Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.

During clinical studies, dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have EXJ API AUG21 V13                                                                   EU SmPC Aug 2021 been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4).


Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of EXJADE (see section 4.4).


Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: 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 seriousness.
Table 5

Blood and lymphatic system disorders
Not known:          Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1
Immune system disorders
Not known:          Hypersensitivity reactions (including anaphylactic reactions and angioedema)1
Metabolism and nutrition disorders
Not known:          Metabolic acidosis1
Psychiatric disorders
Uncommon:           Anxiety, sleep disorder
Nervous system disorders
Common:             Headache
Uncommon:           Dizziness
Eye disorders
Uncommon:           Cataract, maculopathy
Rare:               Optic neuritis
Ear and labyrinth disorders
Uncommon:           Deafness
Respiratory, thoracic and mediastinal disorders
Uncommon:           Laryngeal pain
Gastrointestinal disorders
Common:             Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia
Uncommon:           Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis
Rare:               Oesophagitis
Not known:          Gastrointestinal perforation1, acute pancreatitis1 Hepatobiliary disorders
Common:             Transaminases increased
Uncommon:           Hepatitis, cholelithiasis
Not known:          Hepatic failure1, 2
Skin and subcutaneous tissue disorders
Common:             Rash, pruritus
Uncommon:           Pigmentation disorder
Rare:               Drug reaction with eosinophilia and systemic symptoms (DRESS) Not known:          Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1
EXJ API AUG21 V13                                                                   EU SmPC Aug 2021 Renal and urinary disorders
Very common:          Blood creatinine increased
Common:               Proteinuria
Uncommon:             Renal tubular disorder2 (acquired Fanconi syndrome), glycosuria Not known:            Acute renal failure1, 2, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1
General disorders and administration site conditions
Uncommon:             Pyrexia, oedema, fatigue
1
Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.
2
Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported.


Description of selected adverse reactions
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with deferasirox, (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4).

Creatinine clearance in transfusional iron overload
In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with EXJADE in two randomised and four open label studies of up to five years’ duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed.

Clinical study in patients with non-transfusion-dependent thalassaemia syndromes In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (EXJADE at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients.

Paediatric population
In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4).

Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.

Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome.

Acute pancreatitis has been reported, particularly in children and adolescents.


EXJ API AUG21 V13                                                                    EU SmPC Aug 2021 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/).