Adverse reactions : תופעות לוואי

4.8 Undesirable effects
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 Eucreas. However, bioequivalence of Eucreas with co-administered vildagliptin and metformin has been demonstrated (see section 5.2).
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 (see section 4.4).


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.

EUC API SEP22 V3                                                           EU SmPC 07.2022 Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), 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 anti- diabetic treatments, in clinical trials and in post-marketing experience 

System organ class - adverse reaction                Frequency
Infections and infestations
Upper respiratory tract infection                    Common
Nasopharyngitis                                      Common
Metabolism and nutrition disorders
Hypoglycaemia                                        Uncommon
Loss of appetite                                     Uncommon
Decrease of vitamin B12 absorption and lactic
Very rare* acidosis
Nervous system disorders
Dizziness                                            Common
Headache                                             Common
Tremor                                               Common
Metallic taste                                       Uncommon
Gastrointestinal disorders
Vomiting                                             Common
Diarrhoea                                            Common
Nausea                                               Common
Gastro-oesophageal reflux disease                    Common
Flatulence                                           Common
Constipation                                         Common
Abdominal pain including upper                       Common
Pancreatitis                                         Uncommon
Hepatobiliary disorders
Hepatitis                                            Uncommon
Skin and subcutaneous tissue disorders
Hyperhidrosis                                        Common
EUC API SEP22 V3                                                           EU SmPC 07.2022 Pruritis                                              Common
Rash                                                  Common
Dermatitis                                            Common
Erythema                                              Uncommon
Urticaria                                             Uncommon
Exfoliative and bullous skin lesions, including
Not known† bullous pemphigoid
Cutaneous vasculitis                                  Not known
Musculoskeletal and connective tissue disorders
Arthralgia                                            Common
Myalgia                                               Uncommon
General disorders and administration site conditions
Asthenia                                              Common
Fatigue                                               Uncommon
Chills                                                Uncommon
Oedema peripheral                                     Uncommon
Investigations
Abnormal liver function tests                       Uncommon
* 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
EUC API SEP22 V3                                                          EU SmPC 07.2022 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il