Dose Adjustment/ Noncompliance in a Thalassaemia Patient

1. Dose Adjustment/Noncompliance in a Thalassaemia Patient

2. Background • Adequate dose titration and compliance with chelation therapy are crucial factors in achieving prolonged patient survival • The probability of surviving to at least 25 years of age in poorly chelated patient is only one third that of adequately chelated patients1 1. Brittenham GM et al. N Engl J Med. 1994;331:567-573.

3. Patient Presentation • 30-year-old male with thalassaemia major • Patient presented with baseline liver iron concentration of 11.0 mg Fe/g dry weight and baseline serum ferritin of 2500 ng/mL

4. Thresholds for Parameters Used to Evaluate Iron Overload Parameter Normal Iron Overloaded State Mild Moderate Severe LIC (mg Fe/g dw) <1.2 3–7 >7 >15 Serum ferritin (ng/mL) <300 >1000 to <2500 >2500 Transferrin saturation (%) 20–50 >50 T2* (ms) >20 14–20 8–14 <8 Alanine aminotransferase (U/L) <250 >250 Labile plasma iron (μM) 0–0.4 >0.4 Increased risk of complications Increased risk of cardiac disease Courtesy of A. Taher, MD.

5. Treatment History • Patient receives regular transfusions of 2 units of packed red blood cells per month • Since age 3, patient has been treated with desferrioxamine at 30 mg/kg/d, 5 days per week • Patient expressed dissatisfaction with the burdensome subcutaneous regimen and was often noncompliant with treatment

6. Question What should the next step be? A. Counsel patient about the importance of compliance and continue him on desferrioxamine B. Increase desferrioxamine dosage C. Switch to oral deferasirox

7. Switch to Deferasirox • 3 iron chelators are approved for use in patients with thalassaemia: 2 oral agents, deferiprone (3 times daily) and deferasirox (once daily); and the subcutaneous drug, desferrioxamine • Given patient’s dissatisfaction with infusion treatment, an oral chelator seemed a more promising alternative than continuing on desferrioxamine • Deferiprone is associated with potentially serious neutropaenia and is administered 3 times daily • Because of the favourable toxicity profile and once-daily administration of deferasirox, patient was started on deferasirox 20 mg/kg/da aAlthough 20 mg/kg/d is the usual starting dose of deferasirox, 10 mg/kg/d or 30 mg/kg/d can also be used, depending on transfusion frequency1. 1 European Agency for Evaluation of Medicinal Products guidelines, 2007.

8. Deferasirox Dosing by Transfusion Requirements and Therapeutic Goals Recommended initial deferasirox dose pRBCs >14 mL/kg/mo(~4 adult units) pRBCs <7 mL/kg/mo(~2 adult units) Maintenance of body iron Desferrioxamine 40 mg/kg/d for 5 days per week Deferasirox 20 mg/kg/d 30 mg/kg/d 20 mg/kg/d Reduction of body iron 10 mg/kg/d Starting doses may also be modified as follows: Deferasirox dose Transfusion requirement Therapeutic goal For patients well managed on desferrioxamine, suggested starting dose may be numerically half desferrioxamine dose, eg: EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.

9. Question Approximately 2 weeks after starting deferasirox, the patient developed skin rash of moderate severity. How should the rash be managed? A. Continue treatment B. Stop treatment; reintroduce drug at a low dose after rash has resolved C. Stop treatment; reintroduce drug at low dose in combination with steroid after rash has resolved

10. Skin Rash—Deferasirox Dose-Modification Algorithm Continue treatment without interruption Mild to moderate rash More severe rash • Interrupt treatment • Reintroduce deferasirox at lower dose after resolution of rash • Gradually escalate dose • Interrupt treatment • Reintroduce deferasirox at lower dose maybe in combination with oral steroid after resolution of rash • Gradually escalate dose Severe rash Deferasirox Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.

11. Managing Deferasirox-Related Skin Rash • Patient was continued on treatment without interruption • Rash resolved within 2 weeks

12. Response to Treatment Serum Ferritin • Serum ferritin levels increased from 2500 to 3209 ng/mL between months 3 and 6; therefore, deferasirox dose was increased to 30 mg/kg/day • Serum ferritin showed steady decreases during months 7–9 • During the next 3 months, serum ferritin levels began to increase again  Deferasirox increased to 30 mg/kg/d Courtesy of A. Taher, MD

13. Question What might account for the increase in serum ferritin noted after month 9? A. Inflammation/infection B. Increased transfusion requirement C. Noncompliance with treatment

14. Patient Compliance • There had been no change in patient’s transfusion requirement and there was no clinical indication of inflammation or infection • However, in talking with the patient, the clinician discovered that he had not been fully compliant with treatment, missing some pills and occasionally not taking the full deferasirox suspension • Therefore, lack of compliance seemed the most likely cause of the increase in serum ferritin levels noted after month 9 • The patient was counseled about the importance of compliance and taking the medication as directed

15. Postcounseling Outcome • Patient continued on deferasirox 30 mg/kg/d and was able to comply with the treatment regimen • Steady decreases in serum ferritin were observed • At month 24, serum ferritin levels had decreased to 812 ng/mL and liver iron concentration was 3.4 mg Fe/g dry weight • Deferasirox dose was decreased to a maintenance level of 10 mg/kg/d • Patient’s serum ferritin levels remain constant at around 800 ng/mL • He has had no further adverse events or abnormal laboratory values

16. Overall Response to Treatment Serum Ferritin Liver Iron Concentration Courtesy of A. Taher, MD.

17. Conclusions • Deferasirox dose should be reviewed regularly at 3- to 6-month intervals and adjusted according to changes in serum ferritin levels • Physicians need to stress to their patients the importance of full compliance with therapy if iron burden is to be reduced