Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Safety data were obtained from a total of 3,784 patients exposed to vildagliptin at a daily dose of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in controlled trials of at least 12 weeks duration. Of these patients, 2,264 patients received vildagliptin as monotherapy and 1,520 patients received vildagliptin in combination with another medicinal product. 2,682 patients were treated with vildagliptin 100 mg daily (2,027 with 50 mg twice daily and 655 with 100 mg once daily) and 1,102 patients were treated with vildagliptin 50 mg once daily.

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.

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 GAL API FEB15 CL V11                                            4             REF SmPC 05.14 CDS 30.07.14 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.

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.

Adverse reactions reported in patients who received Galvus 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, <1/10), uncommon (≥1/1,000, <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, undesirable effects are presented in order of decreasing seriousness.

Combination with metformin
In controlled clinical trials with the combination of vildagliptin 100 mg daily + metformin, no withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily + metformin or the placebo + metformin treatment groups.

In clinical trials, the incidence of hypoglycemia was common in patients receiving vildagliptin 100 mg daily in combination with metformin (1%) and uncommon in patients receiving placebo + metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.

In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily was added to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).

Table 1      Adverse reactions reported in patients who received Galvus 100 mg daily in combination with metformin in double-blind studies (N=208)

Nervous system disorders
Common                Tremor
Common                Headache
Common                Dizziness
Uncommon              Fatigue
Gastrointestinal disorders
Common                Nausea
Metabolism and nutrition disorders
Common                Hypoglycemia

Clinical trials of up to more than 2 years' duration did not show any additional safety signals or unforseen risks when vildagliptin was added on to metformin.

Combination with a sulfonylurea
In controlled clinical trials with the combination of vildagliptin 50 mg + a sulfonylurea, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + sulfonylurea vs 0% in the placebo + sulfonylurea treatment group.

In clinical trials, the incidence of hypoglycemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% for placebo + glimepiride. No severe hypoglycemic events were reported in the vildagliptin arms.

In clinical trials, weight did not change from baseline when vildagliptin 50 mg daily was added to glimepiride (-0.1 kg and -0.4 kg for vildagliptin and placebo, respectively).


GAL API FEB15 CL V11                                           5             REF SmPC 05.14 CDS 30.07.14 Table 2      Adverse reactions reported in patients who received Galvus 50 mg in combination with a sulfonylurea in double-blind studies (N=170)

Infections and infestations
Very rare             Nasopharyngitis
Nervous system disorders
Common                Tremor
Common                Headache
Common                Dizziness
Common                Asthenia
Gastrointestinal disorders
Uncommon              Constipation
Metabolism and nutrition disorders
Common                Hypoglycemia

Combination with a thiazolidinedione
In controlled clinical trials with the combination of vildagliptin 100 mg daily + a thiazolidinedione, no withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily + thiazolidinedione or the placebo + thiazolidinedione treatment groups.

In clinical trials, the incidence of hypoglycaemia was uncommon in patients receiving vildagliptin + pioglitazone (0.6%) but common in patients receiving placebo + pioglitazone (1.9%). No severe hypoglycaemic events were reported in the vildagliptin arms.

In the pioglitazone add-on study, the absolute weight increases with placebo, Galvus 100 mg daily were 1.4 and 2.7 kg, respectively.

The incidence of peripheral oedema when vildagliptin 100 mg daily was added to a maximum dose of background pioglitazone (45 mg once daily) was 7.0%, compared to 2.5% for background pioglitazone alone.

Table 3 Adverse reactions reported in patients who received Galvus 100 mg daily in combination with a thiazolidinedione in double-blind studies (N=158)
Metabolism and nutrition disorders
Common          Weight increase
Uncommon        Hypoglycemia
Nervous system disorders
Uncommon        Headache
Uncommon        Asthenia
Vascular disorders
Common          Oedema peripheral

Monotherapy
In addition, in controlled monotherapy trials with vildagliptin the overall incidence of withdrawals due to adverse reactions was no greater for patients treated with vildagliptin at doses of 100 mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).

In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 100 mg 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.

In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively).


GAL API FEB15 CL V11                                           6            REF SmPC 05.14 CDS 30.07.14 Table 4   Adverse reactions reported in patients who received Galvus 100mg daily as monotherapy in double-blind studies (N=1,855)

Nervous system disorder
Common                Dizziness
Uncommon              Headache
Gastrointestinal disorders
Uncommon              Constipation
Musculoskeletal and connective tissue disorders
Uncommon              Arthralgia
Metabolism and nutrition disorders
Uncommon              Hypoglycemia
Infections and infestations
Very rare             Upper respiratory tract infection
Very rare             Nasopharyngitis
Vascular disorders
Uncommon              Oedema peripheral

Clinical trials of up to 2 years' duration did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Combination with metformin and SU

Table 5 Adverse reactions reported in patients who received Galvus 50mg twice daily in combination with metformin and a sulfonylurea (N=157)

Metabolism and nutritional disorders
Common              Hypoglycaemia
Nervous system disorders
Common              Dizziness, tremor
Skin and subcutaneous tissue disorders
Common              Hyperhidrosis
General disorders and administration site condition
Common              Asthenia

There were no withdrawals reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group. vs. 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 group). One 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).

Combination with insulin

Table 6   Adverse reactions reported in patients who received Galvus 100 mg daily in combination with insulin (with or without metformin) in double-blind studies (n=371) 

GAL API FEB15 CL V11                                           7             REF SmPC 05.14 CDS 30.07.14 Metabolism and nutrition disorders

Common                 Decrease blood glucose

Nervous system disorders
Common                 Headache, chills

Gastrointestinal disorders

Common                 Nausea, gastro-oesophageal reflux desease
Uncommon               Diarrhoea, flatulence

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 (14.0% 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, 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).


Post-marketing Experience
During post-marketing experience the following additional adverse drug reactions have been reported 
Table 7 Post-marketing adverse reactions Gastrointestinal disorders
Not known*                                  Pancreatitis
Hepatobiliary disorders
Not known*                                  Hepatitis (reversible upon discontinuation of the medicinal product)
Abnormal liver function tests (reversible upon discontinuation of the medicinal product)
Skin and subcutaneous tissue disorders
Not known*                                  Urticaria
Bullous or exfoliative skin lesions
*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".

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectM edic@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).