VILDAGLIPTIN/METFORMIN

Posology Adults with normal renal function (GFR ≥ 90 ml/min) The dose of antihyperglycaemic therapy with Vildagliptin/Metformin 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.

Vildagliptin/Metformin 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. - For patients inadequately controlled at their maximal tolerated dose of metformin monotherapy: The starting dose of Vildagliptin/Metformin 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: Vildagliptin/Metformin should be initiated at the dose of vildagliptin and metformin already being taken. - For patients inadequately controlled on dual combination with metformin and a sulphonylurea: The doses of Vildagliptin/Metformin 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 Vildagliptin/Metformin is used in combination with a sulphonylurea, a lower dose of the sulphonylurea 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 dose of Vildagliptin/Metformin should provide vildagliptin dosed 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. 2). Renal impairment A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter.

g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. 4) should be reviewed before considering initiation of metformin in patients with GFR<60 ml/min. If no adequate strength of Vildagliptin/Metformin is available, individual monocomponents should be used instead of the fixed dose combination.

GFR ml/min Metformin Vildagliptin 60-89 Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function. No dose adjustment. 45-59 Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

30-44 Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose. <30 Metformin is contraindicated. Maximal daily dose is 50 mg. 8). Paediatric population Vildagliptin/Metformin is not recommended for use in children and adolescents (< 18 years).

The safety and efficacy of Vildagliptin/Metformin in children and adolescents (< 18 years) have not been established. No data are available. Method of administration Oral use. 2).

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. 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 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 acidosis Very rare* 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. 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 meals. A slow increase in the dose may also […]

The safety and efficacy of amlodipine in hypertensive crisis have not been established. Pregnancy Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

6). 4% of patients with uncomplicated hypertension treated with amlodipine/valsartan in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur.

Correction of this condition prior to administration of amlodipine/valsartan or close medical supervision at the start of treatment is recommended. If hypotension occurs with amlodipine/valsartan, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

Treatment can be continued once blood pressure has been stabilised. ) should be undertaken with caution and with frequent monitoring of potassium levels. Renal artery stenosis Amlodipine/valsartan should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation To date there is no experience of the safe use of amlodipine/valsartan in patients who have had a recent kidney transplantation. Hepatic impairment Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established.

Particular caution should be exercised when administering amlodipine/valsartan to patients with mild to moderate hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

73 m2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment. Primary hyperaldosteronism Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is affected by the primary disease.

Angioedema Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicinal products, including ACE inhibitors.

Amlodipine/valsartan should be discontinued immediately in patients who develop angioedema and should not be re-administered. 8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists.

If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred. Heart failure/post-myocardial infarction As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.

In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non- ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. Aortic and mitral valve stenosis As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure).

1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE […]

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