Vildagliptin

Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN).

Liver enzyme monitoring

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function test results returned to normal after discontinuation of treatment. Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin 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 liver function tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT of 3x ULN or greater persist, withdrawal of vildagliptin therapy is recommended.

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue vildagliptin. Following withdrawal of treatment with vildagliptin and LFT normalisation, treatment with vildagliptin should not be reinitiated.

In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of vildagliptin is 50 mg once daily.

A clinical trial of vildagliptin in patients with New York Heart Association NYHA functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive.

There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.

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.

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.

There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors with vildagliptin.

There is limited experience in patients with ESRD on haemodialysis. Therefore vildagliptin should be used with caution in these patients.

There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown.

Due to lack of human data, vildagliptin should not be used during pregnancy.

It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of vildagliptin in milk. Vildagliptin should not be used during breast-feeding.

Fertility

No studies on the effect on human fertility have been conducted for vildagliptin.

No studies on the effects on the ability to drive and use machines have been performed. Patients who experience dizziness as an adverse reaction should avoid driving vehicles or using machines.

Summary of the safety profile

Safety data were obtained from a total of 5 451 patients exposed to vildagliptin at a daily dose of 100 mg (50 mg twice daily) in randomised double-blind placebo-controlled trials of at least 12 weeks duration. Of these patients, 4 622 patients received vildagliptin as monotherapy and 829 patients received placebo.

The majority of adverse reactions in these trials were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose. Hypoglycaemia has been reported in patients receiving vildagliptin concomitantly with sulphonylurea and insulin. The risk of acute pancreatitis has been reported with the use of vildagliptin.

Tabulated list of adverse reactions

Adverse reactions reported in patients who received vildagliptin in double-blind studies as monotherapy and add-on therapies are listed below for each indication 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.

Adverse reactions reported in patients who received vildagliptin as monotherapy or as add-on therapy in controlled clinical studies and in post-marketing experience:

^* Based on post-marketing experience.

Description of selected adverse reactions

Hepatic impairment

Rare cases of hepatic dysfunction (including hepatitis) have been reported. 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.

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 angiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.

Hypoglycaemia

Hypoglycaemia was uncommon when vildagliptin (0.4%) was used as monotherapy in comparative controlled monotherapy studies with an active comparator or placebo (0.2%). No severe or serious events of hypoglycaemia were reported. When used as add-on to metformin, hypoglycaemia occurred in 1% of vildagliptin-treated patients and in 0.4% of placebo-treated patients. When pioglitazone was added, hypoglycaemia occurred in 0.6% of vildagliptin-treated patients and in 1.9% of placebo-treated patients. When sulphonylurea was added, hypoglycaemia occurred in 1.2% of vildagliptin treated patients and in 0.6% of placebo-treated patients. When sulphonylurea and metformin were added, hypoglycaemia occurred in 5.1% of vildagliptin treated patients and in 1.9% of placebo treated patients. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemia was 14% for vildagliptin and 16% for placebo.