SITAGLIPTIN ACCORD 50mg tablets medication leaflet

Sitagliptin Accord 25 mg film-coated tablets

Sitagliptin Accord 50 mg film-coated tablets

Sitagliptin Accord 100 mg film-coated tablets

Sitagliptin Accord 25 mg film-coated tablets

Each tablet contains sitagliptin hydrochloride monohydrate, equivalent to 25 mg sitagliptin.

Sitagliptin Accord 50 mg film-coated tablets

Each tablet contains sitagliptin hydrochloride monohydrate, equivalent to 50 mg sitagliptin.

Sitagliptin Accord 100 mg film-coated tablets

Each tablet contains sitagliptin hydrochloride monohydrate, equivalent to 100 mg sitagliptin.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Sitagliptin Accord 25 mg film-coated tablets

Pink coloured, round, leveled edge, film-coated tablet debossed with ‘S3’ on one side and plain on theother side. Diameter 6 mm to 6.40 mm.

Sitagliptin Accord 50 mg film-coated tablets

Light beige coloured, round, beveled edge, film-coated tablet debossed with ‘S4’ on one side and plainon the other side. Diameter 8 mm to 8.40 mm

Sitagliptin Accord 100 mg film-coated tablets

Beige coloured, round, beveled edge, film-coated tablet debossed with ‘S7’ on one side and plain onthe other side. Diameter 10 mm to 10.40 mm

For adult patients with type 2 diabetes mellitus, Sitagliptin Accord is indicated to improve glycaemiccontrol:

as monotherapy:

* in patients inadequately controlled by diet and exercise alone and for whom metformin isinappropriate due to contraindications or intolerance.

as dual oral therapy in combination with:

* metformin when diet and exercise plus metformin alone do not provide adequate glycaemiccontrol.

* a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone donot provide adequate glycaemic control and when metformin is inappropriate due tocontraindications 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 agonistalone 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 medicinalproducts do not provide adequate glycaemic control.

* a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet andexercise plus dual therapy with these medicinal products do not provide adequate glycaemiccontrol.

Sitagliptin Accord is also indicated as add-on to insulin (with or without metformin) when diet andexercise plus stable dose of insulin do not provide adequate glycaemic control.

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 Sitagliptin Accordadministered concomitantly.

When Sitagliptin Accord is used in combination with a sulphonylurea or with insulin, a lower dose ofthe sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).

If a dose of Sitagliptin Accord is missed, it should be taken as soon as the patient remembers. Adouble dose should not be taken on the same day.

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), nodose adjustment is required.

For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dose adjustment isrequired.

For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of Sitagliptin

Accord 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 doseof Sitagliptin Accord is 25 mg once daily. Treatment may be administered without regard to the timingof dialysis.

Because there is a dose adjustment based upon renal function, assessment of renal function isrecommended prior to initiation of Sitagliptin Accord and periodically thereafter.

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Sitagliptin

Accord 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 notexpected to affect the pharmacokinetics of sitagliptin.

No dose adjustment is necessary based on age.

Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficientefficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not beenstudied in paediatric patients under 10 years of age.

Oral use.

Sitagliptin Accord can be taken with or without food.

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

Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabeticketoacidosis.

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patientsshould be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominalpain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or withoutsupportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or deathhave been reported. If pancreatitis is suspected, sitagliptin and other potentially suspect medicinalproducts should be discontinued; if acute pancreatitis is confirmed, sitagliptin 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 sitagliptin as monotherapy and as part of combination therapy with medicinalproducts not known to cause hypoglycaemia (i.e. metformin and/or a PPAR  agonist), rates ofhypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.

Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or asulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea orinsulin may be considered (see section 4.2).

Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those inpatients with normal renal function, lower doses are recommended in patients with GFR < 45 mL/min,as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and5.2).

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.

Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin havebeen reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditionsincluding Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months afterinitiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction issuspected, sitagliptin 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 inhibitorsincluding sitagliptin. If bullous pemphigoid is suspected, sitagliptin should be discontinued.

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 byco-administered medicinal products is low.

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptinis 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 amore significant role in the elimination of sitagliptin in the setting of severe renal impairment orend-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 inpatients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the settingof 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 aniontransporter-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. Concomitantadministration of OAT3 inhibitors has not been evaluated in vivo.

Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mgsitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type2 diabetes.

Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor ofp-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral doseof sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptinby approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics werenot considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfullyaltered. 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 of0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC ofdigoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No doseadjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should bemonitored for this when sitagliptin and digoxin are administered concomitantly.

In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinicalstudies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a lowpropensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organiccationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals haveshown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.

Due to lack of human data, Sitagliptin Accord should not be used during pregnancy.

It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shownexcretion of sitagliptin in breast milk. Sitagliptin Accord should not be used during breast-feeding.

Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Humandata are lacking.

Sitagliptin Accord 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 havebeen reported.

In addition, patients should be alerted to the risk of hypoglycaemia when Sitagliptin Accord is used incombination with a sulphonylurea or with insulin.

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).

Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies aredefined 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 theavailable data).

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies ofsitagliptin monotherapy and post-marketing experience

Adverse reaction Frequency of adverse reaction

Blood and lymphatic system disordersthrombocytopenia Rare

Immune system disordershypersensitivity reactions including anaphylactic Frequency not knownresponses *,†

Metabolism and nutrition disordershypoglycaemia† Common

Nervous system disordersheadache Commondizziness Uncommon

Respiratory, thoracic and mediastinal disordersinterstitial lung disease* Frequency not known

Gastrointestinal disorders,constipation Uncommonvomiting* Frequency not knownacute pancreatitis*,†,‡, Frequency not knownfatal and non-fatal haemorrhagic and necrotising Frequency not knownpancreatitis*,† ,

Skin and subcutaneous tissue disorderspruritus* Uncommonangioedema*,† Frequency not knownrash*,† Frequency not knownurticaria*,† Frequency not knowncutaneous vasculitis*,† Frequency not knownexfoliative skin conditions including Frequency not known

Stevens-Johnson syndrome*,†bullous pemphigoid* Frequency not known

Musculoskeletal and connective tissue disordersarthralgia* Frequency not knownmyalgia* Frequency not knownback pain* Frequency not knownarthropathy*, Frequency not known

Renal and urinary disordersimpaired renal function* Frequency not knownacute renal failure* Frequency not known

*Adverse reactions were identified through post-marketing surveillance.

† See section 4.4.

‡ See TECOS Cardiovascular Safety Study below.

In addition to the drug-related adverse experiences described above, adverse experiences reportedregardless of causal relationship to medicinal products and occurring in at least 5 % and morecommonly in patients treated with sitagliptin included upper respiratory tract infection andnasopharyngitis. Additional adverse experiences reported regardless of causal relationship tomedication 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 sitagliptinwith other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These includedhypoglycaemia (frequency very common with the combination of sulphonylurea and metformin),influenza (common with insulin [with or without metformin]), nausea and vomiting (common withmetformin), flatulence (common with metformin or pioglitazone), constipation (common with thecombination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or thecombination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin),and dry mouth (uncommon with insulin [with or without metformin]).

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 treatedwith 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 cardiovascular(CV) risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin wassimilar to that in patients receiving placebo.

In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea atbaseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % inplacebo-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 % inplacebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % insitagliptin-treated patients and 0.2 % in placebo-treated patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin wereadministered. Minimal increases in QTc, not considered to be clinically relevant, were observed in onestudy at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinicalstudies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactionsobserved with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mgper 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., removeunabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining anelectrocardiogram), and institute supportive therapy if required.

Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removedover a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinicallyappropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors,

ATC code: A10BH01.

Sitagliptin 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 maybe mediated by enhancing the levels of active incretin hormones. Incretin hormones, includingglucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are releasedby the intestine throughout the day, and levels are increased in response to a meal. The incretins arepart of an endogenous system involved in the physiologic regulation of glucose homeostasis. Whenblood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis andrelease 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 beendemonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis andrelease. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowersglucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higherinsulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucoselevels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucoseconcentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose risesabove normal concentrations. Further, GLP-1 does not impair the normal glucagon response tohypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidlyhydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis ofincretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreasesglucagon 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 fastingand postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinctfrom the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels arelow and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptinis a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-relatedenzymes DPP-8 or DPP-9 at therapeutic concentrations.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,whereas metformin alone increased active and total GLP-1 concentrations to similar extents.

Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.

Sitagliptin, but not metformin, increased active GIP concentrations.

Overall, sitagliptin improved glycaemic control when used as monotherapy or in combinationtreatment in adult patients with type 2 diabetes (see Table 2).

Two studies were conducted to evaluate the efficacy and safety of sitagliptin monotherapy. Treatmentwith sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA1c,fasting plasma glucose (FPG), and 2-hour post-prandial glucose (2-hour PPG), compared to placebo intwo studies, one of 18- and one of 24-weeks duration. Improvement of surrogate markers of beta cellfunction, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, andmeasures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.

The observed incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo.

Body weight did not increase from baseline with sitagliptin therapy in either study, compared to asmall reduction in patients given placebo.

Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters comparedwith placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination withmetformin and one in combination with pioglitazone. Change from baseline in body weight wassimilar for patients treated with sitagliptin relative to placebo. In these studies there was a similarincidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. Theaddition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significantimprovements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in bodyweight compared to those given placebo.

A 26-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin(100 mg once daily) added to the combination of pioglitazone and metformin. The addition ofsitagliptin to pioglitazone and metformin provided significant improvements in glycaemic parameters.

Change from baseline in body weight was similar for patients treated with sitagliptin relative toplacebo. The incidence of hypoglycaemia was also similar in patients treated with sitagliptin orplacebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. Inpatients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.

The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters.

There was no meaningful change from baseline in body weight in either group.

In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily incombination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements inglycaemic parameters compared with either monotherapy. The decrease in body weight with thecombination of sitagliptin and metformin was similar to that observed with metformin alone orplacebo; there was no change from baseline for patients on sitagliptin alone. The incidence ofhypoglycaemia was similar across treatment groups.

Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies*

Study Mean Mean change from Placebo-correctedbaseline baseline HbA1c mean change in

HbA1c (%)† HbA1c (%)†(%) (95 % CI)

Monotherapy studies

Sitagliptin 100 mg once daily§ 8.0 -0.5 -0.6‡(N= 193) (-0.8, -0.4)

Sitagliptin 100 mg once dailyǁ 8.0 -0.6 -0.8‡(N= 229) (-1.0, -0.6)

Combination therapy studies

Sitagliptin 100 mg once daily added 8.0 -0.7 -0.7‡

Study Mean Mean change from Placebo-correctedbaseline baseline HbA1c mean change in

HbA1c (%)† HbA1c (%)†(%) (95 % CI)to ongoing metformin therapyǁ (-0.8, -0.5)(N= 453)

Sitagliptin 100 mg once daily added 8.1 -0.9 -0.7‡to ongoing pioglitazone therapyǁ (-0.9, -0.5)(N= 163)

Sitagliptin 100 mg once daily added 8.4 -0.3 -0.6‡to ongoing glimepiride therapyǁ (-0.8, -0.3)(N= 102)

Sitagliptin 100 mg once daily added 8.3 -0.6 -0.9‡to ongoing glimepiride + metformin (-1.1, -0.7)therapyǁ(N= 115)

Sitagliptin 100 mg once daily added 8.8 -1.2 -0.7‡to ongoing pioglitazone + (-1.0, -0.5)metformin therapy#(N= 152)

Initial therapy (twice daily)ǁ: 8.8 -1.4 -1.6‡

Sitagliptin 50 mg + metformin (-1.8, -1.3)500 mg(N= 183)

Initial therapy (twice daily)ǁ: 8.8 -1.9 -2.1‡

Sitagliptin 50 mg + metformin (-2.3, -1.8)1,000 mg(N= 178)

Sitagliptin 100 mg once daily added 8.7 -0.6¶ -0.6‡,¶to ongoing insulin (+/- metformin) (-0.7, -0.4)therapyǁ(N= 305)

* All patients treated population (an intention-to-treat analysis).† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.‡ p< 0.001 compared to placebo or placebo + combination treatment.§ HbA1c (%) at week 18.ǁ

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 (pre-mixed vs. non-pre-mixed[intermediate- or long-acting]), and baseline value. Treatment by stratum (metformin and insulin use) interactions were notsignificant (p > 0.10).

A 24-week active (metformin)-controlled study was designed to evaluate the efficacy and safety ofsitagliptin 100 mg once daily (N= 528) compared to metformin (N= 522) in patients with inadequateglycaemic control on diet and exercise and who were not on anti-hyperglycaemic therapy (off therapyfor at least 4 months). The mean dose of metformin was approximately 1,900 mg per day. Thereduction in HbA1c from mean baseline values of 7.2 % was -0.43 % for sitagliptin and -0.57 % formetformin (Per Protocol Analysis). The overall incidence of gastrointestinal adverse reactionsconsidered as drug-related in patients treated with sitagliptin was 2.7 % compared with 12.6 % inpatients treated with metformin. The incidence of hypoglycaemia was not significantly differentbetween the treatment groups (sitagliptin, 1.3 %; metformin, 1.9 %). Body weight decreased frombaseline in both groups (sitagliptin, -0.6 kg; metformin -1.9 kg).

In a study comparing the efficacy and safety of the addition of sitagliptin 100 mg once daily orglipizide (a sulphonylurea) in patients with inadequate glycaemic control on metformin monotherapy,sitagliptin was similar to glipizide in reducing HbA1c. The mean glipizide dose used in the comparatorgroup was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of 5 mg/day throughout the study. However, more patients in the sitagliptin group discontinued due tolack of efficacy than in the glipizide group. Patients treated with sitagliptin exhibited a significantmean decrease from baseline in body weight compared to a significant weight gain in patientsadministered glipizide (-1.5 vs. +1.1 kg). In this study, the proinsulin to insulin ratio, a marker ofefficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with glipizidetreatment. The incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantly lowerthan that in the glipizide group (32.0 %).

A 24-week placebo-controlled study involving 660 patients was designed to evaluate the insulin-sparing efficacy and safety of sitagliptin (100 mg once daily) added to insulin glargine with or withoutmetformin (at least 1,500 mg) during intensification of insulin therapy. Baseline HbA1c was 8.74 %and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dosebased on fingerstick fasting glucose values. At week 24, the increase in daily insulin dose was19 IU/day in patients treated with sitagliptin and 24 IU/day in patients treated with placebo.

The reduction in HbA1c in patients treated with sitagliptin and insulin (with or without metformin) was

- 1.31 % compared to -0.87 % in patients treated with placebo and insulin (with or without metformin),a difference of -0.45 % [95 % CI: - 0.60, - 0.29]. The incidence of hypoglycaemia was 25.2 % inpatients treated with sitagliptin and insulin (with or without metformin) and 36.8 % in patients treatedwith placebo and insulin (with or without metformin). The difference was mainly due to a higherpercentage of patients in the placebo group experiencing 3 or more episodes of hypoglycaemia (9.4 vs.

19.1 %). There was no difference in the incidence of severe hypoglycaemia.

A study comparing sitagliptin at 25 or 50 mg once daily to glipizide at 2.5 to 20 mg/day wasconducted in patients with moderate to severe renal impairment. This study involved 423 patients withchronic renal impairment (estimated glomerular filtration rate < 50 mL/min). After 54 weeks, themean reduction from baseline in HbA1c was -0.76 % with sitagliptin and -0.64 % with glipizide(Per-Protocol Analysis). In this study, the efficacy and safety profile of sitagliptin at 25 or 50 mg oncedaily was generally similar to that observed in other monotherapy studies in patients with normal renalfunction. The incidence of hypoglycaemia in the sitagliptin group (6.2 %) was significantly lower thanthat in the glipizide group (17.0 %). There was also a significant difference between groups withrespect to change from baseline body weight (sitagliptin -0.6 kg; glipizide +1.2 kg).

Another study comparing sitagliptin at 25 mg once daily to glipizide at 2.5 to 20 mg/day wasconducted in 129 patients with ESRD who were on dialysis. After 54 weeks, the mean reduction frombaseline in HbA1c was -0.72 % with sitagliptin and -0.87 % with glipizide. In this study, the efficacyand safety profile of sitagliptin at 25 mg once daily was generally similar to that observed in othermonotherapy studies in patients with normal renal function. The incidence of hypoglycaemia was notsignificantly different between the treatment groups (sitagliptin, 6.3 %; glipizide, 10.8 %).

In another study involving 91 patients with type 2 diabetes and chronic renal impairment (creatinineclearance < 50 mL/min), the safety and tolerability of treatment with sitagliptin at 25 or 50 mg oncedaily were generally similar to placebo. In addition, after 12 weeks, the mean reductions in HbA1c(sitagliptin -0.59 %; placebo -0.18 %) and FPG (sitagliptin -25.5 mg /dL; placebo -3.0 mg /dL) weregenerally similar to those observed in other monotherapy studies in patients with normal renal function(see section 5.2).

The TECOS was a randomised study in 14,671 patients in the intention-to-treat population with an

HbA1c of ≥ 6.5 to 8.0 % with established CV disease who received sitagliptin (7,332) 100 mg daily (or50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7,339) added tousual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR< 30 mL/min/1.73 m2 were not to be enrolled in the study. The study population included2,004 patients ≥ 75 years of age and 3,324 patients with renal impairment(eGFR < 60 mL/min/1.73 m2).

Over the course of the study, the overall estimated mean (SD) difference in HbA1c between thesitagliptin and placebo groups was 0.29 % (0.01), 95 % CI (-0.32, -0.27); p < 0.001.

The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death,nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Secondarycardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardialinfarction, or nonfatal stroke; first occurrence of the individual components of the primary composite;all-cause mortality; and hospital admissions for congestive heart failure.

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

Table 3. Rates of composite cardiovascular outcomes and key secondary outcomes

Sitagliptin 100 mg Placebo

Inciden Incidence rate ce rateper 100 per 100patient patient Hazard Ratio

N (%) years* N (%) years* (95 % CI) p-value†

Analysis in the intention-to-treat population

Number of patients 7,332 7,339

Primary compositeendpoint(Cardiovascular death,nonfatal myocardialinfarction, nonfatalstroke, or hospitalizationfor unstable angina) 839 (11.4) 4.1 851 (11.6) 4.2 0.98 (0.89-1.08) < 0.001

Secondary compositeendpoint(Cardiovascular death,nonfatal myocardialinfarction, or nonfatalstroke) 745 (10.2) 3.6 746 (10.2) 3.6 0.99 (0.89-1.10) < 0.001

Secondary outcome

Cardiovascular death 380 (5.2) 1.7 366 (5.0) 1.7 1.03 (0.89-1.19) 0.711

All myocardial infarction(fatal and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5 0.95 (0.81-1.11) 0.487

All stroke (fatal and non-fatal) 178 (2.4) 0.8 183 (2.5) 0.9 0.97 (0.79-1.19) 0.760

Hospitalization forunstable 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 heartfailure‡ 228 (3.1) 1.1 229 (3.1) 1.1 1.00 (0.83-1.20) 0.983

* Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥ 1 event during eligible exposureperiod per total patient-years of follow-up).† Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a test of non-inferiorityseeking to show that the hazard ratio is less than 1.3. For all other endpoints, the p-values correspond to a test of differences inhazard rates.‡ The analysis of hospitalization for heart failure was adjusted for a history of heart failure at baseline.

A 54-week, double-blind study was conducted to evaluate the efficacy and safety of sitagliptin 100 mgonce daily in paediatric patients (10 to 17 years of age) with type 2 diabetes who were not onanti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5 % to 10 %) or were on a stabledose of insulin for at least 12 weeks (with HbA1c 7 % to 10 %). Patients were randomised to sitagliptin100 mg once daily or placebo for 20 weeks.

Mean baseline HbA1c was 7.5 %. Treatment with sitagliptin 100 mg did not provide significantimprovement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with sitagliptin (N= 95)was 0.0 % compared to 0.2% in patients treated with placebo (N= 95), a difference of -0.2 % (95 %

CI: - 0.7, 0.3). See section 4.2.

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 AUCof sitagliptin was 8.52  M*hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin isapproximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on thepharmacokinetics, sitagliptin may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was notestablished for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hrincreased in a less than dose-proportional manner).

The mean volume of distribution at steady state following a single 100-mg intravenous dose ofsitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly boundto plasma proteins is low (38 %).

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 asmetabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected tocontribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that theprimary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contributionfrom 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.

Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100 % ofthe administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week ofdosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance wasapproximately 350 mL /min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.

Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved inthe renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has notbeen established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved inmediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did notreduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50= 160 M) or p-glycoprotein (up to250 M) mediated transport at therapeutically relevant plasma concentrations. In a clinical studysitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be amild inhibitor of p-glycoprotein.

The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients withtype 2 diabetes.

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose ofsitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normalhealthy control subjects. The study included patients with mild, moderate, and severe renalimpairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renalimpairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, orsevere renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased byapproximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to< 90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively.

Because increases of this magnitude are not clinically relevant, dose adjustment in these patients is notnecessary.

Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renalimpairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renalimpairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. Sitagliptin wasmodestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients withnormal renal function, lower doses are recommended in patients with GFR < 45 mL/min (seesection 4.2).

No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment(Child-Pugh score  9). There is no clinical experience in patients with severe hepatic impairment(Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepaticimpairment is not expected to affect the pharmacokinetics of sitagliptin.

No dose adjustment is required based on age. Age did not have a clinically meaningful impact on thepharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase IIdata. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations ofsitagliptin compared to younger subjects.

The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated inpaediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted

AUC of sitagliptin in plasma was approximately 18 % lower compared to adult patients with type 2diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference comparedto adult patients based on the flat PK/PD relationship between the dose of 50 mg and 100 mg. Nostudies with sitagliptin have been performed in paediatric patients with age < 10 years.

Other patient characteristics

No dose adjustment is necessary based on gender, race, or body mass index (BMI). Thesecharacteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on acomposite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of

Phase I and Phase II data.

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the humanexposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teethabnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58-fold based on the 14-week rat study. The relevance of thesefindings for humans is unknown. Transient treatment-related physical signs, some of which suggestneural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration wasalso observed histologically at doses resulting in systemic exposure levels of approximately 23 timesthe human exposure level. A no-effect level for these findings was found at an exposure 6-fold theclinical exposure level.

Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was notcarcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas atsystemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown tocorrelate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in ratswas likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situationin humans.

No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to andthroughout mating.

In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.

Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal ribmalformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levelsmore than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than29 times the human exposure levels. Because of the high safety margins, these findings do not suggesta relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk oflactating rats (milk/plasma ratio: 4:1).

Tablet coremicrocrystalline cellulose (E460)calcium hydrogen phosphatecroscarmellose sodium (E468)magnesium stearate (E470b)

Film coatingpoly(vinyl alcohol)macrogol 3350talc (E553b)titanium dioxide (E171)red iron oxide (E172)yellow iron oxide (E172)

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

PVC/PE/PVDC-aluminium opaque blisters and OPA/alu/PVC/alu opaque blisters. Packs of 28, 30, 56,98 or 100 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6a Planta,08039,Barcelona,

Spain

Sitagliptin Accord 25 mg film-coated tablets

EU/1/22/1633/001

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EU/1/22/1633/004

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EU/1/22/1633/017

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Sitagliptin Accord 50 mg film-coated tablets

EU/1/22/1633/006

EU/1/22/1633/007

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EU/1/22/1633/010

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Sitagliptin Accord 100 mg film-coated tablets

EU/1/22/1633/011

EU/1/22/1633/012

EU/1/22/1633/013

EU/1/22/1633/014

EU/1/22/1633/015

EU/1/22/1633/026

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Date of first authorisation: 25 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.