Leitlinien & Arzneimittelsicherheit

HOS-154236 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Safety data were obtained from a total of 6 197 patients exposed to vildagliptin/metformin in randomised placebo-controlled trials. Of these patients, 3 698 patients received vildagliptin/metformin and 2 499 patients received placebo/metformin. There have been no therapeutic clinical trials conducted with Eucreas. However, bioequivalence of Eucreas 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 daily dose. Vildagliptin use is associated with the risk of development of pancreatitis. Lactic acidosis has been reported following the use of metformin, especially in patients with underlying renal impairment (see section 4.4). Tabulated list of adverse reactions Adverse reactions reported in patients who received vildagliptin in double-blind clinical trials as monotherapy 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 (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse reactions reported in patients who received vildagliptin and metformin (as mono-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 Infections and infestations Upper respiratory tract infection Common Nasopharyngitis Common Metabolism and nutrition disorders Hypoglycaemia Uncommon Loss of appetite Uncommon Decrease of vitamin B12 absorption and lactic Very rare* acidosis Nervous system disorders Dizziness Common Headache Common Tremor Common Metallic taste U

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HOS-154232 · has-contraindication-information · PDF-Seite 4

− 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, 4.4 and 4.8) − Acute alcohol intoxication, alcoholism − Breast-feeding (see section 4.6)

HOS-154231 · has-indication-information · PDF-Seite 2

Eucreas is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 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 metformin hydrochloride, 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 for available data on different combinations).

HOS-154234 · has-interaction-information · PDF-Seite 6

There have been no formal interaction studies for Eucreas. 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. 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. 6 Combination with ACE inhibitors There may be an increased risk of angioedema in patients concomitantly taking ACE inhibitors.(see section 4.8). 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. Metformin Combinations not recommended Alcohol Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment. Iodinated contrast agents Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4). Combinations requiring precautions for use Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, 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 such products in combinatio

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HOS-154235 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no adequate data from the use of Eucreas in pregnant women. For vildagliptin studies in animals have shown reproductive toxicity at high doses. For metformin, studies in animals have not shown reproductive toxicity. Studies in animals performed with vildagliptin and metformin have not shown evidence of teratogenicity, but foetotoxic effects at maternotoxic doses (see section 5.3). The potential risk for humans is unknown. Eucreas should not be used during pregnancy. Breast-feeding Studies in animals have shown excretion of both metformin and vildagliptin in milk. It is unknown 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, Eucreas should not be used during breast-feeding (see section 4.3). 7 Fertility No studies on the effect on human fertility have been conducted for Eucreas (see section 5.3).

HOS-154233 · has-warning-information · PDF-Seite 4

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, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function, or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be 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 lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5). 4 Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate 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 be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5). Patients with known or suspected mitochondrial diseases In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In ca

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