VILGAD

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus:

· as monotherapy in patients for whom metformin is considered inappropriate due to intolerance or contraindications.

· 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 the different combinations).

vildagliptine has a low potential for drug interactions. vildagliptine is neither a substrate, nor an inhibitor, nor an inducer of CYP450 enzymes. As a result, it is unlikely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.

Association with pioglitazone, metformine and glibenclamide

The results of studies conducted with these oral antidiabetics have not shown clinically relevant pharmacokinetic interactions.

Digoxine (gp-P substrate), warfarine (CYP2C9 substrate)

Clinical studies conducted in healthy subjects have not shown clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.

Association with amlodipine, ramipril, valsartan or simvastatine

Drug interaction studies have been conducted in healthy subjects with amlodipine, ramipril, valsartan and simvastatine. In these studies, no clinically relevant pharmacokinetic interaction was observed after concomitant administration with vildagliptine.

Association with angiotensin-converting enzyme inhibitors

The risk of angioedema may be increased in patients taking angiotensin-converting enzyme inhibitors concomitantly (see section 4.8).

As with other oral antidiabetics, the hypoglycaemic effect of vildagliptine may be decreased by certain active substances, notably thiazide diuretics, corticosteroids, thyroid hormones and sympathomimetics.

Pregnancy

There are no sufficiently relevant data on the use of vildagliptine in pregnant women. Studies conducted in animals have shown reproductive toxicity at high doses (see section 5.3). The potential clinical risk is unknown. Due to a lack of data in humans, vildagliptine should not be used during pregnancy.

Breastfeeding

It is unknown whether vildagliptine is excreted in breast milk. Studies conducted in animals have shown the excretion of vildagliptine in breast milk. vildagliptine should not be used during breastfeeding.

Fertility

The effects of vildagliptine on human fertility have not been studied (see section 5.3).

The effects on the ability to drive vehicles and use machines have not been studied. Patients experiencing adverse effects such as sensations of dizziness must avoid driving vehicles or using machines.

Summary of the safety profile

Tolerability data are derived from a total of 5 421 patients treated with vildagliptine at a daily dose of 100 mg (50 mg twice daily) in randomised, double-blind, placebo-controlled studies of at least 12 weeks duration. Of these patients, 4 622 received vildagliptine as monotherapy and 829 received placebo.

The majority of adverse reactions observed in these studies were mild and transient and did not require treatment discontinuation. No relationship was found between adverse reactions and age, ethnicity, duration of exposure or daily dose. Hypoglycaemia was observed in patients receiving vildagliptine in combination with a sulphonylurea and insulin. The risk of acute pancreatitis has been observed following the use of vildagliptine (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions reported in double-blind studies in patients treated with vildagliptine as monotherapy and in combination are listed below for each indication by system organ class and absolute frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100), rare (≥1/10 000, <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 vildagliptine as monotherapy or in combination in controlled clinical studies and during post-marketing experience

Description of selected adverse reactions

Hepatic impairment

Rare cases of hepatic dysfunction (including hepatitis) have been observed. In these cases, patients were generally asymptomatic without clinical sequelae and liver function tests returned to normal after discontinuation of treatment. In controlled trials in monotherapy and add-on therapy of up to 24 weeks duration, the incidence of ALAT or ASAT elevations ≥ 3 x ULN (present on at least two consecutive measurements or at the final treatment visit) was 0.2%, 0.3% and 0.2% for 50 mg once daily vildagliptin, 50 mg twice daily vildagliptin and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive and were not associated with cholestasis or jaundice.

Angioedema

Rare cases of angioedema have been reported with vildagliptin at a rate comparable to controls. A greater proportion of cases was observed when vildagliptin was administered in combination with an angiotensin converting enzyme inhibitor (ACE inhibitor). The majority of events were mild in severity and resolved during ongoing vildagliptin treatment.

Hypoglycaemia

Hypoglycaemia was uncommon when vildagliptin was used as monotherapy (0.4%) in comparative controlled monotherapy studies with an active comparator or placebo (0.2%). No serious or severe hypoglycaemic events were reported. When used in combination with metformin, hypoglycaemia occurred in 1% of patients treated with vildagliptin and in 0.4% of patients treated with placebo.

When used in combination with pioglitazone, hypoglycaemia occurred in 0.6% of patients treated with vildagliptin and in 1.9% of patients treated with placebo. When used in combination with a sulphonylurea, hypoglycaemia occurred in 1.2% of patients treated with vildagliptin and in 0.6% of patients treated with placebo. When used in combination with a sulphonylurea and metformin, hypoglycaemia occurred in 5.1% of patients treated with vildagliptin and in 1.9% of patients treated with placebo. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemia was 14% with vildagliptin and 16% with placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals report any suspected adverse reaction via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.