Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Clinical trials have been conducted with Competact tablets and co-administered pioglitazone and metformin (see section 5.1). At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases. Lactic acidosis is a serious reaction which may occur very rarely (< 1/10,000) (see section 4.4) and other reactions such as bone fracture, weight increase and oedema may occur commonly (≥ 1/100 to < 1/10) (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported in double-blind studies and post-marketing experience are listed below as MedDRA preferred term 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 system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness.

Adverse reaction                          Frequency of adverse reactions Pioglitazone     Metformin       Competact
Infections and infestations
 upper respiratory tract infection                       common                           common sinusitis                                              uncommon                         uncommon Neoplasms benign, malignant and unspecified
(including cysts and polyps) bladder cancer                                       uncommon                           uncommon Blood and lymphatic system disorders anaemia                                                                                  common Immune System Disorders hypersensitivity and allergic reactions1               not known                        not known Metabolism and nutrition disorders
Vitamin B12 absorption decreased2                                       very rare        very rare lactic acidosis                                                         very rare        very rare Nervous system disorders hypo-aesthesia                                          common                           common insomnia                                               uncommon                         uncommon headache                                                                                 common taste disturbance                                                       common           common Eye disorders visual disturbance3                                     common                           common macular oedema                                         not known                        not known Adverse reaction                       Frequency of adverse reactions Pioglitazone     Metformin       Competact
Gastrointestinal disorders  4

 abdominal pain                                                      very common     very common diarrhoea                                                           very common     very common flatulence                                                                           uncommon loss of appetite                                                    very common     very common nausea                                                              very common     very common vomiting                                                            very common     very common Hepatobiliary disorders hepatitis5                                                           not known        not known Skin and subcutaneous tissue disorders erythema                                                              very rare       very rare pruritis                                                              very rare       very rare urticaria                                                             very rare       very rare Musculoskeletal and connective tissue disorders bone fracture6                                        common                           common arthralgia                                                                             common Renal and urinary disorders haematuria                                                                             common Reproductive system and breast disorders erectile dysfunction                                                                   common General disorders and administration site conditions oedema7                                                                                common Investigations weight increased8                                     common                           common alanine aminotransferase increased9                  not known                        not known liver function tests abnormal   5 not known        not known

Description of selected adverse reactions
1
Post-marketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.
2
Long term treatment of metformin has been associated with a decrease of vitamin B12 absorption with decrease of serum levels. Consideration of such aetiology is recommended if a patient presents with megaloplastic anaemia.
3
Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens.
4
Gastrointestinal disorders occur most frequently during initiation of therapy and resolve spontaneously in most cases.
5
Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
6
A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8,100 patients in the pioglitazone-treated groups and 7,400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
In the 3.5 year PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%). Post-marketing, bone fractures have been reported in both male and female patients (see section 4.4).
7
In active comparator controlled trials oedema was reported in 6.3% of patients treated with metformin and pioglitazone, whereas the addition of sulphonylurea to metformin treatment resulted in oedema in 2.2% of patients. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.
8
In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2-3 kg over one year. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg.
9
In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone.

In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. In this study in patients receiving pioglitazone and insulin, a higher percentage of patients with heart failure was observed in patients aged ≥65 years compared with those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the incidence of heart failure was 8.2% in those ≥65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of pioglitazone, and more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure (see section 4.4).

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