Eucreas

/ Novartis

Adults with normal renal function (GFR ≥ 90 ml/min): The dose of antihyperglycaemic therapy with Eucreas should be individualised on the basis of the patient’s current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg vildagliptin. Based on the patient’s current dose of metformin,Eucreas may be initiated at either 50 mg /500 mg or 50 mg/850 mg or 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 Eucreas 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: Eucreas should be initiated at the dose of vildagliptin and metformin already being taken.
For patients inadequately controlled on dual combination with metformin and a sulfonylurea: The doses of Eucreas should provide vildagliptin as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Eucreas is used in combination with a sulfonylurea, a lower dose of the sulfonylurea may be considered to reduce the risk of hypoglycaemia.
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin: The doses of Eucreas should provide vildagliptin 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 a thiazolidinedione have not been established.
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.
Renal impairment: A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR<60 ml/min.
If no adequate strength of Eucreas is available, individual monocomponents should be used instead of the fixed dose combination.
Hepatic impairment: Eucreas 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).
Paediatric population: Eucreas is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of Eucreas in children and adolescents (< 18 years) have not been established. No data are available.
Method of administration: Oral use. Taking Eucreas with or just after food may reduce gastrointestinal symptoms associated with metformin.

This product is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve sufficient glycemic 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. This product is indicated in combination with a sulfonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulfonylurea. This product is indicated in triple combination therapy with insulin as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

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 (Metformin is contraindicated in this patient population). 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 failure (Metformin is contraindicated in patients with heart failure, therefore it is contraindicated in this patient population). Respiratory failure. Recent myocardial infarction. Shock. Hepatic impairment. Acute alcohol intoxication, alcoholism. Lactation.

General Eucreas is not a substitute for insulin in insulin-requiring patients and should not be used in patients with type 1 diabetes.
Lactic acidosis: Lactic 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 acidosis Lactic acidosis is characterized 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 hospitalized immediately.
Renal impairment: As 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 impairment: Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN should not be treated with Eucreas.
Liver enzyme monitoring: 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 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 evaluation 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 normalization, treatment with Eucreas should not be re-initiated.
Skin disorders: Skin lesions, including blistering and ulceration have been reported with vildagliptin in extremities of monkeys in non-clinical toxicology studies. 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.
Pancreatitis: In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain (sometimes radiating to the back) and encouraged to tell their healthcare provider if they have such symptoms. In most cases, resolution of pancreatitis has been observed after discontinuation of vildagliptin. If pancreatitis is suspected, vildagliptin and other potentially suspect medicinal products should be discontinued.
Hypoglycaemia: Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.
Surgery: As 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 agent: The 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-evaluated and found to be normal.
For full details see prescribing information.

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.
Nervous system disorders: Common: Tremor, Headache, Dizziness.
Gastrointestinal disorders: Common: Nausea
Metabolism and nutrition disorders: Common: Hypoglycaemia
For full details see prescribing information.

There have been no formal interaction studies for this specific formulation. The following statements reflect the information available on the individual active substances.
Vildagliptin: Vildagliptin 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.
Metformin: Combinations not recommended There 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 this drug. 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 glycemic 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-evaluated and found to be normal.
See prescribing information for full details.

Pregnancy: There are no adequate data from the use of this product in pregnant women. The potential risk for humans is unknown. This product should not be used during pregnancy.
Lactation: It is not known whether vildagliptin is excreted in human milk, but metformin is excreted in human milk in low amounts. Due to both the potential risk of neonate hypoglycaemia related to metformin and the lack of human data with vildagliptin, This product should not be used during lactation.
See prescribing information for full details.

No data are available with regard to overdose of this product.
Vildagliptin: Information regarding overdose with vildagliptin is limited. Information on the likely symptoms of overdose with vildagliptin was taken from a rising dose tolerability study in healthy subjects given vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paresthesia, fever, edema and a transient increase in lipase levels. At 600 mg, one subject experienced edema of the feet and hands, and increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced edema of the feet, with paresthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.
Metformin: 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.
Management: The most effective method of removing metformin is hemodialysis. However, vildagliptin cannot be removed by hemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportive management is recommended.
See prescribing information for full details.

Taking this product with or just after food may reduce gastrointestinal symptoms associated with metformin.
Storage: Store below 30ºC in the original package in order to protect from moisture.