1 Adverse reactions reported during postmarketing 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.

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 postmarketing experience, hepatic failure, sometimes fatal, has been reported with EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with EXJADE (see section 4.4).

Paediatric population

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 EXJADE.

4.9 Overdose

 Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.

Acute signs of overdose may include nausea, vomiting, headache and diarrhoea. Overdose may be treated by induction of emesis or by gastric lavage, and by symptomatic treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03

Mechanism of action

Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.

Pharmacodynamic effects

In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively.

Clinical efficacy and safety

EXJADE has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias).

Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and s