The data presented 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 (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 LFTs returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials up to 24 weeks in duration, the incidence of ALT or AST elevations ≥3 x 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, nonprogressive in nature and not associated with cholestasis or jaundice.
In clinical trials 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 trials, 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 HCl. In the vildagliptin monotherapy clinical program (n=2264) 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 HCl 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 HCl compared to 18.1% of patients treated with metformin HCl alone.
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 system organ class and absolute frequency. Frequencies are defined as: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Other Adverse Reactions Reported in Patients Who Received Vildagliptin 50 mg Once Daily (n=233) or 50 mg Twice Daily (n=183) as Add-On Therapy to Metformin Compared to Placebo Plus Metformin in Double-Blind Studies: Nervous System Disorders:
Common: Tremor, dizziness, headache.
Long-term clinical trials of up to >2 years did not show any additional safety signal or unforeseen risks when vildagliptin was added on to metformin.
When vildagliptin was studied as initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.
Combination with Insulin:
In controlled clinical trials 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 withdrawals in the placebo group.
The incidence of hypoglycemia was similar in both treatment groups (14% in the vildagliptin group vs 16.4% in the placebo group). Two (2) patients reported severe hypoglycemic events in the vildagliptin group, and 6 patients in the placebo group. At the end of the study, 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).
Adverse Reactions Reported in Patients Who Received Vildagliptin 50 mg Twice Daily in Combination with Insulin [With or Without Metformin (n=371)]: Nervous System Disorders:
Common: Headache, chills.
Common: Nausea, gastroesophageal reflux disease (GERD). Uncommon: Diarrhea, flatulence.
Metabolism and Nutritional Disorders:
Common: Decreased blood glucose.
Combination with SU:
There were no withdrawals 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 (1) severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).
Adverse Reactions Reported in Patients Who Received Vildagliptin 50 mg Twice Daily in Combination With Metformin and SU (n=157): Nervous System Disorders:
Common: Dizziness, tremor.
General Disorders and Administration Site Condition:
Metabolism and Nutritional Disorders:
Skin and Subcutaneous Tissue Disorders:
Adverse reactions for vildagliptin component from monotherapy double-blind studies are presented as follows: Adverse Reactions Reported in Patients Who Received Vildagliptin 50 mg Once Daily (n=409) or 50 mg Twice Daily (n=1373) as Monotherapy in Double-Blind Studies: Nervous System Disorders:
Common: Dizziness. Uncommon: Headache.
General Disorders and Administration Site Conditions:
Uncommon: Peripheral edema.
None of the adverse reactions reported for the vildagliptin monotherapy were observed at clinically significant higher rates when vildagliptin was administered concomitantly with metformin.
The overall incidence of withdrawals from monotherapy trials 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 1373) of patients treated with vildagliptin 50 mg twice daily compared to 0.2% (2 of 1082) 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 trials of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.
During post-marketing experience, the following additional adverse drug reactions have been reported: Rare cases of hepatitis reversible upon drug discontinuation (see Precautions).
Frequency Not Known*
: Urticaria, pancreatitis, localized exfoliation or blisters.
Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frquency which is therefore categorized as "not known".
Known adverse reactions for metformin component are summarized as follows: Metabolism and Nutrition Disorders:
Very Rare: Decrease of vitamin B12 absorption (a decrease of vitamin B12 absorption with decrease of serum levels has been very rarely observed in patients treated long-term with metformin and appears generally to be without clinical significance. Consideration of such etiology is recommended if a patient presents with megaloblastic anaemia.), lactic acidosis.
Nervous System Disorders:
Common: Metallic taste.
Very Common: Nausea, vomiting, diarrhea, abdominal pain, loss of appetite.
Very Rare: Liver function test abnormalities, hepatitis (isolated cases of LFT abnormalities or hepatitis resolving upon metformin discontinuation have been reported.)
Skin and Subcutaneous Tissue Disorders:
Very Rare: Skin reactions eg, erythema, pruritus, urticaria.
Gastrointestinal undesirable effects 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.