SITAGLIPTIN/CLORHIDRAT DE METFORMIN SUN 50mg / 1000mg film-coated tablets medication leaflet

Sitagliptin/Metformin hydrochloride SUN 50 mg/850 mg film-coated tablets

Sitagliptin/Metformin hydrochloride SUN 50 mg/1 000 mg film-coated tablets

Sitagliptin/Metformin hydrochloride SUN 50 mg/850 mg film-coated tablets

Each tablet contains sitagliptin fumarate equivalent to 50 mg of sitagliptin and 850 mg of metforminhydrochloride.

Each film-coated tablet contains 6.9 mg of hydrogenated castor oil.

Sitagliptin/Metformin hydrochloride SUN 50 mg/1 000 mg film-coated tablets

Each tablet contains sitagliptin fumarate equivalent to 50 mg of sitagliptin and 1 000 mg of metforminhydrochloride.

Each film-coated tablet contains 8.0 mg of hydrogenated castor oil.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Sitagliptin/Metformin hydrochloride SUN 50 mg/850 mg film-coated tablets

Pink, capsule-shaped film-coated tablets, dimensions approximately 20 mm x 10 mm x 6 mm,debossed with “SC1”on one side.

Sitagliptin/Metformin hydrochloride SUN 50 mg/1 000 mg film-coated tablets

Brown to reddish brown, capsule-shaped film-coated tablets, dimensions approximately 22 mm x 11mm x 7 mm, debossed with “SC7” on one side.

For adult patients with type 2 diabetes mellitus:

Sitagliptin/Metformin hydrochloride SUN is indicated as an adjunct to diet and exercise to improveglycaemic control in patients inadequately controlled on their maximal tolerated dose of metforminalone or those already being treated with the combination of sitagliptin and metformin.

Sitagliptin/Metformin hydrochloride SUN is indicated in combination with a sulphonylurea (i.e., triplecombination therapy) as an adjunct to diet and exercise in patients inadequately controlled on theirmaximal tolerated dose of metformin and a sulphonylurea.

Sitagliptin/Metformin hydrochloride SUN is indicated as triple combination therapy with aperoxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) as anadjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose ofmetformin and a PPARγ agonist.

Sitagliptin/Metformin hydrochloride SUN is also indicated as add-on to insulin (i.e., triplecombination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients whenstable dose of insulin and metformin alone do not provide adequate glycaemic control.

The dose of antihyperglycaemic therapy with sitagliptin/metformin hydrochloride should beindividualised on the basis of the patient’s current regimen, effectiveness, and tolerability while notexceeding the maximum recommended daily dose of 100 mg sitagliptin.

Adults with normal renal function (GFR ≥ 90 mL/min)

For patients inadequately controlled on maximal tolerated dose of metformin monotherapy

For patients not adequately controlled on metformin alone, the usual starting dose should providesitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin alreadybeing taken.

For patients switching from co-administration of sitagliptin and metformin

For patients switching from co-administration of sitagliptin and metformin, sitagliptin/metforminhydrochloride should be initiated at the dose of sitagliptin and metformin already being taken.

For patients inadequately controlled on dual combination therapy with the maximal tolerated dose ofmetformin and a sulphonylurea

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose ofmetformin similar to the dose already being taken. When sitagliptin/metformin hydrochloride is usedin combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce therisk of hypoglycaemia (see section 4.4).

For patients inadequately controlled on dual combination therapy with the maximal tolerated dose ofmetformin and a PPARγ agonist

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose ofmetformin similar to the dose already being taken.

For patients inadequately controlled on dual combination therapy with insulin and the maximaltolerated dose of metformin

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose ofmetformin similar to the dose already being taken. When sitagliptin/metformin hydrochloride is usedin combination with insulin, a lower dose of insulin may be required to reduce the risk ofhypoglycaemia (see section 4.4).

For the different doses on metformin, Sitagliptin/Metformin hydrochloride SUN is available instrengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1 000 mg metforminhydrochloride.

All patients should continue their recommended diet with an adequate distribution of carbohydrateintake during the day.

No dose adjustment is needed for patients with mild renal impairment (glomerular filtration rate[GFR] ≥ 60 mL/min). A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progressionof renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors thatmay increase the risk of lactic acidosis (see section 4.4) should be reviewed before consideringinitiation of metformin in patients with GFR < 60 mL/min.

If no adequate strength of sitagliptin/metformin hydrochloride is available, individualmonocomponents should be used instead of the fixed-dose combination.

Table 1: Dose adjustment for renal impaired population

GFR mL/min Metformin Sitagliptin60-89 Maximum daily dose is 3000 mg. Dose Maximum daily dose is 100 mg.reduction may be considered in relationto declining renal function.

45-59 Maximum daily dose is 2000 mg. Maximum daily dose is 100 mg.

The starting dose is at most half of themaximum dose.

30-44 Maximum daily dose is 1 000 mg. Maximum daily dose is 50 mg.

The starting dose is at most half of themaximum dose.

< 30 Metformin is contraindicated. Maximum daily dose is 25 mg.

Sitagliptin/metformin hydrochloride must not be used in patients with hepatic impairment (see section5.2).

As metformin and sitagliptin are excreted by the kidney, sitagliptin/metformin hydrochloride shouldbe used with caution as age increases. Monitoring of renal function is necessary to aid in prevention ofmetformin-associated lactic acidosis, particularly in the elderly (see sections 4.3 and 4.4).

Sitagliptin/metformin hydrochloride should not be used in children and adolescents 10 to 17 years ofage because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and5.2. Sitagliptin/metformin hydrochloride has not been studied in paediatric patients under 10 years ofage.

Oral use.

Sitagliptin/metformin hydrochloride should be given twice daily with meals to reduce thegastrointestinal adverse reactions associated with metformin.

Sitagliptin/metformin hydrochloride is contraindicated in patients with:

- hypersensitivity to the active substances or to any of the excipients listed in section 6.1 (seesections 4.4 and 4.8);

- any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);

- diabetic pre-coma;

- severe renal failure (GFR< 30 mL/min) (see section 4.4);

- acute conditions with the potential to alter renal function such as:

- dehydration,

- severe infection,

- shock,

- intravascular administration of iodinated contrast agents (see section 4.4);

- acute or chronic disease which may cause tissue hypoxia such as:

- cardiac or respiratory failure,

- recent myocardial infarction,

- shock;

- hepatic impairment;

- acute alcohol intoxication, alcoholism;

- breast-feeding.

Sitagliptin/metformin hydrochloride should not be used in patients with type 1 diabetes and must notbe used for the treatment of diabetic ketoacidosis.

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/metformin hydrochloride and otherpotentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed,sitagliptin/metformin hydrochloride should not be restarted. Caution should be exercised in patientswith a history of pancreatitis.

Lactic acidosis

Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening ofrenal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acuteworsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should betemporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and

NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lacticacidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis,prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinalproducts that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking metformin and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35),increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2).

Sitagliptin/metformin hydrochloride is contraindicated in patients with GFR < 30 mL/min and shouldbe temporarily discontinued during conditions with the potential to alter renal function (see section4.3).

Patients receiving sitagliptin/metformin hydrochloride in combination with a sulphonylurea or withinsulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea orinsulin may be necessary.

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 sitagliptin, with some reports occurring after the first dose. If ahypersensitivity reaction is suspected, sitagliptin/metformin hydrochloride should be discontinued,other potential causes of the event should be assessed, and alternative treatment for diabetes should beinstituted (see section 4.8).

Bullous pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitorsincluding sitagliptin. If bullous pemphigoid is suspected, sitagliptin/metformin hydrochloride shouldbe discontinued.

Sitagliptin/metformin hydrochloride must be discontinued at the time of surgery under general, spinalor epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery orresumption of oral nutrition and provided that renal function has been re-evaluated and found to bestable.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy,resulting in metformin accumulation and an increased risk of lactic acidosis. Sitagliptin/metforminhydrochloride should be discontinued prior to or at the time of the imaging procedure and not restarteduntil at least 48 hours after, provided that renal function has been re-evaluated and found to be stable(see sections 4.3 and 4.5).

Change in clinical status of patients with previously controlled type 2 diabetes

A patient with type 2 diabetes previously well controlled on sitagliptin/metformin hydrochloride whodevelops laboratory abnormalities or clinical illness (especially vague and poorly defined illness)should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation shouldinclude serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate,and metformin levels. If acidosis of either form occurs, treatment must be stopped immediately andother appropriate corrective measures initiated.

Vitamin B12 Deficiency

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases withincreasing metformin dose, treatment duration, and/or in patients with risk factors known to causevitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia orneuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring couldbe necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should becontinued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment forvitamin B12 deficiency provided in line with current clinical guidelines.

This medicinal product contains hydrogenated castor oil which may cause stomach upset anddiarrhoea

Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1 000 mg twicedaily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patientswith type 2 diabetes.

Pharmacokinetic drug interaction studies with sitagliptin/metformin hydrochloride have not beenperformed; however, such studies have been conducted with the individual active substances,sitagliptin and metformin.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases offasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Sitagliptin/metformin hydrochloride must be discontinued prior to or at the time of the imagingprocedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.3 and 4.4).

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function, which may increase the risk of lacticacidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using suchproducts in combination with metformin, close monitoring of renal function is necessary.

Concomitant use of medicinal products that interfere with common renal tubular transport systemsinvolved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrugand toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine)could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Considerthe benefits and risks of concomitant use. Close monitoring of glycaemic control, dose adjustmentwithin the recommended posology and changes in diabetic treatment should be considered when suchproducts are co-administered.

Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment with such medicinal products. If necessary, thedose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the othermedicinal product and on its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal productand on its discontinuation.

Effects of other medicinal products on sitagliptin

In vitro and clinical data described below suggest that the risk for clinically meaningful interactionsfollowing co-administration of other 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 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 inpatients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the settingof renal impairment have 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.

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 ofsitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin byapproximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were notconsidered 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 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 of sitagliptin (see section 5.3).

A limited amount of data suggests the use of metformin in pregnant women is not associated with anincreased risk of congenital malformations. Animal studies with metformin do not indicate harmfuleffects with respect to pregnancy, embryonic or foetal development, parturition or postnataldevelopment (see section 5.3).

Sitagliptin/metformin hydrochloride should not be used during pregnancy. If a patient wishes tobecome pregnant or if a pregnancy occurs, treatment should be discontinued and the patient switchedto insulin treatment as soon as possible.

No studies in lactating animals have been conducted with the combined active substances of thismedicinal product. In studies performed with the individual active substances, both sitagliptin andmetformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in smallamounts. It is not known whether sitagliptin is excreted in human milk. Sitagliptin/metforminhydrochloride must therefore not be used in women who are breast-feeding (see section 4.3).

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

Sitagliptin/metformin hydrochloride has no or negligible influence on the ability to drive and usemachines. However, when driving or using machines, it should be taken into account that dizzinessand somnolence have been reported with sitagliptin.

In addition, patients should be alerted to the risk of hypoglycaemia when sitagliptin/metforminhydrochloride is used in combination with a sulphonylurea or with insulin.

There have been no therapeutic clinical studies conducted with sitagliptin/metformin hydrochloridetablets however bioequivalence of sitagliptin/metformin hydrochloride with co-administeredsitagliptin and metformin has been demonstrated (see section 5.2).

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.

Hypoglycaemia has been reported in combination with sulphonylurea (13.8 %) and insulin (10.9 %).

Sitagliptin and metformin

Adverse reactions are listed below as MedDRA preferred term by system organ class and absolutefrequency (Table 2). 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 notknown (cannot be estimated from the available data).

Table 2: The frequency of adverse reactions identified from placebo-controlled clinical studies ofsitagliptin and metformin alone, 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

Vitamin B12 decrease/deficiency† Common

Nervous system disorderssomnolence Uncommon

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

Gastrointestinal disordersdiarrhoea Uncommonnausea Commonflatulence Commonconstipation Uncommonupper abdominal pain Uncommonvomiting Commonacute pancreatitis*,†,‡ Frequency not knownfatal and non-fatal haemorrhagic and necrotizing 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 knownpain in extremity* 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.

Some adverse reactions were observed more frequently in studies of combination use of sitagliptin andmetformin with other anti-diabetic medicinal products than in studies of sitagliptin and metforminalone. These included hypoglycaemia (frequency very common with sulphonylurea or insulin),constipation (common with sulphonylurea), peripheral oedema (common with pioglitazone), andheadache and dry mouth (uncommon with insulin).

Sitagliptin

In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactionsreported were headache, hypoglycaemia, constipation, and dizziness.

Among these patients, adverse events reported regardless of causal relationship to medicinal productoccurring in at least 5 % included upper respiratory tract infection and nasopharyngitis. In addition,osteoarthritis and pain in extremity were reported with frequency uncommon (> 0.5 % higher amongsitagliptin users than that in the control group).

Gastrointestinal symptoms were reported very commonly in clinical studies and post-marketing use ofmetformin. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss ofappetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

Additional adverse reactions associated with metformin include metallic taste (common); lacticacidosis, liver function disorders, hepatitis, urticaria, erythema, and pruritus (very rare).

Frequency categories are based on information available from metformin Summary of Product

Characteristics available in the EU.

In clinical studies with sitagliptin/metformin hydrochloride in paediatric patients with type 2 diabetesmellitus aged 10 to 17 years, the profile of adverse reactions was generally comparable to thatobserved in adults. In paediatric patients on or not on background insulin, sitagliptin was associatedwith an increased risk of hypoglycaemia.

TECOS Cardiovascular Safety Study

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7332 patientstreated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and< 50 mL/min/1.73 m2), and 7339 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 inpatients 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 % 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 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 studies 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.

A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosiswhich is a medical emergency and must be treated in hospital. The most effective method to removelactate and metformin is haemodialysis.

In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysissession. Prolonged haemodialysis may be considered if clinically appropriate. It is not known ifsitagliptin is dialysable by peritoneal dialysis.

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.

Pharmacotherapeutic group: Medicinal products used in diabetes, Combinations of oral blood glucoselowering medicinal products, ATC code: A10BD07

Sitagliptin/Metformin hydrochloride SUN combines two antihyperglycaemic medicinal products withcomplementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes:sitagliptin fumarate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, amember of the biguanide class.

Sitagliptin

Sitagliptin fumarate is an orally-active, potent, and highly selective inhibitor of the dipeptidylpeptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class ofagents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levelsof two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependentinsulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in thephysiologic regulation of glucose homeostasis. When blood glucose concentrations are normal orelevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 alsolowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.

When blood glucose levels are low, insulin release is not enhanced and glucagon secretion is notsuppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does notinhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs inchemical structure and pharmacological action from GLP-1 analogues, insulin, sulphonylureas ormeglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues.

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.

In clinical studies, sitagliptin as monotherapy improved glycaemic control with significant reductionsin haemoglobin A1c (HbA1c) and fasting and postprandial glucose. Reduction in fasting plasma glucose(FPG) was observed at 3 weeks, the first time point at which FPG was measured. The observedincidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo. Body weightdid not increase from baseline with sitagliptin therapy. Improvements in 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.

Studies of sitagliptin in combination with metformin

In a 24-week, placebo-controlled clinical study to evaluate the efficacy and safety of the addition ofsitagliptin 100 mg once daily to ongoing metformin, sitagliptin provided significant improvements inglycaemic parameters compared with placebo. Change from baseline in body weight was similar forpatients treated with sitagliptin relative to placebo. In this study there was a similar incidence ofhypoglycaemia reported for patients treated with sitagliptin or placebo.

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.

Study of sitagliptin in combination with metformin and a sulphonylurea

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 in combination with metformin). The addition ofsitagliptin to glimepiride and metformin provided significant improvements in glycaemic parameters.

Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to thosegiven placebo.

Study of sitagliptin in combination with metformin and a PPARγ agonist

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.

Study of sitagliptin in combination with metformin and insulin

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 1500 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.

Data from the 73 % of patients who were taking metformin are presented in Table 3. The addition ofsitagliptin to insulin provided significant improvements in glycaemic parameters. There was nomeaningful change from baseline in body weight in either group.

Table 3: HbA1c results in placebo-controlled combination therapy studies of sitagliptin andmetformin*

Mean

Study baseline Mean change from Placebo-corrected meanbaseline HbA (%) change in HbA1c (%)

HbA1c (%) 1c (95 % CI)

Sitagliptin 100 mg oncedaily added to ongoing † -0.7†,‡metformin therapy II 8.0 -0.7 (-0.8, -0.5)(N=453)

Sitagliptin 100 mg oncedaily added to ongoing †,‡glimepiride + metformin 8.3 -0.6† -0.9therapy II (-1.1, -0.7)(N=115)

Sitagliptin 100 mg oncedaily added to ongoing †,‡pioglitazone + metformin 8.8 -1.2† -0.7therapy¶ (-1.0, -0.5)(N=152)

Sitagliptin 100 mg oncedaily added to ongoing§,‡insulin + metformin 8.7 -0.7§ -0.5therapy II (-0.7, -0.4)(N=223)

Initial Therapy (twicedaily) II:

†,‡

Sitagliptin 50 mg + 8.8 -1.4† -1.6metformin 500 mg (-1.8, -1.3)(N=183)

Initial Therapy (twicedaily) II:

†,‡

Sitagliptin 50 mg + 8.8 -1.9† -2.1metformin 1 000 mg (-2.3, -1.8)(N=178)

* 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.

II HbA1c (%) at week 24.¶ HbA1c (%) at week 26.§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.

In a 52-week study, comparing the efficacy and safety of the addition of sitagliptin 100 mg once dailyor glipizide (a sulphonylurea) in patients with inadequate glycaemic control on metforminmonotherapy, sitagliptin was similar to glipizide in reducing HbA1c (-0.7 % mean change frombaselines at week 52, with baseline HbA1c of approximately 7.5 % in both groups). The mean glipizidedose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring aglipizide dose of ≤ 5 mg/day throughout the study. However, more patients in the sitagliptin groupdiscontinued due to lack of efficacy than in the glipizide group. Patients treated with sitagliptinexhibited a significant mean decrease from baseline in body weight (-1.5 kg) compared to a significantweight gain in patients administered glipizide (+1.1 kg). In this study, the proinsulin to insulin ratio, amarker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated withglipizide treatment. The incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantlylower than 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 1500 mg) during intensification of insulin therapy. Among patients takingmetformin, baseline HbA1c was 8.70 % and baseline insulin dose was 37 IU/day. Patients wereinstructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. Amongpatients taking metformin, at Week 24, the increase in daily insulin dose was 19 IU/day in patientstreated with sitagliptin and 24 IU/day in patients treated with placebo. The reduction in HbA1c forpatients treated with sitagliptin, metformin, and insulin was -1.35 % compared to -0.90 % for patientstreated with placebo, metformin, and insulin, a difference of -0.45 % [95 % CI: -0.62, -0.29]. Theincidence of hypoglycaemia was 24.9 % for patients treated with sitagliptin, metformin, and insulinand 37.8 % for patients treated with placebo, metformin, and insulin. The difference was mainly due toa higher percentage of patients in the placebo group experiencing 3 or more episodes ofhypoglycaemia (9.1 vs. 19.8 %). There was no difference in the incidence of severe hypoglycaemia.

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandialplasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via three mechanisms:

- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake andutilisation

- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metforminincreases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and

GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term or long-termclinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.

The prospective randomised (UKPDS) study has established the long-term benefit of intensive bloodglucose control in type 2 diabetes. Analysis of the results for overweight patients treated withmetformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (29.8 events/1 000 patient-years) versus diet alone (43.3 events/1 000 patient-years),p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1events/1 000 patient-years), p=0.0034

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5events/1 000 patient-years, diet alone 12.7 events/1 000 patient-years, p=0.017

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1 000patient-years versus diet alone 20.6 events/1 000 patient-years, (p=0.011), and versus thecombined sulphonylurea and insulin monotherapy groups 18.9 events/1 000 patient-years(p=0.021)

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1 000patient-years, diet alone 18 events/1 000 patient-years, (p=0.01).

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 (7332) 100 mg daily (or50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7339) 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 included 2004patients ≥ 75 years of age and 3324 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 hospitalisation 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 hospitalisation for heart failure compared to usualcare without sitagliptin in patients with type 2 diabetes (Table 4).

Table 4: Rates of composite cardiovascular outcomes and key secondary outcomes

Sitagliptin 100 mg Placebo

Incidence Incidencerate per rate per100 100patient- patient- Hazard Ratio p-

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

Analysis in the Intention-to-Treat Population

Number of patients 7332 7339

Primary Composite Endpoint(Cardiovascular death, nonfatalmyocardial infarction, nonfatal 839 (11.4) 4.1 851 (11.6) 4.2 0.98 (0.89- <0.001stroke, or hospitalisation for 1.08)unstable angina)

Secondary Composite

Endpoint(Cardiovascular death, nonfatal 745 (10.2) 3.6 746 (10.2) 3.6 0.99 (0.89- <0.001myocardial infarction, or 1.10)nonfatal stroke)

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 0.95 (0.81-and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5 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

Hospitalisation for unstableangina 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

Hospitalisation 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 ofpatients 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 differencesin hazard rates.‡ The analysis of hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

The European Medicines Agency has waived the obligation to submit the results of studies withsitagliptin/metformin hydrochloride in all subsets of the paediatric population in type 2 diabetesmellitus (see section 4.2 for information on paediatric use).

The safety and efficacy of the addition of sitagliptin in paediatric patients aged 10 to 17 years withtype 2 diabetes and inadequate glycaemic control on metformin with or without insulin was assessedin two studies over 54 weeks. The addition of sitagliptin (administered as sitagliptin + metformin orsitagliptin + metformin extended release (XR)) was compared to the addition of placebo to metforminor metformin XR.

While superiority of HbA1c reduction was demonstrated for sitagliptin + metformin/sitagliptin +metformin XR over metformin at Week 20 in the pooled analysis of these two studies, results from theindividual studies were inconsistent. Furthermore, greater efficacy for sitagliptin + metformin /sitagliptin + metformin XR compared to metformin was not observed at Week 54. Therefore,sitagliptin/metformin hydrochloride should not be used in paediatric patients aged 10 to 17 years oldbecause of insufficient efficacy (see section 4.2 for information on paediatric use).

Sitagliptin/metformin hydrochloride

A bioequivalence study in healthy subjects demonstrated that sitagliptin/metformin hydrochloridecombination tablets are bioequivalent to co-administration of sitagliptin and metformin hydrochlorideas individual tablets.

The following statements reflect the pharmacokinetic properties of the individual active substances of

Sitagliptin/Metformin hydrochloride SUN.

Sitagliptin

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 µM*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 isoenzymes 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 t½ 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 µM) or p-glycoprotein (up to 250µM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptinhad a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitorof p-glycoprotein.

The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type2 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 patients with ESRD on haemodialysis. Sitagliptin wasmodestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting 4hours post-dose).

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. No studies with sitagliptin have been performed in paediatric patients < 10years of age.

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.

After an oral dose of metformin, Tmax is reached in 2.5 h. Absolute bioavailability of a 500 mgmetformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbedfraction recovered in faeces was 20-30 %.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosingschedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1µg/mL. In controlled clinical studies, maximum metformin plasma levels (Cmax) did not exceed 5µg/mL, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administrationof a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC and a 35 minprolongation of time to peak plasma concentration was observed. The clinical relevance of thisdecrease is unknown.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lowerthan the plasma peak and appears at approximately the same time. The red blood cells most likelyrepresent a secondary compartment of distribution. The mean Vd ranged between 63 - 276 L.

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerularfiltration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life isapproximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion tothat of creatinine and thus the elimination half-life is prolonged, leading to increased levels ofmetformin in plasma.

No animal studies have been conducted with sitagliptin/metformin hydrochloride.

In 16-week studies in which dogs were treated with either metformin alone or a combination ofmetformin and sitagliptin, no additional toxicity was observed from the combination. The NOEL inthese studies was observed at exposures to sitagliptin of approximately 6 times the human exposureand to metformin of approximately 2.5 times the human exposure.

The following data are findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

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 approximately 23times 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 treatment related effects on fertility were observed in male and female rats given sitagliptin prior toand throughout mating.

In a pre-/post-natal development study performed in rats sitagliptin showed no adverse reactions.

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 than 29times the human exposure levels. Because of the high safety margins, these findings do not suggest arelevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk oflactating rats (milk/plasma ratio: 4:1).

Preclinical data for metformin reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction.

Hydroxypropylcellulose (E463)

Calcium hydrogen phosphate (E341)

Crospovidone (E1202)

Hydrogenated castor oil

Glycerol dibehenate

Magnesium stearate (E470b)

Hypromellose

Hydroxypropylcellulose (E463)

Titanium dioxide (E171)

Talc (E553b)

Stearic acid

Red iron oxide (E172)

Yellow iron oxide (E172)

Not applicable.

2 years.

Do not store above 25 °C.

HDPE bottle with silica gel/carbon desiccant.

Pack sizes of 28 and 56 film-coated tablets in bottle with child-resistant closure or 200 film-coatedtablets in bottle with screw cap.

Not all pack sizes may be marketed.

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

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 872132JH Hoofddorp

The Netherlands

Sitagliptin/Metformin hydrochloride SUN 50 mg/850 mg film-coated tablets

EU/1/23/1720/001

EU/1/23/1720/002

EU/1/23/1720/003

Sitagliptin/Metformin hydrochloride SUN 50 mg/1 000 mg film-coated tablets

EU/1/23/1720/004

EU/1/23/1720/005

EU/1/23/1720/006

Date of first authorisation: 31 March 2023

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

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