sitagliptin: prescribing information – dosing, contraindications, interactions, side effects

For adult patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control:
as monotherapy:
- in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with:
- metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
- a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

- a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycaemic control.
as triple oral therapy in combination with:
- a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
- a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
Januvia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR agonist, the dose of metformin and/or PPAR agonist should be maintained, and Januvia administered concomitantly.
When Januvia is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
If a dose of Januvia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations
Renal impairment
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no dose adjustment is required.
For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is required.
For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of Januvia is 50 mg once daily.
For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of Januvia is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Januvia and periodically thereafter.
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment and care should be exercised (see section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is necessary based on age.
Paediatric population
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been studied in paediatric patients under 10 years of age.
Method of administration
Januvia can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

Summary of the safety profile
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (4.7 %-13.8 %) and insulin (9.6 %) (see section 4.4).
Tabulated list of adverse reactions
Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic responses*,† Frequency not known Metabolism and nutrition disorders hypoglycaemia† Common Nervous system disorders headache Common dizziness Uncommon

Adverse reaction
Frequency of adverse reaction
Respiratory, thoracic and mediastinal disorders interstitial lung disease*
Frequency not known
Gastrointestinal disorders constipation
Uncommon vomiting*
Frequency not known acute pancreatitis*,†,‡
Frequency not known fatal and non-fatal haemorrhagic and necrotizing pancreatitis*,† Frequency not known Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,† Frequency not known urticaria*,† Frequency not known cutaneous vasculitis*,† Frequency not known exfoliative skin conditions including Stevens-Johnson syndrome*,† Frequency not known bullous pemphigoid* Frequency not known Musculoskeletal and connective tissue disorders arthralgia* Frequency not known myalgia* Frequency not known back pain* Frequency not known arthropathy* Frequency not known Renal and urinary disorders impaired renal function* Frequency not known acute renal failure* Frequency not known *Adverse reactions were identified through post-marketing surveillance.
† See section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
Description of selected adverse reactions
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.

TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population.
Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors.
The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-treated patients and 0.2 % in placebo-treated patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

General
Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Januvia and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Januvia should not be restarted.
Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of Januvia as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Renal impairment
Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is

suspected, Januvia should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Januvia should be discontinued.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pregnancy
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Due to lack of human data, Januvia should not be used during pregnancy.
Breast-feeding
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Januvia should not be used during breast-feeding.
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Januvia has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported.
In addition, patients should be alerted to the risk of hypoglycaemia when Januvia is used in combination with a sulphonylurea or with insulin.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.
Mechanism of action
Januvia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and

release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. 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.

Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Januvia may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, 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 plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination

For adult patients with type 2 diabetes mellitus, Ristaben is indicated to improve glycaemic control:
as monotherapy:
- in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with:
- metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
- a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

- a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycaemic control.
as triple oral therapy in combination with:
- a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
- a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
Ristaben is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR agonist, the dose of metformin and/or PPAR agonist should be maintained, and Ristaben administered concomitantly.
When Ristaben is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
If a dose of Ristaben is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations
Renal impairment
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no dose adjustment is required.
For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is required.
For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of Ristaben is 50 mg once daily.
For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of Ristaben is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Ristaben and periodically thereafter.
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Ristaben has not been studied in patients with severe hepatic impairment and care should be exercised (see section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is necessary based on age.
Paediatric population
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been studied in paediatric patients under 10 years of age.
Method of administration
Ristaben can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

Summary of the safety profile
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (4.7 %-13.8 %) and insulin (9.6 %) (see section 4.4).
Tabulated list of adverse reactions
Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic responses*,† Frequency not known Metabolism and nutrition disorders hypoglycaemia† Common Nervous system disorders headache Common dizziness Uncommon

Adverse reaction
Frequency of adverse reaction
Respiratory, thoracic and mediastinal disorders interstitial lung disease*
Frequency not known
Gastrointestinal disorders constipation
Uncommon vomiting*
Frequency not known acute pancreatitis*,†,‡
Frequency not known fatal and non-fatal haemorrhagic and necrotizing pancreatitis*,† Frequency not known Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,† Frequency not known urticaria*,† Frequency not known cutaneous vasculitis*,† Frequency not known exfoliative skin conditions including Stevens-Johnson syndrome*,† Frequency not known bullous pemphigoid* Frequency not known Musculoskeletal and connective tissue disorders arthralgia* Frequency not known myalgia* Frequency not known back pain* Frequency not known arthropathy* Frequency not known Renal and urinary disorders impaired renal function* Frequency not known acute renal failure* Frequency not known *Adverse reactions were identified through post-marketing surveillance.
† See section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
Description of selected adverse reactions
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.

TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population.
Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors.
The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-treated patients and 0.2 % in placebo-treated patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

General
Ristaben should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Ristaben and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Ristaben should not be restarted.
Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of Ristaben as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Renal impairment
Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is

suspected, Ristaben should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Ristaben should be discontinued.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pregnancy
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Due to lack of human data, Ristaben should not be used during pregnancy.
Breast-feeding
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Ristaben should not be used during breast-feeding.
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Ristaben has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported.
In addition, patients should be alerted to the risk of hypoglycaemia when Ristaben is used in combination with a sulphonylurea or with insulin.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01 Mechanism of action Ristaben is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and

release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. 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.

Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Ristaben may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, 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 plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination

For adult patients with type 2 diabetes mellitus, Tesavel is indicated to improve glycaemic control:
as monotherapy:
- in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with:
- metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
- a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

- a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycaemic control.
as triple oral therapy in combination with:
- a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
- a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
Tesavel is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR agonist, the dose of metformin and/or PPAR agonist should be maintained, and Tesavel administered concomitantly.
When Tesavel is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
If a dose of Tesavel is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations
Renal impairment
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no dose adjustment is required.
For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is required.
For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of Tesavel is 50 mg once daily.
For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of Tesavel is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Tesavel and periodically thereafter.
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Tesavel has not been studied in patients with severe hepatic impairment and care should be exercised (see section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is necessary based on age.
Paediatric population
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been studied in paediatric patients under 10 years of age.
Method of administration
Tesavel can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

Summary of the safety profile
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (4.7 %-13.8 %) and insulin (9.6 %) (see section 4.4).
Tabulated list of adverse reactions
Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic responses*,† Frequency not known Metabolism and nutrition disorders hypoglycaemia† Common Nervous system disorders headache Common dizziness Uncommon

Adverse reaction
Frequency of adverse reaction
Respiratory, thoracic and mediastinal disorders interstitial lung disease*
Frequency not known
Gastrointestinal disorders constipation
Uncommon vomiting*
Frequency not known acute pancreatitis*,†,‡
Frequency not known fatal and non-fatal haemorrhagic and necrotizing pancreatitis*,† Frequency not known Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,† Frequency not known urticaria*,† Frequency not known cutaneous vasculitis*,† Frequency not known exfoliative skin conditions including Stevens-Johnson syndrome*,† Frequency not known bullous pemphigoid* Frequency not known Musculoskeletal and connective tissue disorders arthralgia* Frequency not known myalgia* Frequency not known back pain* Frequency not known arthropathy* Frequency not known Renal and urinary disorders impaired renal function* Frequency not known acute renal failure* Frequency not known *Adverse reactions were identified through post-marketing surveillance.
† See section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
Description of selected adverse reactions
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.

TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population.
Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors.
The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-treated patients and 0.2 % in placebo-treated patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

General
Tesavel should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Tesavel and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Tesavel should not be restarted.
Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of Tesavel as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Renal impairment
Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is

suspected, Tesavel should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Tesavel should be discontinued.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pregnancy
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Due to lack of human data, Tesavel should not be used during pregnancy.
Breast-feeding
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Tesavel should not be used during breast-feeding.
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Tesavel has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported.
In addition, patients should be alerted to the risk of hypoglycaemia when Tesavel is used in combination with a sulphonylurea or with insulin.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.
Mechanism of action
Tesavel is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and

release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. 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.

Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Tesavel may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, 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 plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination

For adult patients with type 2 diabetes mellitus, Xelevia is indicated to improve glycaemic control:
as monotherapy:
- in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with:
- metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
- a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

- a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycaemic control.
as triple oral therapy in combination with:
- a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
- a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
Xelevia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR agonist, the dose of metformin and/or PPAR agonist should be maintained, and Xelevia administered concomitantly.
When Xelevia is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
If a dose of Xelevia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations
Renal impairment
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no dose adjustment is required.
For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is required.
For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of Xelevia is 50 mg once daily.
For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of Xelevia is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Xelevia and periodically thereafter.
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Xelevia has not been studied in patients with severe hepatic impairment and care should be exercised (see section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is necessary based on age.
Paediatric population
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been studied in paediatric patients under 10 years of age.
Method of administration
Xelevia can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

Summary of the safety profile
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (4.7 %-13.8 %) and insulin (9.6 %) (see section 4.4).
Tabulated list of adverse reactions
Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic responses*,† Frequency not known Metabolism and nutrition disorders hypoglycaemia† Common Nervous system disorders headache Common dizziness Uncommon

Adverse reaction
Frequency of adverse reaction
Respiratory, thoracic and mediastinal disorders interstitial lung disease*
Frequency not known
Gastrointestinal disorders constipation
Uncommon vomiting*
Frequency not known acute pancreatitis*,†,‡
Frequency not known fatal and non-fatal haemorrhagic and necrotizing pancreatitis*,† Frequency not known Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,† Frequency not known urticaria*,† Frequency not known cutaneous vasculitis*,† Frequency not known exfoliative skin conditions including Stevens-Johnson syndrome*,† Frequency not known bullous pemphigoid* Frequency not known Musculoskeletal and connective tissue disorders arthralgia* Frequency not known myalgia* Frequency not known back pain* Frequency not known arthropathy* Frequency not known Renal and urinary disorders impaired renal function* Frequency not known acute renal failure* Frequency not known *Adverse reactions were identified through post-marketing surveillance.
† See section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
Description of selected adverse reactions
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.

TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population.
Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors.
The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-treated patients and 0.2 % in placebo-treated patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

General
Xelevia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Xelevia and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Xelevia should not be restarted.
Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of Xelevia as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Renal impairment
Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is

suspected, Xelevia should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Xelevia should be discontinued.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pregnancy
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Due to lack of human data, Xelevia should not be used during pregnancy.
Breast-feeding
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Xelevia should not be used during breast-feeding.
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

Xelevia has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported.
In addition, patients should be alerted to the risk of hypoglycaemia when Xelevia is used in combination with a sulphonylurea or with insulin.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.
Mechanism of action
Xelevia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and

release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. 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.

Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Xelevia may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, 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 plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination