Galvusmet Adverse Reactions

Summary of the safety profile: Vildagliptin/Metformin: The data presented here relate to the administration of vildagliptin and metformin as a free or fixed dose combination.
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.
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 tests (LFTs) returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy studies 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 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.
In clinical studies with the combination of vildagliptin + metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg twice daily + metformin or the placebo + metformin treatment groups.
In clinical studies, the incidence of hypoglycemia was uncommon in patients receiving vildagliptin 50 mg once daily in combination with metformin (0.9%), patients receiving vildagliptin 50 mg twice daily in combination with metformin (0.5%) and in patients receiving placebo and metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.
Vildagliptin is weight neutral when administered in combination with metformin.
Gastrointestinal adverse reactions including diarrhea and nausea are known to occur very commonly during the introduction of metformin hydrochloride. In the vildagliptin monotherapy clinical program (n=2,264) where vildagliptin was administered 50 mg once daily, 50 mg twice daily, or 100 mg once daily, the rate of diarrhea was 1.2%, 3.5% and 0.8% respectively and the rate of nausea was 1.7%, 3.7% and 1.7% respectively as compared to 2.9% for both in the placebo group (n=347) and 26.2% and 10.3%, respectively, in the metformin hydrochloride group (n=252).
Overall, gastrointestinal symptoms were reported in 13.2% (50 mg once daily or twice daily) of patients treated with the combination of vildagliptin and metformin hydrochloride compared to 18.1% of patients treated with metformin hydrochloride alone.
Tabulated summary of adverse drug reactions from clinical studies: Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on to metformin and as monotherapy, are listed as follows, for each indication, by MedDRA system organ class and absolute frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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). (See Table 2.)

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Long term clinical studies of up to more than 2 years did not show any additional safety signals or unforeseen risks when vildagliptin was added on to metformin.
When vildagliptin was studied as an initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.
Combination with insulin: In controlled clinical studies using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was 0.3% in the vildagliptin treatment group and there were no cases of withdrawal in the placebo group.
The incidence of hypoglycemia was similar in both treatment groups (14.0% in the vildagliptin group vs 16.4% in the placebo group). Two patients reported severe hypoglycemic events in the vildagliptin group, and 6 patients - in the placebo group.
At the end of the study, the effect on mean body weight was neutral (+0.6 kg change from baseline in the vildagliptin group and no weight change in the placebo group). (See Table 3.)

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Combination with SU: There were no cases of withdrawal reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group versus 0.6% in the placebo + metformin + glimepiride treatment group.
The incidence of hypoglycemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride vs. 1.9% for the placebo + metformin + glimepiride). One severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, the effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group). (See Table 4.)

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Vildagliptin: Adverse reactions for vildagliptin component from monotherapy double blind studies are presented in Table 5. (See Table 5.)

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None of the adverse reactions reported for the vildagliptin monotherapy were observed at clinically significantly higher rates when vildagliptin was administered concomitantly with metformin.
The overall incidence of withdrawals from monotherapy studies due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg once daily (0.2%) or vildagliptin at a dose of 50 mg twice daily (0.1%) than for placebo (0.6%) or comparators (0.5%).
In monotherapy studies, hypoglycemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1,373) of patients treated with vildagliptin 50 mg twice daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported. Vildagliptin is weight neutral when administered as monotherapy.
Long term clinical studies of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.
Adverse drug reactions from spontaneous reports and literature cases - post-marketing experience (frequency not known): The following adverse drug reactions have been derived from post-marketing experience via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known: Hepatitis, reversible upon drug discontinuation (see also PRECAUTIONS); Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid; Cutaneous vasculitis; Pancreatitis; Arthralgia, sometimes severe; Cholecystitis.
Metformin Hydrochloride: Known adverse reactions for the metformin component are summarized in Table 6. (See Table 6.)

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Gastrointestinal adverse effects occur most frequently during initiation of therapy and resolve spontaneously in most cases.