Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Tabulated list of adverse reactions
Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patients receiving pioglitazone in double-blind studies 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 frequency grouping, adverse reactions are presented in order of decreasing incidence and seriousness.


Adverse          Frequency of adverse reactions of pioglitazone by treatment regimen reaction
Combination

Mono-        with             with         with       with insulin therapy     metformin         sulpho-    metformin nylurea    and sulpho- nylurea
Infections and infestations upper respiratory     common       common          common       common        common tract infection bronchitis                                                                    common sinusitis            uncommon     uncommon         uncommon    uncommon      uncommon Blood and lymphatic system disorders anaemia                            common
Immune System
Disorders
Hypersensitivity     Not known    Not known        Not known   Not known     Not known and allergic reactions 1
Metabolism and nutrition disorders hypo-glycaemia                                     uncommon       very        common common appetite increased                                 uncommon
Nervous system disorders hypo-aesthesia        common       common           common      common        common headache                           common          uncommon dizziness                                           common insomnia             uncommon     uncommon         uncommon    uncommon      uncommon Eye disorders visual                common       common          uncommon disturbance2 macular oedema       not known     not known       not known   not known     not known Ear and labyrinth disorders vertigo                                            uncommon
Cardiac disorders heart failure3                                                                common 
Adverse            Frequency of adverse reactions of pioglitazone by treatment regimen reaction
Combination

Mono-        with           with          with       with insulin therapy     metformin       sulpho-     metformin nylurea     and sulpho- nylurea
Neoplasms benign,
malignant and unspecified
(including cysts and polyps) bladder cancer   uncommon      uncommon      uncommon      uncommon      uncommon Respiratory,
thoracic and mediastinal disorders dyspnoea                                                                    common Gastrointestinal disorders flatulence                      uncommon       common
Skin and subcutaneous tissue disorders sweating                                       uncommon
Musculoskeletal and connective tissue disorders fracture bone4      common       common        common         common        common arthralgia                       common                       common        common back pain                                                                   common Renal and urinary disorders haematuria                       common glycosuria                                     uncommon proteinuria                                    uncommon
Reproductive system and breast disorders erectile                         common dysfunction
General disorders and administration site conditions
Oedema5                                                                       very common fatigue                                        uncommon


Adverse             Frequency of adverse reactions of pioglitazone by treatment regimen reaction
Combination

Mono-           with            with            with         with insulin therapy        metformin        sulpho-       metformin nylurea       and sulpho- nylurea
Investigations weight increased6    common          common          common          common          common blood creatine                                                       common phospho-kinase increased increased lactic                                    uncommon dehydro-genase alanine             not known       not known       not known       not known       not known aminotransferase increased 7
1
Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.
2
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 as seen with other hypoglycaemic treatments.


3
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 rarely with marketing use of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.
4
A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 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%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. 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)


5
Oedema was reported in 6–9% of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2–5%. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.
6
In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2–3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.
7
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. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.


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.