Deferasirox at oral doses up to 75mg/kg per day (0.6times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES
The primary efficacy study, Study1, was a multicenter, open-label, randomized, active comparator control study to compare Exjade(deferasirox) and deferoxamine in patients with β-thalassemia and transfusional hemosiderosis. Patients ≥2years of age were randomized in a 1:1ratio to receive either oral Exjade at starting doses of 5, 10, 20 or 30mg/kg once daily or subcutaneous Desferal(deferoxamine) at starting doses of 20 to 60mg/kg for at least 5days per week based on LIC (liver iron concentration) at baseline (2-3, >3-7, >7-14 and >14mg Fe/g dry weight). Patients randomized to deferoxamine who had LICvalues <7mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.

Patients were to have a liver biopsy at baseline and end of study (after 12months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥3mg Fe/g dry weight for baseline values ≥10mg Fe/g dry weight, reduction of baseline values between 7 and <10 to <7mg Fe/g dry weight, or maintenance or reduction for baseline values <7mg Fe/g dry weight.

A total of 586patients were randomized and treated, 296 with Exjade and 290 with deferoxamine. The mean age was 17.1years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553patients (Exjade n=276; deferoxamine n=277) who had LIC eva luated at baseline and 12months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine. The relative efficacy of Exjade to deferoxamine cannot be determined from this study.

In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4mg Fe/g dry weight in patients treated with Exjade and -2.9 mg Fe/g dry weight in patients treated with deferoxamine.

Reduction of LIC and serum ferritin was observed with Exjade doses of 20 to 30mg/kg per day. Exjade doses below 20mg/kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure1). Therefore, a starting dose of 20mg/kg per day is recommended [see Dosage and Administration(2.1)].

Figure 1. Changes in Liver Iron Concentration and Serum Ferritin Following EXJADE (5-30mg/kg per day) in Study1

Study2 was an open-label, noncomparative trial of efficacy and safety of Exjade given for 1year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study1, patients received 5, 10, 20, or 30mg/kg per day of Exjade based on baseline LIC.

A total of 184patients were treated in this study: 85patients with β-thalassemia and 99patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were <16years of age and 16% were ≥65years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2mg Fe/g dry weight).

Study3 was a multicenter, open-label, randomized trial of the safety and efficacy of Exjade relative to deferoxamine given for 1year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Exja