药品信息: 英文药名: Eucreas (Vildagliptin/Metformin Tablets)
中文药名: 复方维格列汀和二甲双胍片剂
生产厂家: Novartis
药物简介
Eucreas于2007年11月14日在欧盟获得批准用于治疗2型糖尿病
Eucreas是由诺华制药公司研制的Galvus® (维格列汀) 和二甲双胍的复方制剂。 Eucreas将用于二甲双胍最大耐受剂量仍不能有效控制的患者或现已在联合使用Galvus与二甲双胍单药的患者。
Eucreas的推荐剂量为Galvus 50mg/二甲双胍850mg和Galvus 50mg/二甲双胍1000mg，一天两次，分早晚服用。
Galvus是由诺华制药公司研制的全新DPP-4抑制剂，并在今年9月获得欧盟批准用于治疗2型糖尿病，可与最常用的口服降糖药：二甲双胍，噻唑烷二酮或磺脲联合使用。Galvus 通过全新的作用机制直接针对胰岛功能失调，刺激胰岛素分泌和抑制胰升糖素的过度分泌，从而控制血糖水平。
临床试验证明，Galvus不良反应的总体发病率与安慰剂相似。最常见的不良反应包括鼻塞、头痛、头晕和上呼吸道感染，但不会导致现有药物像SU和TZD类药物常见的低血糖和体重增加等不良反应。
Eucreas 50 mg/850 mg film-coated tabletsEucreas 50 mg/1000 m
1. NAME OF THE MEDICINAL PRODUCT
Eucreas 50 mg/850 mg film-coated tablets
Eucreas 50 mg/1000 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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).
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
Eucreas 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.
4. CLINICAL PARTICULARS
4.1 Therapeutic 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.
4.2 Posology and method of administration
Adults
Based 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 (see also section 5.2).
Additional information on special populations
Renal impairment
Eucreas should not be used in patients with creatinine clearance < 60 ml/min (see sections 4.3, 4.4 and 5.2).
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) (see sections 4.3, 4.4 and 4.8).
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 sections 4.4 and 5.2).
Paediatric population (< 18 years)
Eucreas is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
4.3 Contraindications
− 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 (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
− Lactation (see section 4.6)
4.4 Special warnings and precautions for use
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 (see also sections 4.3 and 4.5).
Diagnosis of lactic acidosis
Lactic 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 (see section 4.9).
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 (see sections 4.2, 4.3 and 4.8).
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 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 failure
Experience with vildagliptin therapy in patients with congestive heart failure of New York Heart Association (NYHA) functional class I-II 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 III-IV 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 (see section 4.3).
Skin disorders
Skin 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.
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-eva luated and found to be normal (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
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.
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
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 Eucreas (see section 4.4). 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 (see section 4.4).
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 use
Glucocorticoids, 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.
4.6 Pregnancy and lactation
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 lactation (see section 4.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness as an undesirable effect should avoid driving vehicles or using machines.
4.8 Undesirable effects
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 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 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, 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)
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