erum ferritin was reduced by about -36 and -926 μg/l on average, respectively. At these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to desferrioxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration 7 mg Fe/g dw treated with EXJADE (20 and 30 mg/kg) or desferrioxamine (35 to 50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with EXJADE (5 and 10 mg/kg) or desferrioxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on desferrioxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving EXJADE.
It appeared from preclinical and clinical studies that EXJADE could be as active as desferrioxamine when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the desferrioxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration 7 mg Fe/g dw with various rare anaemias or sickle cell disease, EXJADE up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia.
5.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconj
