Metformin and Vildagliptin

A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR <60 ml/min.

If no adequate strength of metformin/vildagliptin is available, individual monocomponents should be used instead of the fixed dose combination.

There are no adequate data from the use of metformin/vildagliptin 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. The potential risk for humans is unknown. Metformin/vildagliptin should not be used during pregnancy.

Studies in animals have shown excretion of both metformin and vildagliptin in milk. It is 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, metformin/vildagliptin should not be used during breast-feeding.

Fertility

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

No studies on the effects on the ability to drive and use machines have been performed. Patients who may 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 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 the vildagliptin/metformin combination. However, bioequivalence of it with co-administered vildagliptin and metformin has been demonstrated.

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. Lactic acidosis has been reported following the use of metformin, especially in patients with underlying renal impairment.

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 antidiabetic treatments, in clinical trials and in post-marketing experience:

^* 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. 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 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.

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 improve gastrointestinal tolerability.