ICANDRA 50mg / 850mg tablets medication leaflet

Icandra 50 mg/850 mg film-coated tablets

Icandra 50 mg/1000 mg film-coated tablets

Icandra 50 mg/850 mg film-coated tablets

Each film-coated tablet contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride(corresponding to 660 mg of metformin).

Icandra 50 mg/1000 mg film-coated tablets

Each film-coated tablet contains 50 mg of vildagliptin and 1000 mg of metformin hydrochloride(corresponding to 780 mg of metformin).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Icandra 50 mg/850 mg film-coated tablets

Yellow, ovaloid film-coated tablet with bevelled edge, imprinted with “NVR” on one side and “SEH”on the other side.

Icandra 50 mg/1000 mg film-coated tablets

Dark yellow, ovaloid film-coated tablet with bevelled edge, imprinted with “NVR” on one side and“FLO” on the other side.

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

- in patients who are inadequately controlled with metformin hydrochloride alone.

- in patients who are already being treated with the combination of vildagliptin and metforminhydrochloride, as separate tablets.

- 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).

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

The dose of antihyperglycaemic therapy with Icandra should be individualised on the basis of thepatient’s current regimen, effectiveness and tolerability while not exceeding the maximumrecommended daily dose of 100 mg vildagliptin. Icandra may be initiated at either the 50 mg/850 mgor 50 mg/1000 mg tablet strength twice daily, one tablet in the morning and the other in the evening.

- For patients inadequately controlled at their maximal tolerated dose of metformin monotherapy:

The starting dose of Icandra should provide vildagliptin as 50 mg twice daily (100 mg total daily dose)plus the dose of metformin already being taken.

- For patients switching from co-administration of vildagliptin and metformin as separate tablets:

Icandra should be initiated at the dose of vildagliptin and metformin already being taken.

- For patients inadequately controlled on dual combination with metformin and a sulphonylurea:

The doses of Icandra should provide vildagliptin as 50 mg twice daily (100 mg total daily dose) and adose of metformin similar to the dose already being taken. When Icandra is used in combination with asulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk ofhypoglycaemia.

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

The dose of Icandra should provide vildagliptin dosed as 50 mg twice daily (100 mg total daily dose)and a dose of metformin similar to the dose already being taken.

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

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renalfunction, elderly patients taking Icandra should have their renal function monitored regularly (seesections 4.4 and 5.2).

A GFR should be assessed before initiation of treatment with metformin-containing products and atleast annually thereafter. In patients at increased risk of further progression of renal impairment and inthe 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 Icandra is available, individual monocomponents should be used instead ofthe fixed dose combination.

GFR ml/min Metformin Vildagliptin60-89 Maximum daily dose is 3000 mg. No dose adjustment.

Dose reduction may be considered inrelation to declining renal function.

45-59 Maximum daily dose is 2000 mg. Maximal daily dose is 50 mg.

The starting dose is at most half of themaximum dose.

30-44 Maximum daily dose is 1000 mg.

The starting dose is at most half of themaximum dose.

<30 Metformin is contraindicated.

Icandra should not be used in patients with hepatic impairment, including those with pre-treatmentalanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit ofnormal (ULN) (see sections pct. 4.3, pct. 4.4 and 4.8).

Icandra is not recommended for use in children and adolescents (< 18 years). The safety and efficacyof Icandra in children and adolescents (< 18 years) have not been established. No data are available.

Oral use.

Taking Icandra with or just after food may reduce gastrointestinal symptoms associated withmetformin (see also section 5.2).

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 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 (see sections 4.2, pct. 4.4 and 4.8) Acute alcohol intoxication, alcoholism Breast-feeding (see section 4.6)

Icandra is not a substitute for insulin in insulin-requiring patients and should not be used in patientswith type 1 diabetes.

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worseningof renal 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 diarrhoea or vomiting, fever or reduced fluid intake), metformin shouldbe temporarily 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.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy,resulting in metformin accumulation and increased risk of lactic acidosis. Metformin should bediscontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and4.5).

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

Metformin is contraindicated in patients with GFR < 30 ml/min and should be temporarilydiscontinued in the presence of conditions that alter renal function (see section 4.3).

Concomitant medicinal products that may affect renal function, result in significant haemodynamicchange, or inhibit renal transport and increase metformin systemic exposure, should be used withcaution (see section 4.5).

Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN, shouldnot be treated with Icandra (see sections 4.2, pct. 4.3 and 4.8).

Liver enzyme monitoring

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In thesecases, the patients were generally asymptomatic without clinical sequelae and liver function tests(LFTs) returned to normal after discontinuation of treatment. LFTs should be performed prior to theinitiation of treatment with Icandra in order to know the patient’s baseline value. Liver function shouldbe monitored during treatment with Icandra 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 LFTsuntil the abnormality(ies) return(s) to normal. Should an increase in AST or in ALT of 3x ULN orgreater persist, withdrawal of Icandra therapy is recommended. Patients who develop jaundice or othersigns suggestive of liver dysfunction should discontinue Icandra.

Following withdrawal of treatment with Icandra and LFT normalisation, treatment with Icandra shouldnot be re-initiated.

Skin lesions, including blistering and ulceration have been reported with vildagliptin in extremities ofmonkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observedat an increased incidence in clinical trials, there was limited experience in patients with diabetic skincomplications. Furthermore, there have been post-marketing reports of bullous and exfoliative skinlesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders,such as blistering 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.

Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia.

Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutritionand provided that renal function has been re-evaluated and found to be stable.

There have been no formal interaction studies for Icandra. The following statements reflect theinformation available on the individual active substances.

Vildagliptin

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.

Results from clinical trials conducted with the oral antidiabetics pioglitazone, metformin andglyburide in combination with vildagliptin have shown no clinically relevant pharmacokineticinteractions in the target population.

Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin (CYP2C9substrate) in healthy subjects have shown no clinically relevant pharmacokinetic interactions after co-administration with vildagliptin.

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. However, this has not been established in the targetpopulation.

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.

Combinations not recommended

Alcohol

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

Iodinated contrast agents

Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted untilat least 48 hours after, provided that renal function has been re-evaluated and found to be stable (seesections 4.2 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.

Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patientshould be informed and more frequent blood glucose monitoring performed, especially at thebeginning of treatment. If necessary, the dosage of Icandra may need to be adjusted duringconcomitant therapy and on its discontinuation.

Angiotensin converting enzyme (ACE) inhibitors may decrease the blood glucose levels. If necessary,the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with theother medicinal product and on its discontinuation.

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.

There are no adequate data from the use of Icandra in pregnant women. For vildagliptin studies inanimals have shown reproductive toxicity at high doses. For metformin, studies in animals have notshown reproductive toxicity. Studies in animals performed with vildagliptin and metformin have notshown evidence of teratogenicity, but foetotoxic effects at maternotoxic doses (see section 5.3). Thepotential risk for humans is unknown. Icandra should not be used during pregnancy.

Studies in animals have shown excretion of both metformin and vildagliptin in milk. It is unknownwhether vildagliptin is excreted in human milk, but metformin is excreted in human milk in lowamounts. Due to both the potential risk of neonate hypoglycaemia related to metformin and the lack ofhuman data with vildagliptin, Icandra should not be used during breast-feeding (see section 4.3).

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

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

Safety data were obtained from a total of 6 197 patients exposed to vildagliptin/metformin inrandomised placebo-controlled trials. Of these patients, 3 698 patients received vildagliptin/metforminand 2 499 patients received placebo/metformin.

There have been no therapeutic clinical trials conducted with Icandra. However, bioequivalence of

Icandra with co-administered vildagliptin and metformin has been demonstrated (see section 5.2).

The majority of adverse reactions were mild and transient, not requiring treatment discontinuations.

No association was found between adverse reactions and age, ethnicity, duration of exposure or dailydose. Vildagliptin use is associated with the risk of development of pancreatitis. Lactic acidosis hasbeen reported following the use of metformin, especially in patients with underlying renal impairment(see section 4.4).

Adverse reactions reported in patients who received vildagliptin in double-blind clinical trials asmonotherapy and add-on therapies are listed below by system organ class and absolute frequency.

Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1 Adverse reactions reported in patients who received vildagliptin and metformin (asmono-components or as fixed dose combination), or in combination with other anti-diabetic treatments, in clinical trials and in post-marketing experience

System organ class - adverse reaction Frequency

Upper respiratory tract infection Common

Nasopharyngitis Common

Hypoglycaemia Uncommon

Loss of appetite Uncommon

Decrease of vitamin B12 absorption and lactic

Very rare*acidosis

Dizziness Common

Headache Common

Tremor Common

Metallic taste Uncommon

Vomiting Common

Diarrhoea Common

Nausea Common

Gastro-oesophageal reflux disease Common

Flatulence Common

Constipation Common

Abdominal pain including upper Common

Pancreatitis Uncommon

Hepatitis Uncommon

Hyperhidrosis Common

Pruritis Common

Rash Common

Dermatitis Common

Erythema Uncommon

Urticaria Uncommon

Exfoliative and bullous skin lesions, including

Not known†bullous pemphigoid

Cutaneous vasculitis Not known†

Arthalgia Common

Myalgia Uncommon

Asthenia Common

Fatigue Uncommon

Chills Uncommon

Oedema peripheral Uncommon

Abnormal liver function tests Uncommon

* Adverse reactions reported in patients who received metformin as monotherapy and that werenot observed in patients who received vildalgiptin+metformin fixed dose combination. Referto summary of product characteristics for metformin for additional information.† Based on post-marketing experience.

Vildagliptin

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In thesecases, the patients were generally asymptomatic without clinical sequelae and liver function returnedto normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapytrials of up to 24 weeks in duration, the incidence of ALT or AST elevations ≥ 3x ULN (classified aspresent on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators,respectively. These elevations in transaminases were generally asymptomatic, non-progressive innature and not associated 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 an ACEinhibitor. The majority of events were mild in severity and resolved with ongoing vildagliptintreatment.

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.

Decrease of vitamin B12 absorption

A decrease in vitamin B12 absorption with decrease in serum levels has been observed very rarely inpatients who have been treated with metformin over a long period. Consideration of such aetiology isrecommended if a patient presents with megaloblastic anaemia.

Isolated cases of liver function test abnormalities or hepatitis resolving upon metformindiscontinuation have been reported.

Gastrointestinal adverse reactions occur most frequently during initiation of therapy and resolvespontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 dailydoses during or after meals. A slow increase in the dose may also improve gastrointestinal tolerability.

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.

No data are available with regard to overdose of Icandra.

Vildagliptin

Information regarding overdose with vildagliptin is limited.

Information on the likely symptoms of overdose with vildagliptin was taken from a rising dosetolerability study in healthy subjects given vildagliptin for 10 days. At 400 mg, there were three casesof muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and a transientincrease in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, andincreases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin levels.

Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptomsand laboratory abnormalities resolved without treatment after discontinuation of the study medicinalproduct.

A large overdose of metformin (or co-existing risk of lactic acidosis) may lead to lactic acidosis,which is a medical emergency and must be treated in hospital.

The most effective method of removing metformin is haemodialysis. However, vildagliptin cannot beremoved by haemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportivemanagement is recommended.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD08

Icandra combines two antihyperglycaemic agents with complimentary mechanisms of action toimprove glycaemic control in patients with type 2 diabetes: vildagliptin, a member of the isletenhancer class, and metformin hydrochloride, a member of the biguanide class.

Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4(DPP-4) inhibitor. Metformin acts primarily by decreasing endogenous hepatic glucose production.

Vildagliptin

Vildagliptin acts primarily by inhibiting DPP-4, the enzyme responsible for the degradation of theincretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropicpolypeptide).

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity resultingin increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 and GIP.

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.

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

Metformin may exert its glucose-lowering effect via three mechanisms:

- by reduction of hepatic glucose production through inhibition of gluconeogenesis andglycogenolysis;

- 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 and increasesthe 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 serum levels of total cholesterol, LDL cholesterol andtriglycerides.

The prospective randomised UKPDS (UK Prospective Diabetes Study) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results foroverweight patients treated with metformin after failure of diet alone showed:

- a significant reduction in 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(40.1 events/1 000 patient-years), p=0.0034;

- a significant reduction in the absolute risk of diabetes-related mortality: metformin7.5 events/1 000 patient-years, diet alone 12.7 events/1 000 patient-years, p=0.017;

- a significant reduction in the absolute risk of overall mortality: metformin13.5 events/1 000 patient-years versus diet alone 20.6 events/1 000 patient-years (p=0.011), andversus the combined 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: metformin11 events/1 000 patient-years, diet alone 18 events/1 000 patient-years (p=0.01).

Vildagliptin added to patients whose glycaemic control was not satisfactory despite treatment withmetformin monotherapy resulted after 6-month treatment in additional statistically significant meanreductions in HbA1c compared to placebo (between group differences of -0.7% to -1.1% forvildagliptin 50 mg and 100 mg, respectively). The proportion of patients who achieved a decrease in

HbA1c of ≥ 0.7% from baseline was statistically significantly higher in both vildagliptin plusmetformin groups (46% and 60%, respectively) versus the metformin plus placebo group (20%).

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 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 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 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 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).

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

Icandra

Bioequivalence has been demonstrated between Icandra at three dose strengths (50 mg/500 mg,50 mg/850 mg and 50 mg/1000 mg) versus free combination of vildagliptin and metforminhydrochloride tablets at the corresponding doses.

Food does not affect the extent and rate of absorption of vildagliptin from Icandra. The rate and extentof absorption of metformin from Icandra 50 mg/1000 mg were decreased when given with food asreflected by the decrease in Cmax by 26%, AUC by 7% and delayed Tmax (2.0 to 4.0 h).

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

Icandra.

Vildagliptin

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%) compared to dosing in the fasting state. However, the magnitude ofchange is not clinically significant, so that vildagliptin can be given with or without food. The absolutebioavailability 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 amide hydrolysis product (4% ofdose). DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using

DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent,and accordingly the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated thatvildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely to affectmetabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19,

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 was recovered in the faeces. Renal excretion of the unchangedvildagliptin accounted for 23% of the dose after oral administration. After intravenous administrationto healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively.

The mean elimination half-life after intravenous administration is approximately 2 hours. Theelimination 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.

Gender: No clinically relevant differences in the pharmacokinetics of vildagliptin were observedbetween male and female healthy subjects within a wide range of age and body mass index (BMI).

DPP-4 inhibition by vildagliptin is not affected by gender.

Age: In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily)was increased by 32%, with an 18% increase in peak plasma concentration as compared to younghealthy subjects (18-40 years). These changes are not considered to be clinically relevant, however.

DPP-4 inhibition by vildagliptin is not affected by age.

Hepatic impairment: In subjects with mild, moderate or severe hepatic impairment (Child-Pugh A-C)there were no clinically significant changes (maximum ~30%) in exposure to vildagliptin.

Renal impairment: In subjects with mild, moderate, or severe renal impairment, systemic exposure tovildagliptin was increased (Cmax 8-66%; AUC 32-134%) and total body clearance was reducedcompared to subjects with normal renal function.

Ethnic group: Limited data suggest that race does not have any major influence on vildagliptinpharmacokinetics.

After an oral dose of metformin, the maximum plasma concentration (Cmax) is achieved after about2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthysubjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption are non-linear. At the usual metformin doses and dosingschedules, steady state plasma concentrations are reached within 24-48 h and are generally less than1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed4 µg/ml, even at maximum doses.

Food slightly delays and decreases the extent of the absorption of metformin. Followingadministration of a dose of 850 mg, the plasma peak concentration was 40% lower, AUC wasdecreased by 25% and time to peak plasma concentration was prolonged by 35 minutes. The clinicalrelevance of this decrease is unknown.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The mean volume ofdistribution (Vd) ranged between 63-276 litres.

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

Metformin is eliminated by renal excretion. Renal clearance of metformin is > 400 ml/min, indicatingthat metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, theapparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renalclearance is decreased in proportion to that of creatinine and thus the elimination half-life isprolonged, leading to increased levels of metformin in plasma.

Animal studies of up to 13-week duration have been conducted with the combined substances in

Icandra. No new toxicities associated with the combination were identified. The following data arefindings from studies performed with vildagliptin or metformin individually.

Vildagliptin

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. Embryofoetal 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.

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

Hydroxypropylcellulose

Magnesium stearate

Hypromellose

Titanium dioxide (E 171)

Iron oxide, yellow (E 172)

Macrogol 4000

Talc

Not applicable.

PA/alu/PVC/alu 2 years

PCTFE/PVC/alu 18 months

PVC/PE/PVDC/alu 18 months

Do not store above 30°C.

Store in the original package (blister) in order to protect from moisture.

Aluminium/Aluminium (PA/alu/PVC/alu) blister

Available in packs containing 10, 30, 60, 120,180 or 360 film-coated tablets and in multi-packscontaining 120 (2 packs of 60), 180 (3 packs of 60) or 360 (6 packs of 60) film-coated tablets.

Polychlorotrifluoroethylene (PCTFE/PVC/alu) blister

Available in packs containing 10, 30, 60, 120, 180 or 360 film-coated tablets and in multi-packscontaining 120 (2 packs of 60), 180 (3 packs of 60) or 360 (6 packs of 60) film-coated tablets.

Polyvinylchloride/Polyethylene/Polyvinylidene chloride/Aluminium (PVC/PE/PVDC/alu) blister

Available in packs containing 10, 30, 60, 120, 180 or 360 film-coated tablets and in multi-packscontaining 120 (2 packs of 60), 180 (3 packs of 60) or 360 (6 packs of 60) film-coated tablets.

Not all pack sizes and tablet strengths 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

Icandra 50 mg/850 mg film-coated tablets

EU/1/08/484/001-006

EU/1/08/484/013-015

EU/1/08/484/019-024

EU/1/08/484/031-033

EU/1/08/484/037-045

Icandra 50 mg/1000 mg film-coated tablets

EU/1/08/484/007-012

EU/1/08/484/016-018

EU/1/08/484/025-030

EU/1/08/484/034-036

EU/1/08/484/046-054

Date of first authorisation: 01 December 2008

Date of latest renewal: 31 July 2013

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

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