XILIARX 50mg tablets medication leaflet

Xiliarx 50 mg tablets

Each tablet contains 50 mg of vildagliptin.

Excipient with known effect: Each tablet contains 47.82 mg lactose (anhydrous).

For the full list of excipients, see section 6.1.

Tablet.

White to light yellowish, round (8 mm diameter), flat-faced, bevelled-edge tablet. One side isdebossed with “NVR”, and the other side with “FB”.

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults withtype 2 diabetes mellitus:

* as monotherapy in patients in whom metformin is inappropriate due to contraindications orintolerance.

* in combination with other medicinal products for the treatment of diabetes, including insulin,when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 foravailable data on different combinations).

When used as monotherapy, in combination with metformin, in combination with thiazolidinedione, incombination with metformin and a sulphonylurea, or in combination with insulin (with or withoutmetformin), the recommended daily dose of vildagliptin is 100 mg, administered as one dose of 50 mgin the morning and one dose of 50 mg in the evening.

When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mgonce daily administered in the morning. In this patient population, vildagliptin 100 mg daily was nomore effective than vildagliptin 50 mg once daily.

When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be consideredto reduce the risk of hypoglycaemia.

Doses higher than 100 mg are not recommended.

If a dose of Xiliarx is missed, it should be taken as soon as the patient remembers. A double doseshould not be taken on the same day.

The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and athiazolidinedione have not been established.

Additional information on special populations

No dose adjustments are necessary in elderly patients (see also sections 5.1 and 5.2).

No dose adjustment is required in patients with mild renal impairment (creatinine clearance≥ 50 ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease(ESRD), the recommended dose of Xiliarx is 50 mg once daily (see also sections 4.4, 5.1 and 5.2).

Xiliarx should not be used in patients with hepatic impairment, including patients with pre-treatmentalanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal(ULN) (see also sections 4.4 and 5.2).

Xiliarx is not recommended for use in children and adolescents under (< 18 years). The safety andefficacy of Xiliarx in children and adolescents (< 18 years) have not been established. No data areavailable (see also section 5.1).

Oral use

Xiliarx can be administered with or without a meal (see also section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Xiliarx is not a substitute for insulin in insulin-requiring patients. Xiliarx should not be used inpatients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

There is limited experience in patients with ESRD on haemodialysis. Therefore Xiliarx should be usedwith caution in these patients (see also sections 4.2, 5.1 and 5.2).

Xiliarx should not be used in patients with hepatic impairment, including patients with pre-treatment

ALT or AST > 3x ULN (see also sections 4.2 and 5.2).

Liver enzyme monitoring

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patientswere generally asymptomatic without clinical sequelae and liver function test results returned tonormal after discontinuation of treatment. Liver function tests should be performed prior to theinitiation of treatment with Xiliarx in order to know the patient’s baseline value. Liver function shouldbe monitored during treatment with Xiliarx at three-month intervals during the first year andperiodically thereafter. Patients who develop increased transaminase levels should be monitored with asecond liver function evaluation to confirm the finding and be followed thereafter with frequent liverfunction tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT of 3x

ULN or greater persist, withdrawal of Xiliarx therapy is recommended.

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue

Xiliarx.

Following withdrawal of treatment with Xiliarx and LFT normalisation, treatment with Xiliarx shouldnot be reinitiated.

Cardiac failure

A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functionalclass I-III showed that treatment with vildagliptin was not associated with a change in left-ventricularfunction or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinicalexperience in patients with NYHA functional class III treated with vildagliptin is still limited andresults are inconclusive (see section 5.1).

There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IVand therefore use is not recommended in these patients.

Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increasedincidence in clinical trials, there was limited experience in patients with diabetic skin complications.

Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions.

Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such asblistering or ulceration, is recommended.

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should beinformed of the characteristic symptom of acute pancreatitis.

If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed,vildagliptin should not be restarted. Caution should be exercised in patients with a history of acutepancreatitis.

Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combinationwith a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea maybe considered to reduce the risk of hypoglycaemia.

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodiumfree’.

Vildagliptin has a low potential for interactions with co-administered medicinal products. Sincevildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducersof these enzymes.

Combination with pioglitazone, metformin and glyburide

Results from studies conducted with these oral antidiabetics have shown no clinically relevantpharmacokinetic interactions.

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)

Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokineticinteractions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan or simvastatin

Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartanand simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observedafter co-administration with vildagliptin.

Combination with ACE-inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors.(seesection 4.8).

As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may bereduced by certain active substances, including thiazides, corticosteroids, thyroid products andsympathomimetics.

There are no adequate data from the use of vildagliptin 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, Xiliarx should not be used during pregnancy.

It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion ofvildagliptin in milk. Xiliarx should not be used during breast-feeding.

No studies on the effect on human fertility have been conducted for Xiliarx (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Patients whoexperience dizziness as an adverse reaction should avoid driving vehicles or using machines.

Safety data were obtained from a total of 5 451 patients exposed to vildagliptin at a daily dose of100 mg (50 mg twice daily) in randomised double-blind placebo-controlled trials of at least 12 weeksduration. Of these patients, 4 622 patients received vildagliptin as monotherapy and 829 patientsreceived placebo.

The majority of adverse reactions in these trials were mild and transient, not requiring treatmentdiscontinuations. No association was found between adverse reactions and age, ethnicity, duration ofexposure or daily dose. Hypoglycaemia has been reported in patients receiving vildagliptinconcomitantly with sulphonylurea and insulin. The risk of acute pancreatitis has been reported withthe use of vildagliptin (see section 4.4).

Adverse reactions reported in patients who received Xiliarx in double-blind studies as monotherapyand add-on therapies are listed below for each indication by system organ class and absolutefrequency. 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), not known (cannot beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 1 Adverse reactions reported in patients who received vildagliptin as monotherapy oras add-on therapy in controlled clinical studies and in post-marketing experience

System organ class - adverse reaction Frequency

Nasopharyngitis Very common

Upper respiratory tract infection Common

Hypoglycaemia Uncommon

Dizziness Common

Headache Common

Tremor Common

Vision blurred Common

Constipation Common

Nausea Common

Gastro-oesophageal reflux disease Common

Diarrhoea Common

Abdominal pain, including upper Common

Vomiting Common

Flatulence Uncommon

Pancreatitis Rare

Hepatitis Not known*

Hyperhidrosis Common

Rash Common

Pruritis Common

Dermatitis Common

Urticaria Uncommon

Exfoliative and bullous skin lesions, including bullous pemphigoid Not known*

Cutaneous vasculitis Not known*

Arthralgia Common

Myalgia Common

Erectile dysfunction Uncommon

Asthenia Common

Oedema peripheral Common

Fatigue Uncommon

Chills Uncommon

Abnormal liver function tests Uncommon

Weight increase Uncommon

* Based on post-marketing experience.

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patientswere generally asymptomatic without clinical sequelae and liver function returned to normal afterdiscontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to24 weeks in duration, the incidence of ALT or AST elevations  3x ULN (classified as present on atleast 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% forvildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. Theseelevations in transaminases were generally asymptomatic, non-progressive in nature and notassociated with cholestasis or jaundice.

Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greaterproportion of cases were reported when vildagliptin was administered in combination with anangiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild inseverity and resolved with ongoing vildagliptin treatment.

Hypoglycaemia was uncommon when vildagliptin (0.4%) was used as monotherapy in comparativecontrolled monotherapy studies with an active comparator or placebo (0.2%). No severe or seriousevents of hypoglycaemia were reported. When used as add-on to metformin, hypoglycaemia occurredin 1% of vildagliptin-treated patients and in 0.4% of placebo-treated patients. When pioglitazone wasadded, hypoglycaemia occurred in 0.6% of vildagliptin-treated patients and in 1.9% of placebo-treatedpatients. When sulphonylurea was added, hypoglycaemia occurred in 1.2% of vildagliptin treatedpatients and in 0.6% of placebo-treated patients. When sulphonylurea and metformin were added,hypoglycaemia occurred in 5.1% of vildagliptin treated patients and in 1.9% of placebo treatedpatients. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemiawas 14% for vildagliptin and 16% for placebo.

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.

Information regarding overdose with vildagliptin is limited.

Information on the likely symptoms of overdose was taken from a rising dose tolerability study inhealthy subjects given Xiliarx for 10 days. At 400 mg, there were three cases of muscle pain, andindividual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipaselevels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatinephosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobinlevels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. Allsymptoms and laboratory abnormalities resolved without treatment after discontinuation of the studymedicinal product.

In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removedby haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed byhaemodialysis.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATCcode: A10BH02

Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity,resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1(glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivityof beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment withvildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved markers of betacell function including HOMA- (Homeostasis Model Assessment-), proinsulin to insulin ratio andmeasures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic(normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucoselevels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells toglucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretinhormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading toreduced glycaemia.

The known effect of increased GLP-1 levels delaying gastric emptying is not observed withvildagliptin treatment.

More than 15 000 patients with type 2 diabetes participated in double-blind placebo- or active-controlled clinical trials of up to more than 2 years’ treatment duration. In these studies, vildagliptinwas administered to more than 9 000 patients at daily doses of 50 mg once daily, 50 mg twice daily or100 mg once daily. More than 5 000 male and more than 4 000 female patients received vildagliptin50 mg once daily or 100 mg daily. More than 1 900 patients receiving vildagliptin 50 mg once daily or100 mg daily were ≥ 65 years. In these trials, vildagliptin was administered as monotherapy in drug-naïve patients with type 2 diabetes or in combination in patients not adequately controlled by otherantidiabetic medicinal products.

Overall, vildagliptin improved glycaemic control when given as monotherapy or when used incombination with metformin, a sulphonylurea, and a thiazolidinedione, as measured by clinicallyrelevant reductions in HbA1c from baseline at study endpoint (see Table 2).

In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients withhigher baseline HbA1c.

In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline HbA1cby -1% compared to -1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was notachieved. Patients treated with vildagliptin reported significantly lower incidences of gastrointestinaladverse reactions versus those treated with metformin.

In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared torosiglitazone (8 mg once daily). Mean reductions were -1.20% with vildagliptin and -1.48% withrosiglitazone in patients with mean baseline HbA1c of 8.7%. Patients receiving rosiglitazoneexperienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced noweight gain (-0.3 kg). The incidence of peripheral oedema was lower in the vildagliptin group than inthe rosiglitazone group (2.1% vs. 4.1% respectively).

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to gliclazide (upto 320 mg/day). After two years, mean reduction in HbA1c was -0.5% for vildagliptin and -0.6% forgliclazide, from a mean baseline HBA1c of 8.6%. Statistical non-inferiority was not achieved.

Vildagliptin was associated with fewer hypoglycaemic events (0.7%) than gliclazide (1.7%).

In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily)in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions frombaseline HbA1c of 8.4% were -0.9% with vildagliptin added to metformin and -1.0% with pioglitazoneadded to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazoneadded to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to glimepiride(up to 6 mg/day - mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily dose:

1894 mg). After 1 year mean reductions in HbA1c were -0.4% with vildagliptin added to metforminand -0.5% with glimepiride added to metformin, from a mean baseline HbA1c of 7.3%. Body weightchange with vildagliptin was -0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycaemiawas significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). Atstudy endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and thebody weight changes and hypoglycaemia differences were maintained.

In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose:

229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline1928 mg/day). After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin added tometformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (meanbaseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 - 0.20). Body weightchange with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.

In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (graduallytitrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy indrug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1cby -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin 1000 mg twicedaily by -1.36% and vildagliptin 50 mg twice daily by -1.09% from a mean baseline HbA1c of 8.6%.

The decrease in HbA1c observed in patients with a baseline ≥10.0% was greater.

A 24-week, multi-centre, randomised, double-blind, placebo-controlled trial was conducted to evaluatethe treatment effect of vildagliptin 50 mg once daily compared to placebo in 515 patients with type 2diabetes and moderate renal impairment (N=294) or severe renal impairment (N=221). 68.8% and80.5% of the patients with moderate and severe renal impairment respectively were treated withinsulin (mean daily dose of 56 units and 51.6 units respectively) at baseline. In patients with moderaterenal impairment vildagliptin significantly decreased HbA1c compared with placebo (differenceof -0.53%) from a mean baseline of 7.9%. In patients with severe renal impairment, vildagliptinsignificantly decreased HbA1c compared with placebo (difference of -0.56%) from a mean baseline of7.7%.

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 318 patients toevaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin(≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin andglimepiride significantly decreased HbA1c compared with placebo.The placebo-adjusted meanreduction from a mean baseline HbA1c of 8.8% was -0.76%.

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 449 patients toevaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable doseof basal or premixed insulin (mean daily dose 41 units), with concomitant use of metformin (N=276)or without concomitant metformin (N=173). Vildagliptin in combination with insulin significantlydecreased HbA1c compared with placebo. In the overall population, the placebo-adjusted meanreduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with orwithout concomitant metformin the placebo-adjusted mean reduction in HbA1c was -0.63%and -0.84%, respectively. The incidence of hypoglycaemia in the overall population was 8.4% and7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin experiencedno weight gain (+0.2 kg) while those receiving placebo experienced weight reduction (-0.7 kg).

In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled oninsulin (short and longer acting, average insulin dose 80 IU/day), the mean reduction in HbA1c whenvildagliptin (50 mg twice daily) was added to insulin was statistically significantly greater than withplacebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycaemia was lower in the vildagliptingroup than in the placebo group (22.9% vs. 29.6%).

A 52-week multi-centre, randomised, double-blind trial was conducted in patients with type 2 diabetesand congestive heart failure (NYHA functional class I-III) to evaluate the effect of vildagliptin 50 mgtwice daily (N=128) compared to placebo (N=126) on left-ventricular ejection fraction (LVEF).

Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing

CHF. Adjudicated cardiovascular events were balanced overall. There were more cardiac events invildagliptin treated patients with NYHA class III heart failure compared to placebo. However, therewere imbalances in baseline cardiovascular risk favouring placebo and the number of events was low,precluding firm conclusions. Vildagliptin significantly decreased HbA1c compared with placebo(difference of 0.6%) from a mean baseline of 7.8% at week 16. In the subgroup with NYHA class III,the decrease in HbA1c compared to placebo was lower (difference 0.3%) but this conclusion is limitedby the small number of patients (n=44). The incidence of hypoglycaemia in the overall population was4.7% and 5.6% in the vildagliptin and placebo groups, respectively.

A five-year multi-centre, randomised, double-blind study (VERIFY) was conducted in patients withtype 2 diabetes to evaluate the effect of an early combination therapy with vildagliptin and metformin(N = 998) against standard-of-care initial metformin monotherapy followed by combination withvildagliptin (sequential treatment group) (N = 1 003) in newly diagnosed patients with type 2 diabetes.

The combination regimen of vildagliptin 50 mg twice daily plus metformin resulted in a statisticallyand clinically significant relative reduction in hazard for “time to confirmed initial treatment failure”(HbA1c value ≥7%) vs metformin monotherapy in treatment-naïve patients with type 2 diabetes overthe 5-year study duration (HR [95%CI]: 0.51 [0.45, 0.58]; p<0.001). The incidence of initial treatmentfailure (HbA1c value ≥7%) was 429 (43.6%) patients in the combination treatment group and614 (62.1%) patients in the sequential treatment group.

A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase

III and IV monotherapy and combination therapy clinical studies of up to more than 2 years duration(mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) was performed and showedthat vildagliptin treatment was not associated with an increase in cardiovascular risk versuscomparators. The composite endpoint of adjudicated major adverse cardiovascular events (MACE)including acute myocardial infarction, stroke or cardiovascular death was similar for vildagliptinversus combined active and placebo comparators [Mantel-Haenszel risk ratio (M-H RR) 0.82 (95% CI0.61-1.11)]. A MACE occurred in 83 out of 9 599 (0.86%) vildagliptin-treated patients and in 85 outof 7 102 (1.20%) comparator-treated patients. Assessment of each individual MACE componentshowed no increased risk (similar M-H RR). Confirmed heart failure (HF) events defined as HFrequiring hospitalisation or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patientsand 32 (0.45%) comparator-treated patients with M-H RR 1.08 (95% CI 0.68-1.70).

Table 2 Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and inadd-on combination therapy trials (primary efficacy ITT population)

Monotherapy placebo Mean Mean change Placebo-correctedcontrolled studies baseline from baseline in mean change in

HbA1c (%) HbA1c (%) at HbA1c (%) atweek 24 week 24 (95% CI)

Study 2301: Vildagliptin 50 mg 8.6 -0.8 -0.5* (-0.8, -0.1)twice daily (N=90)

Study 2384: Vildagliptin 50 mg 8.4 -0.7 -0.7* (-1.1, -0.4)twice daily (N=79)

* p< 0.05 for comparison versus placebo

Add-on/Combination studies

Vildagliptin 50 mg twice daily + 8.4 -0.9 -1.1* (-1.4, -0.8)metformin (N=143)

Vildagliptin 50 mg daily + 8.5 -0.6 -0.6* (-0.9, -0.4)glimepiride (N=132)

Vildagliptin 50 mg twice daily + 8.7 -1.0 -0.7* (-0.9, -0.4)pioglitazone (N=136)

Vildagliptin 50 mg twice daily + 8.8 -1.0 -0.8* (-1.0, -0.5)metformin + glimepiride (N=152)

* p< 0.05 for comparison versus placebo +comparator

The European Medicines Agency has waived the obligation to submit the results of studies withvildagliptin in all subsets of the paediatric population with type 2 diabetes mellitus (see section 4.2 forinformation on paediatric use).

Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasmaconcentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with foodresulted in a decreased Cmax (19%). However, the magnitude of change is not clinically significant, sothat Xiliarx can be given with or without food. The absolute bioavailability is 85%.

The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally betweenplasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state afterintravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of thedose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product ofthe cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and theamide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that thekidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its majorinactive metabolite, LAY151. DPP-4 contributes partially to the hydrolysis of vildagliptin based on anin vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to anyquantifiable extent. Accordingly, the metabolic clearance of vildagliptin is not anticipated to beaffected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstratedthat vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely toaffect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.

Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted intothe urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptinaccounted for 23% of the dose after oral administration. After intravenous administration to healthysubjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The meanelimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

The Cmax for vildagliptin and the area under the plasma concentrations versus time curves (AUC)increased in an approximately dose proportional manner over the therapeutic dose range.

Characteristics in specific groups of patients

No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between maleand female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibitionby vildagliptin is not affected by gender.

In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily) wasincreased by 32%, with an 18% increase in peak plasma concentration as compared to young healthysubjects (18-40 years). These changes are, however, not considered to be clinically relevant. DPP-4inhibition by vildagliptin is not affected by age.

The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in patientswith mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6for mild to 12 for severe) in comparison with healthy subjects. The exposure to vildagliptin after asingle dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%,respectively), while the exposure to vildagliptin for patients with severe impairment was increased by22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which isnot considered to be clinically relevant. There was no correlation between the severity of the hepaticdisease and changes in the exposure to vildagliptin.

A multiple-dose, open-label trial was conducted to evaluate the pharmacokinetics of the lowertherapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renalimpairment defined by creatinine clearance (mild: 50 to <80 ml/min, moderate: 30 to <50 ml/min andsevere: <30 ml/min) compared to normal healthy control subjects.

Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severerenal impairment, respectively, compared to normal healthy subjects. AUC of the metabolites

LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with mild, moderateand severe renal impairment, respectively. Limited data from patients with end stage renal disease(ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment.

LAY151 concentrations were approximately 2-3-fold higher than in patients with severe renalimpairment.

Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3-4 hour haemodialysissession starting 4 hours post dose).

Ethnic group

Limited data suggest that race does not have any major influence on vildagliptin pharmacokinetics.

Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg (7-fold human exposure based on Cmax).

Accumulation of foamy alveolar macrophages in the lung was observed in rats and mice. The no-effect dose in rats was 25 mg/kg (5-fold human exposure based on AUC) and in mice 750 mg/kg (142-fold human exposure).

Gastrointestinal symptoms, particularly soft faeces, mucoid faeces, diarrhoea and, at higher doses,faecal blood were observed in dogs. A no-effect level was not established.

Vildagliptin was not mutagenic in conventional in vitro and in vivo tests for genotoxicity.

A fertility and early embryonic development study in rats revealed no evidence of impaired fertility,reproductive performance or early embryonic development due to vildagliptin. Embryo-foetal toxicitywas evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats inassociation with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-foldhuman exposure). In rabbits, decreased foetal weight and skeletal variations indicative ofdevelopmental delays were noted only in the presence of severe maternal toxicity, with a no-effectdose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed inrats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included atransient decrease in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately200 times human exposure at the maximum recommended dose). No increases in tumour incidenceattributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted inmice at oral doses up to 1000 mg/kg. An increased incidence of mammary adenocarcinomas andhaemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in miceis considered not to represent a significant risk to humans based on the lack of genotoxicity ofvildagliptin and its principal metabolite, the occurrence of tumours only in one species and the highsystemic exposure ratios at which tumours were observed.

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisterswere observed. They were reversible despite continued treatment and were not associated withhistopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlatinghistopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUCexposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skinlesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.

Lactose, anhydrous

Cellulose, microcrystalline

Sodium starch glycolate (type A)

Magnesium stearate

Not applicable.

3 years

Store in the original package in order to protect from moisture.

Aluminium/Aluminium (PA/Al/PVC//Al) blister

Available in packs containing 7, 14, 28, 30, 56, 60, 90, 112, 180 or 336 tablets and in multipackscontaining 336 (3 packs of 112) tablets.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/08/486/001-011

Date of first authorisation: 19 November 2008

Date of latest renewal: 28 November 2013

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

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