Novartis Pharmaceuticals UK Ltd

During post-marketing experience the following additional adverse drug reactions have been reported

·                Cases of abnormal liver function tests and cases of hepatitis, reversible upon discontinuation of the medicinal product, have been reported (see also section 4.4).

·                Frequency not known: urticaria, pancreatitis.

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.

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.

Resolution of pancreatitis has been observed after discontinuation of vildagliptin. If pancreatitis is suspected, vildagliptin and other potentially suspect medicinal products should be discontinued.

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.

as present........ 

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). Eucreas has not been studied in patients older than 75 years. Therefore the use of Eucreas is not recommended in this population.

4.6     Fertility, Ppregnancy 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 not 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).

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)

Table 2       Adverse reactions reported in patients who received vildagliptin 100 mg daily as monotherapy in double-blind studies (N=1855)

2 July 2010

24 January 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

During post-marketing experience the following additional adverse drug reactions haves been reported (frequency not known): urticaria, pancreatitis.

In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose: 229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline 1928 mg/day). After 1 year, mean reductions in HbA_1c were ‑0.81% with vildagliptin added to metformin (mean baseline HbA_1c 8.4%) and ‑0.85% with gliclazide added to metformin (mean baseline HbA_1c 8.5%); statistical non-inferiority was achieved (95% CI ‑0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.

In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA_1c by ‑1.82% ,vildagliptin/metformin 50 mg/500 mg twice daily by ‑1.61%, metformin 1000 mg twice daily by ‑1.36% and vildagliptin 50 mg twice daily by ‑1.09% from a mean baseline HbA_1c of 8.6%. The decrease in HbA_1c observed in patients with a baseline ≥10.0% was greater.

Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or unforeseen risks when vildagliptin was added on to metformin.

and

Clinical trials of up to 2 years’ duration did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

and

Post-marketing experience

During post-marketing experience the following additional adverse drug reaction has been reported (frequency not known): urticaria.

Update to section 5.1 to include the following:

In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions from baseline HbA_1c of 8.4% were ‑0.9% with vildagliptin added to metformin and ‑1.0% with pioglitazone added to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg/day – mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily dose: 1894 mg). After 1 year mean reductions in HbA_1c were ‑0.4% with vildagliptin added to metformin and ‑0.5% with glimepiride added to metformin, from a mean baseline HbA_1c of 7.3%. Body weight change with vildagliptin was ‑0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycaemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA_1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycaemia differences were maintained.

In section 4.8 (Undesirable effects), in Table 2, Metabolism and nutrition disorders with Uncommon – Hypoglycaemia, Added.

In section 5.1 (Pharmacodynamic Properties), first paragraph. ATC code A10BD08, added.