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Dose Adjustment/
Noncompliance in a
Thalassaemia Patient
1
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.
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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
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Thresholds for Parameters Used to
Evaluate Iron Overload
Parameter
Normal
LIC (mg Fe/g dw)
<1.2
Serum ferritin (ng/mL)
<300
Transferrin saturation (%)
20–50
Iron Overloaded State
Mild
3–7
Moderate
Severe
>7
>15
>1000 to <2500
>2500
>50
T2* (ms)
>20
14–20
8–14
Alanine aminotransferase (U/L)
<250
>250
Labile plasma iron (μM)
0–0.4
>0.4
<8
Increased risk of complications
Increased risk of cardiac disease
4
Courtesy of A. Taher, MD.
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
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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
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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 oncedaily 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
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transfusion frequency1.
1 European Agency for Evaluation of Medicinal Products guidelines, 2007.
Deferasirox Dosing by Transfusion
Requirements and Therapeutic Goals
Recommended initial
deferasirox dose
20 mg/kg/d
Starting doses may also be modified as follows:
Transfusion requirement
Therapeutic goal
Deferasirox dose
pRBCs >14 mL/kg/mo
(~4 adult units)
Reduction of body iron
30 mg/kg/d
pRBCs <7 mL/kg/mo
(~2 adult units)
Maintenance of body iron
10 mg/kg/d
For patients well managed on desferrioxamine, suggested starting dose may be
numerically half desferrioxamine dose, eg:
Desferrioxamine
40 mg/kg/d for
5 days per week
Deferasirox 20 mg/kg/d
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EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.
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
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Skin Rash—Deferasirox Dose-Modification
Algorithm
Mild to moderate rash
Continue treatment without
interruption
1. Interrupt treatment
More severe rash
2. Reintroduce deferasirox at lower
dose after resolution of rash
3. Gradually escalate dose
1. Interrupt treatment
Severe rash
2. Reintroduce deferasirox at lower
dose maybe in combination with
oral steroid after resolution of rash
3. Gradually escalate dose
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Deferasirox Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.
Managing Deferasirox-Related
Skin Rash
• Patient was continued on treatment
without interruption
• Rash resolved within 2 weeks
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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
Serum Ferritin (ng/mL)
3500
3000

2500
2000
Deferasirox increased to
30 mg/kg/d
1500
1000
500
0
0
Courtesy of A. Taher, MD
1
2
3
4
5
6
7
Month
8
9 10 11 12
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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
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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
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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
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Overall Response to Treatment
12
3000
10
2000
1500
1000
812
500
11
8
mg Fe/g dw
ng/mL
Serum Ferritin
2500
2500
Liver Iron Concentration
3500
6
4
3.4
2
0
0
Baseline
24 Months
Time
Baseline
24 Month
Time
Courtesy of A. Taher, MD.
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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
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