1. Exjade One Year Experience Dr Khawla Belhoul Director Thalassemia Center 9 Th February 2008

2. The Aim of This Presentation Is to present our experience with Exjade (Deferasirox or ICL670) in the context of 1.Effects on serum Ferritin in chronically transfused patients who had received Desferoxamine earlier. 2.Side effects and patients tolerance to the drug 3.Effects on Serum Creatinine and liver Transaminases 4.Improving patients quality of life 5.Other side observations

3.  N=135  > 12 months taking Exjade  Transfusion-dependent (Thalassemia Major) with ≥ 100 ml/kg cumulative prior PRBC  Prior DFO therapy at an average daily dose of = 40mg/kg/day  Average starting S. Ferritin =2353mg/dl  Exjade dose was prescribed according to FDA approved prescribing information  Exjade 20 to 30 mg/kg/day for 1 year  The youngest patient was 4 yr old & the oldest was 38 yr old Exjade One Year Experience at Thalassemia Center Dubai

4. Exjade One Year Experience at Thalassemia Center Dubai

5. 95 Patients (71%) were ≤18 yr Exjade One Year Experience at Thalassemia Center Dubai 47% 24% 29%

6. Exjade One Year Experience at Thalassemia Center Dubai

7. Exjade One Year Experience at Thalassemia Center Dubai

8. Baseline Serum Ferritin ≤ 2000mg in 60% 12.5% 27.5% 60% Exjade One Year Experience at Thalassemia Center Dubai

9. Exjade Staring dose was 20mg /kg /day Dose increment was slow for the first 4 months because of frequent initial supply interruptions The supply was constant and adequate for the last 6 months Exjade Average Dose in the Last 6 months was 26mg/kg/day Max. dose achieved was 32 mg/kg/day

10. Average Dose (mg/kg/day) in the Last 6 months =26mg/kg Max. dose = 32 mg/kg/day Exjade One Year Experience at Thalassemia Center Dubai Average Dose in mg/kg/day NO. of patients

11. Low Baseline Ferritin <=2000 81 Medium Baseline Ferritin 2000 to 4000 37 High Baseline Ferritin >=4000 17 Exjade One Year Experience at Thalassemia Center Dubai Serum Ferritin remained static at an average Exjade dose of 26mg/kg/day compared to earlier average Desferal dose of 40 mg/kg /day..

12. Exjade One Year Experience at Thalassemia Center Dubai The effect on serum Ferritin was consistent whatever the initial serum Ferritin.

13. Exjade One Year Experience at Thalassemia Center Dubai The absolute change in serum Ferritin was dose dependent and started to be negative as we moved toward higher doses.

14. Exjade One Year Experience at Thalassemia Center Dubai Serum Ferritin remained static at an average Exjade dose of 26mg/kg/day compared to earlier average Desferal dose of 40 mg/kg /day. Significant reduction in serum Ferritin in chronically transfused patients on Exjade was commonly observed with an average daily dose equal or above 30mg/kg daily Serum Ferritin is reliable at low and normal levels, but loses accuracy as the iron load rises. Many factors independent from iron stores, may significantly alter the serum Ferritin concentration.

15. S. Creatinine Normal Values It depends on muscle mass. A normal value is 0.8-1.3 mg/dL for men and 0.6 to 1.0 mg/dL for women. It is important to take into account serum creatinine trend rather than isolated values. A Creatinine of 1.0mg/dL might be normal or might be abnormal if it has recently increased from 0.6 to 1.0 mg/dL.

16. The P value is 0.0011 Exjade One Year Experience at Thalassemia Center Dubai Serum creatinine rise above baseline was observed in almost all the patients but remained within normal range. The consistency in Serum creatinine rise was statistically Significant (P value = 0.0011)

17. S. Creatinine rise N=135 Exjade One Year Experience at Thalassemia Center Dubai

18. S. Creatinine rise N=135 Exjade One Year Experience at Thalassemia Center Dubai

19. S. Creatinine rise was frequent. S. Creatinine rise was often transient. Serum creatinine rise > 30% at 2 consecutive readings post baseline was higher among our patients compared to the internationally released data. But less patients required dose interruption because of sustained creatinine increase. Paediatric age group and those with law starting serum Ferritin appeared to be more liable to creatinine rise. The Creatinine elevations remained within the normal range Significant or persistent rise reverted to baseline once treatment temporarily adjusted or stopped. None of the patients needed to be excluded from the treatment because of sustained Creatinine rise. None Developed renal failure Exjade One Year Experience at Thalassemia Center Dubai

20. Exjade One Year Experience at Thalassemia Center Dubai

21. Exjade One Year Experience at Thalassemia Center Dubai

22. Exjade One Year Experience at Thalassemia Center Dubai

23. Action% Treatment was discontinued in only one patient because of drug fever 0.75% Treatment was continued in 134 out of 135 patients 99.25% Exjade One Year Experience at Thalassemia Center Dubai

24. Causes of Low Neutrophils ’ Count observed in 5 patientsNo. Hypersplenism2 Interferon & Rebavirin therapy for Hepatitis C2 Hydroxyurea, count improved after stopping it1 Exjade One Year Experience at Thalassemia Center Dubai

25. In 30% Who Completed Annual Tests ENTNil Ophthalmic Nil Echo*Nil Exjade One Year Experience at Thalassemia Center Dubai *NO INCREMENT OR DETERIORATION OBSERVED IN EF

26. Patients’ Satisfaction

27. Patients’ Satisfaction Questionnaire

30. Patients’ Satisfaction I was troubled by nausea and I was finding it difficult to go to sleep in the beginning but after few weeks I felt normal and I enjoyed being free from daily injections. The taste wasn't terrible but it took 15 MINUTES to dissolve this stuff!! As much as I'm complaining - it's still much better than 12 hours/night Desferal. It doesn’t taste good but taste doesn’t matter, it’s a hundred times better than poking yourself at night.

31. Patients’ Compliance Exjade introduction appeared to have improved our patients adherence to medication……….

32. Adherence to chronic pharmacologic therapy is always challenging. Chelation adherence is an important issue in the course of treatment of patients with Thalassemia major. The effect of patients’ education and motivation was thoroughly investigated among patients with many other chronic disorders, but was never tested among Thalassemia Major patients..

33. Method  40 Thalassemia major patients randomly selected, regardless of the type of iron chelator used.  Age was 10years and above.  These patients were subjected to compliance improvement project.  Improvement in compliance was assessed by observing the effect on serum Ferritin.

34. These patients were subjected to intensive education for 6 weeks (2 visits ) in the form of  Self-compliance assessment scale  Compliance assessment scale by doctors, social worker and nurses  Extensive education Health care provider intervention tool Group PowerPoint presentation and discussion on iron overload and iron chelator use. Group Round table discussions. Method

35.  The patients were also called every other week by phone.  The education stopped at 6 weeks and patients Serum Ferritin trend was observed for the following 10 weeks.

36. Doctor,nurse and social worker intervention tool

37. Patients’ Compliance

38. Compliance Improvement Project Intensive education period Intensive education stopped

39. Compliance Improvement Project

40. Intensive education period Intensive education stopped

41. Serum Ferritin declined while on intensive education irrespective of the chelating agent used. Serum Ferritin started to rise again once intensive education was interrupted irrespective of the chelating agent used. Causes of noncompliance were also studied among the same group of patients intensively

42. Causes of Non-compliance to Desferal

43. Causes of Non-Compliance to Exjade

44. Non-Compliance to Iron Chelation CAUSE EXJADEDESFERAL Forgetting 38.7%30.7% Inconvenience 9.7%46.1% Nil 32.2%7.7% ? ?

45. – Serum Ferritin remained static at an average dose of 25mg/kg/day compared to earlier average Desferal dose of 40 mg/kg /day – Exjade Was generally well tolerated – Mild Creatinine elevations, skin rash and mild gastrointestinal side effects were the commonest adverse experiences – Serum creatinine rise > 30% at 2 consecutive readings post baseline was higher among our patients – But less patients required dose reduction or interruption because of sustained creatinine increase – Paediatric age group and those with law starting serum Ferritin appeared to be more liable to creatinine rise. – The Creatinine elevations remained within the normal range – Side effects appeared to be potentially related to excessive and rapid chelation – No cases of arthropathy, or agranulocytosis – No renal failure – No deaths Exjade One Year Experience at Thalassemia Center Dubai Summary

46. Exjade One Year Experience at Thalassemia Center Dubai Summary Patient adherence to medical therapy has been called “the next frontier in quality improvement.” Exjade introduction appeared to have improved our patients adherence to medication. Without effective patients’ education and motivation, the benefits of such valuable and expensive drug can simply be wasted.