Vildagliptin / Metformin Hydrochloride Accord

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 Vildagliptin/Metformin hydrochloride Accord . 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. 4). Tabulated list of adverse reactions Adverse reactions reported in patients who received vildagliptin in double-blind clinical trialas 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 acidosis Very rare* 9 Nervous system disorders Dizziness Common Headache Common Tremor Common Metallic taste Uncommon Gastrointestinal disorders Vomiting Common Diarrhoea Common Nausea Common Gastro-oesophageal reflux disease Common Flatulence Common Constipation Common Abdominal pain including upper Common Pancreatitis Uncommon Hepatobiliary disorders Hepatitis Uncommon Skin and subcutaneous tissue disorders Hyperhidrosis Common Pruritis Common Rash Common Dermatitis Common Erythema Uncommon Urticaria Uncommon Exfoliative and bullous skin lesions, including bullous pemphigoid Not known† Cutaneous vasculitis Not known† Musculoskeletal and connective tissue disorders Arthalgia Common Myalgia Uncommon General disorders and administration site conditions Asthenia Common Fatigue Uncommon Chills Uncommon Oedema peripheral Uncommon Investigations Abnormal liver function tests Uncommon * Adverse reactions reported in patients who received metformin as monotherapy and that were not observed in patients who received vildalgiptin+metformin fixed dose combination.

Refer to summary of product characteristics for metformin for additional information. † Based on post-marketing experience. Description of selected adverse reactions Vildagliptin Hepatic impairment 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. 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. 10 Angioedema 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. 2%). No severe or serious events of hypoglycaemia were reported.

4% of placebo-treated patients. 9% of placebo-treated patients. 6% of placebo-treated patients. 9% of placebo-treated patients. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemia was 14% for vildagliptin and 16% for placebo.

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

Liver function Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin discontinuation have been reported. Gastrointestinal disorders Gastrointestinal adverse reactions 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 […]

General Vildagliptin/Metformin hydrochloride Accord 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. 5). 5 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.

35), increased plasma lactate levels (> 5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.

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 case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed. 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.

5). 2). 3). 5). 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 vildagliptin/metformin hydrochloride in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin/metformin hydrochloride 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 vildagliptin/metformin hydrochloride therapy is recommended.

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue vildagliptin/metformin hydrochloride. Following withdrawal of treatment with Vildagliptin/Metformin hydrochloride Accord and LFT normalisation, treatment with Vildagliptin/Metformin hydrochloride Accord should not be re- initiated.

3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions.

Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended. Acute pancreatitis Use of vildagliptin has been associated with a risk of developing acute pancreatitis.

Patients should be informed 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 acute pancreatitis.

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 Metformin must be discontinued at […]

4). − Acute or chronic disease which may cause tissue hypoxia, such as: - cardiac or respiratory failure, - recent myocardial infarction, - shock. 6)