eGFR <30 mL/min), including those with ESRD on hemodialysis. Sitagliptin is moderately removed by hemodialysis (13.5% of the administered dose over a 3–4 hour hemodialysis session initiated 4 hours after dosing). To achieve plasma concentrations similar to those in patients with normal renal function, lower doses are recommended for patients with eGFR <45 mL/min (see section "Dosage and administration").

Patients with hepatic impairment

Dose adjustment of sitagliptin is not 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, since the drug is primarily eliminated via the kidneys, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Elderly patients

Age does not have a clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared to younger patients, elderly patients (65–80 years) have approximately 19% higher sitagliptin concentrations. Dose adjustment based on age is not required.

Pediatric patients

Studies of sitagliptin use in pediatric patients have not been conducted.

Other patients

Dose adjustment is not required based on gender, race, or body mass index, as these characteristics have no clinically significant effect on the pharmacokinetics of sitagliptin.

Clinical characteristics.

Indications.

For adult patients with type 2 diabetes, the medicinal product SITEN®-FARMAC is indicated to improve glycemic control:

as monotherapy:

  • when the patient's condition is not adequately controlled by 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 in combination with metformin alone do not provide adequate glycemic control;
  • sulfonylurea, when diet and exercise in combination with the maximum tolerated dose of a sulfonylurea alone do not provide adequate glycemic control, and when metformin cannot be used due to contraindications or intolerance;
  • gamma-agonist of peroxisome proliferator-activated receptor (PPARγ) (i.e., thiazolidinedione), when PPARγ agonist therapy is appropriate and when diet and exercise in combination with a single PPARγ agonist do not provide adequate glycemic control;

as triple oral therapy in combination with:

  • sulfonylurea and metformin, when diet and exercise in combination with dual therapy using these medicinal products do not provide adequate glycemic control;
  • PPARγ agonist and metformin, when PPARγ agonist use is appropriate and when diet and exercise in combination with dual therapy using these medicinal products do not provide adequate glycemic control.

SITEN®-FARMAC is also indicated as an adjunct to insulin (with or without metformin), when diet and exercise in combination with a stable dose of insulin do not provide adequate glycemic control.

Contraindications.

  • Hypersensitivity to any component of the medicinal product.
  • Type 1 diabetes.
  • Diabetic ketoacidosis.

Interaction with other medicinal products and other forms of interaction.

Metformin

Concomitant administration of 1000 mg metformin and 50 mg sitagliptin twice daily over a prolonged period did not substantially alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Cyclosporine

A study evaluating the effect of cyclosporine, a potent p-glycoprotein inhibitor, on the pharmacokinetics of sitagliptin was conducted. Concomitant administration of a single oral dose of 100 mg sitagliptin and a single oral dose of 600 mg cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. No clinically significant interaction between the medicinal product and cyclosporine or other p-glycoprotein inhibitors has been observed.

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-mediated 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 renal disease (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.

Effect of sitagliptin on other medicinal products

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

Digoxin

Sitagliptin has a minor effect on digoxin plasma concentrations. Following concomitant administration of 0.25 mg digoxin with 100 mg sitagliptin daily for 10 days, the AUC for digoxin increased on average by 11%, and Cmax in plasma by 18%. Dose adjustment of digoxin is not recommended.

However, patients at risk of digoxin toxicity should be closely monitored when sitagliptin and digoxin are used concomitantly.

Special precautions for use.

Acute pancreatitis

The use of DPP-4 inhibitors is associated with a risk of developing acute pancreatitis. Cases of acute pancreatitis, including necrotizing or hemorrhagic pancreatitis, and/or fatal outcomes have been reported (see section "Adverse reactions"). Patients should be informed about the characteristic symptom of acute pancreatitis—persistent, severe abdominal pain. Symptoms of pancreatitis resolved after discontinuation of sitagliptin (with or without concomitant supportive therapy). If acute pancreatitis is suspected, treatment with SITEN®-PHARMAC should be discontinued. If acute pancreatitis is confirmed, resumption of the drug is not recommended. Caution should be exercised when prescribing to patients with a history of pancreatitis.

Hypoglycemia

In clinical trials, the incidence of hypoglycemia with SITEN®-PHARMAC used as monotherapy or in combination with metformin or a PPARγ agonist (thiazolidinedione) was similar to that observed with placebo. As with other antihyperglycemic agents, episodes of hypoglycemia were observed when sitagliptin was used in combination with insulin or a sulfonylurea. Therefore, to reduce the risk of hypoglycemia, a lower dose of the sulfonylurea or insulin should be considered (see section "Adverse reactions").

Renal impairment

Sitagliptin is excreted via the kidneys. To achieve plasma concentrations of SITEN®-PHARMAC similar to those in patients with normal renal function, lower doses are recommended for patients with eGFR < 45 mL/min, as well as for patients with ESRD requiring hemodialysis or peritoneal dialysis (see sections "Pharmacological properties" and "Dosage and administration").

When considering the use of sitagliptin in combination with another antidiabetic agent, the specific recommendations for use in patients with renal impairment should be reviewed.

Hypersensitivity reactions

During the post-marketing period, serious allergic reactions have been reported with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin disorders, including Stevens-Johnson syndrome (see section "Adverse reactions"). These reactions occurred within the first 3 months after initiating sitagliptin treatment, and sometimes after the first dose. If an allergic reaction is suspected, SITEN®-PHARMAC should be discontinued, other potential causes should be evaluated, and alternative diabetes treatment should be initiated.

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, treatment with SITEN®-PHARMAC should be discontinued.

Use during pregnancy or breastfeeding.

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

There are no data on the excretion of sitagliptin in human breast milk; therefore, the drug is not recommended during breastfeeding.

Animal studies have shown reproductive toxicity when the drug was administered at high doses.

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

Data from human studies are lacking.

Ability to affect the speed of reactions when driving or operating machinery.

Patients should be advised to exercise caution when driving or operating machinery, due to the potential for adverse reactions affecting the nervous system (dizziness, somnolence).

Patients should be warned about the risk of hypoglycemia when SITEN®-PHARMAC is used as part of combination therapy.

Dosage and Administration

SITEN®-FARMAK is recommended at a dose of 100 mg once daily as monotherapy or in combination with metformin and/or a PPARγ agonist (e.g., thiazolidinedione).

When SITEN®-FARMAK is prescribed in combination with a sulfonylurea or insulin, it is considered that a lower dose of the sulfonylurea or insulin may reduce the risk of hypoglycemia (see section "Special Precautions").

If a patient misses a dose, the dose should be taken as soon as remembered. It is not recommended to take a double dose of SITEN®-FARMAK on the same day.

SITEN®-FARMAK can be taken independently of food intake.

Patients with Renal Impairment

Since dosage depends on renal function, renal function assessment is recommended before initiating treatment and periodically during therapy.

Patients with mild renal impairment (eGFR ≥60 to <90 mL/min) do not require dose adjustment of SITEN®-FARMAK.

Patients with moderate renal impairment (eGFR ≥45 to <60 mL/min) do not require dose adjustment of SITEN®-FARMAK.

For patients with moderate renal impairment (eGFR ≥30 to <45 mL/min), the dose of SITEN®-FARMAK is 50 mg once daily.

For patients with severe renal impairment (eGFR ≥15 to <30 mL/min) or end-stage renal disease (eGFR <15 mL/min), including those requiring hemodialysis or peritoneal dialysis, the dose of SITEN®-FARMAK is 25 mg once daily.

Patients with Hepatic Impairment

No dose adjustment of SITEN®-FARMAK is required for patients with mild to moderate hepatic impairment. The use of SITEN®-FARMAK in patients with severe hepatic impairment has not been studied; therefore, caution should be exercised.

Elderly Patients

No dose adjustment of SITEN®-FARMAK is required for elderly patients.

Children

The efficacy and safety of SITEN®-FARMAK in patients under 18 years of age have not been established; therefore, the drug should not be prescribed to this age group.

Overdose

In clinical studies involving healthy volunteers, a single dose of 800 mg of sitagliptin was generally well tolerated. Minimal changes in the QTc interval, not considered clinically significant, were observed in one study with 800 mg of sitagliptin daily. Doses exceeding 800 mg daily have not been studied.

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

Sitagliptin is poorly dialyzed. In clinical studies, only 13.5% of the dose was eliminated during a 3–4 hour dialysis session. Prolonged dialysis may be considered if clinically necessary. There are no data on the effectiveness of sitagliptin removal by peritoneal dialysis.

Adverse reactions.

Serious adverse reactions have been reported, including pancreatitis and allergic reactions. Hypoglycaemia has been reported when the medicinal product was used in combination with sulphonylureas (4.7–13.8%) and insulin (9.6%) (see section "Special warnings and precautions for use").

Adverse reactions are listed by system organ classes and absolute frequency (see Table 3). Frequency is defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).

Table 3.

Frequency of adverse reactions was determined based on results from placebo-controlled clinical trials and post-marketing surveillance.

Adverse reaction

Frequency of adverse reactions

Immune system disorders

hypersensitivity reactions, including anaphylactic reactions*,†

frequency unknown

Metabolism and nutrition disorders

hypoglycemia†

common

Nervous system disorders

headache

common

dizziness

uncommon

Respiratory, thoracic and mediastinal disorders

interstitial lung disease*

frequency unknown

Gastrointestinal disorders

constipation

uncommon

vomiting*

frequency unknown

acute pancreatitis*,†,‡

frequency unknown

fatal and non-fatal hemorrhagic and necrotizing pancreatitis*,†

frequency unknown

Skin and subcutaneous tissue disorders

pruritus*

uncommon

angioedema*,†

frequency unknown

rash*,†

frequency unknown

urticaria*,†

frequency unknown

cutaneous vasculitis*,†

frequency unknown

skin exfoliation conditions, including Stevens-Johnson syndrome*,†

frequency unknown

bullous pemphigoid*

frequency unknown

Musculoskeletal and connective tissue disorders

arthralgia*

frequency unknown

myalgia*

frequency unknown

back pain*

frequency unknown

arthropathy*

frequency unknown

Renal and urinary disorders

worsening of renal function*

frequency unknown

acute kidney injury*

frequency unknown

*Adverse reactions were identified during post-marketing surveillance.

†See section "Special precautions".

‡See below "TECOS cardiovascular safety study".

Description of selected adverse reactions

The following adverse reactions, regardless of causal relationship to the drug, were observed in at least 5% of patients treated with the medicinal product, and more frequently: upper respiratory tract infections and nasopharyngitis. Additionally, osteoarthritis and limb pain were reported uncommonly (0.5% more frequently in patients receiving sitagliptin compared to the control group).

Some adverse reactions were observed more frequently when sitagliptin was used in combination with other antidiabetic medicinal products than with sitagliptin monotherapy:

  • hypoglycaemia (very common) – in combination with sulfonylurea and metformin;
  • influenza (common) – with insulin (with or without metformin);
  • nausea or vomiting (common) – with metformin;
  • flatulence (common) – with metformin or pioglitazone;
  • constipation (common) – in combination with sulfonylurea and metformin;
  • peripheral oedema (common) – with pioglitazone or in combination of pioglitazone with metformin;
  • somnolence and diarrhoea (uncommon) – with metformin;
  • dry mouth (uncommon) – with insulin (with or without metformin).

TECOS cardiovascular safety study.

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

In the overall population of patients who started treatment, among patients receiving insulin and/or sulfonylurea, the incidence of episodes of severe hypoglycaemia at first assessment was 2.7% in patients receiving sitagliptin and 2.5% in patients receiving placebo. Among patients not receiving insulin and/or sulfonylurea, the incidence of episodes of severe hypoglycaemia at first assessment was 1.0% in patients receiving sitagliptin and 0.7% in the placebo group.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister. 3 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.