Drug Class Description
Combinations of oral blood glucose lowering drugs
Generic Name
Vildagliptin and metformin hydrochloride
Drug Description
Eucreas 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).Eucreas 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).
Presentation
Film-coated tabletEucreas 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.Eucreas 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
Indications
Eucreas is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone or who are already treated with the combination of vildagliptin and metformin as separate tablets.
Adult Dosage
AdultsBased on the patient's current dose of metformin, Eucreas may be initiated at either the 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily, one tablet in the morning and the other in the evening. The recommended daily dose is 100 mg vildagliptin plus 2000 mg metformin hydrochloride.Patients receiving vildagliptin and metformin from separate tablets may be switched to Eucreas containing the same doses of each component.Doses higher than 100 mg of vildagliptin are not recommended.There is no clinical experience of vildagliptin and metformin in triple combination with other antidiabetic agents.Taking Eucreas with or just after food may reduce gastrointestinal symptoms associated with metformin.Additional information on special populationsRenal impairmentEucreas should not be used in patients with creatinine clearance < 60 ml/min.Hepatic impairmentEucreas should not be used in patients with hepatic impairment, including those with pre-treatment alanine aminotransferase [ALT] or aspartate aminotransferase [AST]> 3 times the upper limit of normal [ULN].Elderly ( 65 years)As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Eucreas should have their renal function monitored regularly. Eucreas has not been studied in patients older than 75 years. Therefore the use of Eucreas is not recommended in this population.Paediatric population (< 18 years)Eucreas is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Child Dosage
Paediatric population ( < 18 years) - Eucreas is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Elderly Dosage
Elderly ( = 65 years) - As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Eucreas should have their renal function monitored regularly (See Special Precuations). Eucreas has not been studied in patients older than 75 years. Therefore the use of Eucreas is not recommended in this population.
Contra Indications
− Hypersensitivity to the active substances or to any of the excipients− Diabetic ketoacidosis or diabetic pre-coma− Renal failure or renal dysfunction defined as creatinine clearance < 60 ml/min− Acute conditions with the potential to alter renal function, such as: - dehydration,- severe infection,- shock,- intravascular administration of iodinated contrast agents.− 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− Lactation
Special Precautions
GeneralEucreas is not a substitute for insulin in insulin-requiring patients and should not be used in patients with type 1 diabetes.Lactic acidosisLactic acidosis is a very rare but serious metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. In patients with impaired liver function, lactate clearance may be restricted. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.Diagnosis of lactic acidosisLactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l and increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately.Renal impairmentAs metformin is excreted by the kidney, serum creatinine concentrations should be monitored regularly:- at least once a year in patients with normal renal function- at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients.Renal impairment in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with an NSAID.Hepatic impairmentPatients with hepatic impairment, including those with pre-treatment ALT or AST> 3x ULN, should not be treated with Eucreas.Liver enzyme monitoringRare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, 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 the initiation of treatment with Eucreas in order to know the patient's baseline value. Liver function should be monitored during treatment with Eucreas at three-month intervals during the first year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function eva luation to confirm the finding and be followed thereafter with frequent LFTs until the abnormality(ies) return(s) to normal. Should an increase in AST or in ALT of 3x ULN or greater persist, withdrawal of Eucreas therapy is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Eucreas.Following withdrawal of treatment with Eucreas and LFT normalisation, treatment with Eucreas should not be re-initiated.Cardiac failureExperience with vildagliptin therapy in patients with congestive heart failure of New York Heart Association (NYHA) functional class III is limited and therefore vildagliptin should be used cautiously in these patients. There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IIIIV and therefore use is not recommended in these patients.Metformin is contraindicated in patients with heart failure, therefore Eucreas is contraindicated in this patient population.Skin disordersSkin lesions, including blistering and ulceration have been reported with vildagliptin in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.SurgeryAs Eucreas contains metformin, the treatment should be discontinued 48 hours before elective surgery with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.Administration of iodinated contrast agentThe intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure. Therefore, due to the metformin active substance, Eucreas should be discontinued prior to, or at the time of, the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal.
Interactions
There have been no formal interaction studies for Eucreas. The following statements reflect the information available on the individual active substances.VildagliptinVildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.Results from clinical trials conducted with the oral antidiabetics pioglitazone, metformin and glyburide in combination with vildagliptin have shown no clinically relevant pharmacokinetic interactions in the target population.Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin (CYP2C9 substrate) 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, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin. However, this has not been established in the target population.As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.MetforminCombinations not recommendedThere is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Eucreas. Consumption of alcohol and medicinal products containing alcohol should be avoided.Cationic active substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems and hence delay the elimination of metformin, which may increase the risk of lactic acidosis. A study in healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation with the risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal.Combinations requiring precautions for useGlucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment. If necessary, the dosage of Eucreas may need to be adjusted during concomitant 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 the other medicinal product and on its discontinuation.
Adverse Reactions
There have been no therapeutic clinical trials conducted with Eucreas. However, bioequivalence of Eucreas with co-administered vildagliptin and metformin has been demonstrated. The data presented here relate to the co-administration of vildagliptin and metformin, where vildagliptin has been added to metformin. There have been no studies of metformin added to vildagliptin.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 daily dose.Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations 3x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on therapy to metformin (Table 1) and as monotherapy (Table 2) are listed below by system organ class and absolute frequency. Adverse reactions listed in Table 3 are based on information available from the metformin Summary of Product Characteristics available in the EU. Frequencies are defined as very common (1/10); common (1/100, <1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Table 1 Adverse reactions reported in patients who received vildagliptin 100 mg daily as add-on therapy to metformin compared to placebo plus metformin in double-blind studies (N=208)Nervous system disordersCommonCommonHeadacheCommonDizzinessUncommonFatigueGastrointestinal disordersCommonNauseaMetabolism and nutrition disordersCommonHypoglycaemiaIn controlled clinical trials with the combination of vildagliptin 100 mg daily plus metformin, no withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily plus metformin or the placebo plus metformin treatment groups.In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin in combination with metformin (1%) and uncommon in patients receiving placebo + metformin (0.4%). No severe hypoglycaemic events were reported in the vildagliptin arms.In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily was added to metformin (+0.2 kg and 1.0 kg for vildagliptin and placebo, respectively).Additional information on the individual active substances of the fixed combinationVildagliptinTable 2 Adverse reactions reported in patients who received vildagliptin 100 mg daily as monotherapy in double-blind studies (N=1855)Nervous system disordersCommonDizzinessUncommonHeadacheGastrointestinal disorders UncommonConstipationMusculoskeletal and connective tissue disordersUncommonArthralgiaMetabolism and nutrition disordersUncommonHypoglycaemiaInfections and infestationsVery rareUpper respiratory tract infectionVery rarNasopharyngitisVascular disorders UncommonOedema peripheralThe overall incidence of withdrawals from controlled monotherapy trials due to adverse reactions was no greater for patients treated with vildagliptin at doses of 100 mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 100 mg daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily was administered as monotherapy (0.3 kg and 1.3 kg for vildagliptin and placebo, respectively).MetforminTable 3 Known adverse reactions for metformin componentMetabolism and nutrition disorders Very RareDecrease of vitamin B12 absorption and lactic acidosis*Nervous system disordersCommonMetallic tasteGastrointestinal disorders Very commonNausea, vomiting, diarrhoea, abdominal pain and loss of appetiteHepatobiliary disordersVery rareLiver function test abnormalities or hepatitis**Skin and subcutaneous tissue disorders Very rareSkin reactions such as erythema, pruritus and urticaria*A decrease in vitamin B12 absorption with decrease in serum levels has been very rarely observed in patients treated long-term with metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin discontinuation have been reported.Gastrointestinal undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 daily doses during or after meals. A slow increase in the dose may also improve gastrointestinal tolerability.
Manufacturer
Novartis Pharma
Drug Availability
(POM)
Updated
11 August 2009
