Special Article

Deferasirox : Oral, Once Daily Iron Chelator - An Expert

Opinion
M.B. Agarwal

Hematologist and Hemato-Oncologist, Bombay Hospital Institute of Medical Sciences, Marine Lines, Mumbai, India

ABSTRACT
Iron overload is a serious and potentially fatal condition that results from multiple blood transfusions required over a long period
of time to treat certain types of anemias such as, that caused by -thalassemia, sickle cell disease and myelodysplastic
syndrome. Deferoxamine, which has been used since four decades as an iron chelator has limited efficacy due to its
demanding therapeutic regimen, leading to poor compliance. Deferasirox, once daily oral iron chelator provides an effective
alternative to Deferoxamine in the treatment of transfusional hemosiderosis. In this review, the role of Deferasirox as an ideal
iron chelator has been discussed. Pubmed searches on Deferasirox were carried out for the same. Several studies
demonstrated the safety and efficacy of Deferasirox in reducing iron burden in iron-overloaded patients with -thalassemia,
sickle cell anemia and myelodysplastic anemia. Thus, convenient, effective and tolerable chelation therapy with oral
Deferasirox is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide
constant chelation coverage and the potential to improve compliance. [Indian J Pediatr 2010; 77 (2) : 185-191] E-mail:
mbagarwal@hotmail.com

Key words: Chelation; Deferasirox; Iron; Thalassemia

Normal iron balance is characterized by the highly
efficient reprocessing of catabolic iron derived from
senescent red blood cells and its reutilization in the
production of new erythrocytes. This cycle represents
about 85% of the plasma iron turnover, with only a small
percentage of the plasma iron originating from intestinal
absorption. Normal body iron stores in humans is 3-4g;
however, an excess of iron of 20g or more can lead to
organ damage.1
Iron overload is a serious and potentially fatal
condition that results from multiple blood transfusions
required over a long period of time, to treat certain types
of anemia such as that caused by -thalassemia, sickle cell
disease and myelodysplastic syndrome.2 As there is no
natural mechanism for the body to eliminate excess iron,
the iron in the transfused blood cells builds up and
becomes toxic to tissues and organs, particularly the liver
and the heart.
In patients receiving repeated transfusions without
chelation therapy, symptomatic cardiac disease is
generally reported within 10 yrs of receiving the first
Correspondence and Reprint requests : Dr. M.B. Agarwal,
Hematology Centre, Ghamat Lodge, Above ING Vaiysha Bank,
2nd Floor, 804-A, Dr. B. Ambedkar Road, Dadar TT, Mumbai-
400014, India.
[Received January 6, 2010; Accepted January 6, 2010]
transfusion.2 Cardiac damage caused by iron overload
toxicity is the main cause of death in Thalassemia patients.
This may occur in the second and third decade of life,
especially in patients not receiving sufficient or effective
chelation therapy. An increased risk of iron-induced
cardiac disease is observed in Thalassemia patients with
Liver Iron Concentration (LIC) values above 15 mg of iron
per gram of dry weight of liver (15 mg Fe/g/dw), and in
patients with serum ferritin values above 2500 microgm/
litre.3 In patients receiving blood transfusions, portal
fibrosis is often observed within 2 yrs of the first
transfusion4,5 and liver cirrhosis can develop within the
first decade of life if the overload remains untreated.
The rate of iron loading depends mainly on the rate of
blood transfusions, which is usually aimed at maintaining
Hb levels at or about 11.0 mg/dl. To achieve this goal,
about 1-3 units, each of which contains 200-250 ml of
packed cells, equivalent to about 200-250 mg of iron, are
transfused every 2-4 wk. This rate of transfusion causes a
net iron deposition in the body, of about 15-20 mg/day. A
few milligrams of dietary iron can also be deposited in the
body from increased gastro-intestinal absorption, because
of the underlying anemia before transfusions. Within this
context, the aim of chelation therapy is to remove
sufficient amounts of iron (>15-20 mg/day), in order to
maintain a negative iron balance, by comparison to
accumulated iron in the body mainly from blood
transfusions.6

Indian Journal of Pediatrics, Volume 77February, 2010 185

 M.B. Agarwal
Unmet Medical Need/ Therapy Gap in Clinical Practice
In 1963, the introduction of Deferoxamine (DFO), a
hexadentate chelator marked a breakthrough in the
management of iron overload. However, Deferoxamine
requires subcutaneous or intravenous infusions.
Moreover, patients with severe anemia cannot achieve
iron depletion by the periodic removal of blood
(therapeutic phlebotomy), because they cannot tolerate
exacerbation of anemia that occurs as an unavoidable
consequence of therapeutic phlebotomy7. Clearly, the
removal of excess body iron is vital to improve morbidity
and mortality in patients with transfusional
hemosiderosis. Table 1 compares deferasirox with existing
iron chelators i.e., deferoxamine and deferiprone.
Goals of Chelation therapy
In clinical practice, key goal of chelation therapy is
prevention of iron accumulation, as this will prevent a rise
in liver iron concentration and the secondary
redistribution of iron to other organs, including the
pituitary, endocrine glands and the heart. In order to
achieve an iron balance, two key iron pools need to be
accessed by chelators.
(i) Intracellular labile iron pool (LIP)
In iron overload, the hepatocytes are the major cells of
iron storage, with liver iron closely approximating total
body iron.8 Therefore, liver is the major key target for
chelation therapy.
(ii) Iron from red cell catabolism
The second major source of chelatable iron is that derived
from red cell catabolism in macrophages, which is
increased during ineffective erythropoiesis. Because this
iron pool is rapidly (re)incorporated into ferritin and only
transiently available for chelation therapy, its iron-
detoxifying effect depends upon the drug availability for
24 hr a day; called as protection time.9
Discovery of a novel chelator: From desferrithiocin to
Deferasirox
Several efforts have been made over the past four to five
decades, to synthesize orally active iron chelators.
Ferferrithiocin was first discovered in 1980, followed by
TABLE 1. Comparison of Deferasirox with Existing Iron Chelators28
Feature Deferrioxamine
Iron binding efficiency (drug : iron) 1:1
Iron selectivity Highly selective
Regimen SC or IV infusion
Tolerability issues Local reactions
Long-term safety profile Proven
186
the synthesis of the tridentate desferrithiocin, whose
activity via oral administration have raised a hope.
However, animal studies confirmed the compound to be
toxic. The discovery of bishydroxyphenyltriazoles, a new
chemical class of iron chelators, renewed the pursuit of a
safe tridentate chelator.10
A combination of rational design, intuition and
experience paved the way for the discovery of the basic
structure of this completely new chemical class of iron
chelators. More than forty derivatives of the triazole series
were synthesized at Novartis. After screening more than
700 chelators from various chemical classes, Deferasirox
emerged as a bishydroxyphenyltriazole entity, which best
combined high oral potency and tolerability in animals.10
Stucture Activity Relationship (SAR)
Deferasirox is a bis-hydroxyphenyl-triazole benzoic acid
derivative (Fig. 1). 1,2,4-triazoles can be regarded as
condensation products of imides with hydrazines.
Thionylchloride mediated condensation of salicylic acid
with salicylic amide results in the formation of a
hydroxyphenylbenzoxazinone, a derivative form of the
imide. This intermediate is ideally activated to react with
hydrazines, forming bishydroxyphenyl-triazoles in just
two steps from salicylic acid.10
Fig. 1. Chemical structure of Deferasirox
Pharmacodynamics
Deferasirox is an orally active chelator that is highly
selective for iron. It is a tridentate chelator that mobilizes
iron stores by binding selectively to the ferric (Fe3+) form
of iron. 11 Tridentate chelators require two ligand
molecules to bind one iron atom. The selectivity for iron
is high, with low affinity for trace metals, such as zinc or
copper.12
Deferiprone Deferasirox
3:1 2 :1
Zinc is also excreted Highly selective
Oral, 3 times a day Oral, once a day
Joint problems Skin rashes
Severe neutropenia Emerging
Indian Journal of Pediatrics, Volume 77February, 2010
 Deferasirox : Oral, Once Daily Iron Chelator - An Expert Opinion
Deferasirox readily enters most of the cells and
efficiently reaches the major intracellular sites of iron
accumulation.13
Hepatic iron
Radiolabelled iron probes have been used to investigate
the source of iron chelated by Deferasirox, in vivo. 14
Deferasirox appeared to be four to five times more
effective than parenterally administered Deferoxamine in
promoting the excretion of chelatable iron from
hepatocellular iron stores. This suggests that Deferasirox
chelates excess iron that enters the reticuloendothelial
system as insoluble ferritin rather than iron required for
enzyme activity, which may explain the lack of enzyme-
related adverse effects seen with Deferasirox treatment. In
addition, the iron complex of Deferasirox appears inert
enough to be excreted to a large extent in the faeces, rather
than being redistributed.15
Labile plasma iron (LPI)
Iron loading may lead to excessive cellular accumulation
of labile iron in susceptible parenchymal tissue, such as
the liver, heart and endocrine system. This labile iron may
prove to be a key mediator of iron toxicity due to its
ability to catalyze production of reactive oxygen species
(ROS), such as free radicals.
A subgroup analysis of the 1-yr ESCALATOR trial
evaluated the effect of Deferasirox in reducing LPI, in
heavily iron-overloaded -thalassaemia patients, all of
whom had achieved inadequate chelation with
Deferoxamine or deferiprone. Deferasirox 20-30 mg/kg/
day significantly reduced levels of toxic LPI and
maintained them within normal limits, despite a high
baseline iron burden. Deferasirox daily trough levels were
within the therapeutic range, which indicated a constant
24-hr chelation coverage. Decreases in LPI were also
associated with decreases in mean LIC and SF, indicating
effective iron removal by Deferasirox. The results of the
ESCALATOR study highlight the importance of timely
Deferasirox dose adjustments, based on serum ferritin
levels and transfusional iron intake to ensure patients
achieve their therapeutic goal of maintenance or reduction
in iron burden.16
Myocardial iron
In vitro and in vivo preclinical data have demonstrated that
Deferasirox has the ability to enter myocardial cells and
chelate iron from these cells. It was also observed from
studies in myocyte cultures that Deferasirox rapidly
gained entry in the myocytes and bound to labile
intracellular iron, leading to decreased free radical
production. Effective cardiac iron removal has also been
demonstrated by Deferasirox in an iron-loaded gerbil
model. In this study Deferasirox removed more hepatic
iron than deferiprone, for a given cardiac iron burden.17
Indian Journal of Pediatrics, Volume 77February, 2010
Clinical trials evaluating effect of Deferasirox in iron
overloaded patients have proved that Deferasirox chelates
cardiac iron without affecting the left ventricular ejection
fraction (LVEF). The effects of Deferasirox on myocardial
iron, in a subset of patients enrolled in two clinical studies,
were recently reported. In a subgroup of 23 patients
(mean age, 24.6 yr; range, 9-50 yr), who received
Deferasirox 10-30 mg/kg/day, at a single center for a
mean S.D. of 13.1 0.78 months, the mean myocardial
T2*, a cardiovascular magnetic resonance imaging (MRI)
measurement inversely related to myocardial iron
content, significantly increased into the normal range (p =
0.013). Likewise, eight patients who received Defero-
xamine had increases in mean cardiac T2*, although these
changes were small and did not achieve statistical
significance (p = 0.11). Deferasirox treatment led to
significant reductions from baseline in mean S.D. serum
ferritin concentrations (3173 410 g/L to 2451 242 g/
L, p = 0.023) and LICs (18.3 2.2 mg iron/g dw to 10.0
1.49 mg iron/g dw, p = 0.0002), while no changes in LVEF
were noted.18
One study monitored cardiac siderosis using T2 MRI in
a cohort of 19 heavily iron-overloaded patients with -
thalassemia major, receiving iron chelation therapy with
Deferasirox over an 18-month period. Deferasirox therapy
significantly improved mean standard deviation cardiac
T2 from a baseline of 17.210.8 to 21.512.8 ms (+25.0%;
P=0.02). A concomitant reduction in median serum
ferritin from a baseline of 5,497 to 4,235 ng/mL (23.0%;
P=0.001), and mean liver iron concentration from 24.29.0
to 17.6 12.9 mg Fe/g dry weight (27.1%; P=0.01) was
also seen. Improvements were seen in patients with
various degrees of cardiac siderosis, including those
patients with a baseline cardiac T2 of <10 ms, indicative of
high cardiac iron burden.19
Thus, the available data show promising results on the
effect of Deferasirox on cardiac iron. Further trials are
ongoing, to elucidate the effect of Deferasirox on cardiac
iron and function.
Pharmacokinetics
Due to its relatively small size (MW 373.4), Deferasirox is
well absorbed through the gastrointestinal tract. The
median time to maximum plasma concentration (Tmax) is
about 1.5 to 4 hr and an absolute bioavailability (AUC) of
about 70%. Deferasirox is highly (99%) protein bound to
plasma proteins, almost exclusively serum albumin and
has a volume of distribution of approximately 14 L in
adults. Deferasirox plasma levels persisted at a detectable
level for at least 24 hr after single and multiple doses of 10
and 20 mg/kg.20
Glucuronidation is the main metabolic pathway for
Deferasirox, with subsequent biliary excretion. No
evidence for induction or inhibition of enzymes at
187

Deferasirox 10 mg/kg/day
120
mol/L
100
Deferasirox concentration (
80
60
40
20
0
0 4 8 12
Time (hours)
Fig. 2. Mean steady-state plasma concentrations (+SD) of Defera-
sirox following a dose of 10 or 20 mg/kg/day.
therapeutic doses has been observed. The mean
elimination half-life (t1/2) ranges from 8 - 16 hr
supporting the once-daily dosing schedule. The
pharmacokinetics of Deferasirox were not influenced by
liver transaminase levels up to 5 times the upper limit of
the normal range. In children younger than 6 yr old,
exposure was about 50 % lower than in adults.
Deferasirox and its metabolites are primarily excreted in
the faeces (84% of the dose). Renal excretion of
Deferasirox and its metabolites is minimal (8% of the
dose).
Achieving an effective, well tolerated and convenient
therapy that provided 24-hr chelation coverage, has
proved difficult with previous therapies so far, thus
making patients vulnerable to organ loading between the
doses of chelator. The protection time of 24 hr offered
by Deferasirox can make it an ideal chelator.
Clinical Efficacy of Deferasirox
Deferasirox has been studied in adult as well as pediatric
patients who had transfusion-related iron overload and
underlying thalassemia, sickle cell anemia,
myelodysplastic syndrome, DiamondBlackfan
syndrome, or other rare anemias. 20,21
Thalassemia
The first phase I dose escalation study concluded that
Deferasirox in doses of 20-30 mg/kg/day could
effectively reduce iron burden in iron-overloaded patients
with -thalassemia. Hence, the recommended starting
dose of Deferasirox for most patients is 20 mg/kg/day.
188
M.B. Agarwal
Deferaxirox 20 mg/kg/day However, the dose can be modified depending on the
number of transfusions a patient is receiving and whether
the objective of the chelation therapy is to decrease or
maintain body iron levels.22
Another phase II study evaluated the efficacy and
pharmacokinetics of long term administration of
Deferasirox in adult -thalassemia patients. The study
compared two doses of Deferasirox (10 mg/kg/day and
20 mg/kg/day) vs a standard dose of Deferoxamine (40
mg/kg/day) administered over 48 wk in 71 adults with
transfusional hemosiderosis. Decreases in liver iron
concentration (LIC) were comparable in the Deferasirox
20 mg/kg/day and Deferoxamine groups (baseline
values of 8.5 and 7.9 mg Fe/g dw decreased to 6.6 and 5.9
mg Fe/g dw, respectively) by 48 wk. Deferasirox showed
a plasma elimination half-life of 8-16 hr, supporting its
once-daily administration. The trial concluded that
16 20 24
Deferasirox 20 mg/kg given orally, once daily was as
effective and well-tolerated as Deferoxamine 40 mg/kg
given by sc infusions for 5 days each wk.23
In a comparative phase III trial, patients with -
Thalassaemia major were randomized to receive either
Deferasirox (296 patients) or Deferoxamine (290 patients),
dosed according to their baseline LIC. A Deferasirox dose
of 30 mg/kg/day reduced serum ferritin by about 1,200
mg/L and achieved negative iron balance, with a fall in
LIC of 8.9 mg/g dry weight over 1 year. Over 90% of
patients treated with Deferasirox reported that their
treatment was convenient significantly more than patients
treated with Deferoxamine (only 11 21%) and nearly 97%
reported a preference for Deferasirox over
Deferoxamine.21
Sickle Cell Anemia
Deferasirox has been evaluated in a randomized open-
label, phase II trial in iron overloaded patients with sickle
cell anemia, the primary objective of this trial being
comparison of safety and tolerability of Deferasirox with
Deferoxamine in this population. A total of 195 adult and
pediatric patients received Deferasirox (n = 132) or
Deferoxamine (n = 63). Over 1 yr, similar dose-dependent
LIC reductions were observed with Deferasirox and
Deferoxamine. Adverse events associated with
Deferasirox were mild. Once-daily oral Deferasirox had
acceptable tolerability and similar efficacy to
Deferoxamine, in reducing iron burden in transfused
patients with sickle cell disease.24
Myelodysplastic Syndrome (MDS)
The efficacy of Deferasirox has been evaluated in a 1-yr
phase II trial in regularly transfused patients with
myelodysplastic syndromes, -thalassaemia, Diamond
Blackfan anaemia and other rare anaemias. In patients
with baseline LIC 7 mg FeD g dw, Deferasirox initiated
Indian Journal of Pediatrics, Volume 77February, 2010
 Deferasirox : Oral, Once Daily Iron Chelator - An Expert Opinion
at 20 or 30 mgD kgD d produced statistically significant
decreases in LIC (P < 0.001). Chelation efficiency and iron
excretion did not differ significantly between disease
groups, hence the differences in LIC changes are
consistent with mean transfusional iron intake.
Deferasirox had a safety profile compatible with long-
term use. There were no disease-specific safety or
tolerability effects, the most common adverse events were
gastrointestinal disturbances, skin rash. 25,26
Therapeutic Indications
Deferasirox is indicated for the treatment of chronic iron
overload due to blood transfusions (transfusional
hemosiderosis) in adult and pediatric patients (aged 2 yr
and over). 12, 27
Dosage and administration
Deferasirox therapy should be started when a patient has
evidence of chronic iron overload, such as the transfusion
of approximately 100 ml/kg of packed red blood cells
(approximately 20 units for a 40 kg patient) and a serum
ferritin consistently greater than 1000mcg/l. The
recommended starting daily dose is 20 mg per kg body
weight. Serum ferritin should be monitored monthly and
the dose adjusted if necessary every 3-6months based on
serum ferritin trends and attainment of clinical goals.
Dose adjustments should be made in increments of 5 or
10mg/kg. If the serum ferritin consistently falls below 500
mcg/l, temporary interruption of therapy should be
considered. Deferasirox should be taken once daily on an
empty stomach at least 30 minutes prior to food,
preferably at the same time each day.28
Safety profile
In clinical trials, Deferasirox was generally well tolerated
with clinically manageable safety profile with regular
patient monitoring, and the most common adverse events
were usually mild and/or transient in nature and
resolved spontaneously.29 The most frequent reactions
reported during treatment with Deferasirox in adult and
pediatric patients included gastrointestinal disturbances
in about 26% of patients (mainly nausea, vomiting,
diarrhea, or abdominal pain), and skin rash in about 7% of
patients. These reactions were dose-dependent, mostly
mild to moderate, generally transient and mostly resolved
even if treatment was continued.30
Mild, non-progressive increases in serum creatinine,
mostly within the normal range, occurred in about 36% of
patients. These were dose-dependent, often resolved
spontaneously and were sometimes alleviated by
reducing the dose. Elevations of liver transaminases were
reported in about 2% of patients.
Place of Deferasirox in Transfusional Hemosiderosis
Iron overload is an undesirable and unavoidable effect of
ongoing transfusion therapy, regardless of the underlying
Indian Journal of Pediatrics, Volume 77February, 2010
cause of anemia. Iron chelation therapy is recommended
for patients requiring frequent blood transfusions,
including those with -thalassemia, sickle cell disease or
myelodysplastic syndrome.28
Deferoxamine has been used as a iron chelation
therapy for the past 40 yr. However, chelation therapy
with Deferoxamine requires slow, subcutaneous infusions
for a period of 812 hr, 57 times each wk, which results
in poor patient compliance. The efficacy of a chelation
therapy is dependent on good compliance.
Randomized, comparative clinical trials have
demonstrated Deferasirox 20-30 mg/kg/day to be as
effective as Deferoxamine in reducing iron burden in iron-
overloaded patients with -thalassemia, sickle cell anemia
and myelodysplastic anemia.20-25 Thus, the availability of
Deferasirox, an easily administered iron chelator provides
an effective alternative to Deferoxamine in treatment of
transfusional hemosiderosis. This improvement in
compliance with Deferasirox as compared to
Deferoxamine, could translate into a long-term health
related benefits and reduced healthcare costs.
It has been shown that Deferasirox maintains constant
24 hr levels within the plasma, thus it exerts a sustained
reduction in toxic plasma labile iron.20 In vivo studies have
proved that Deferasirox is more effective than
parenterally administered Deferoxamine in promoting the
excretion of chelatable iron from hepatocellular iron
stores. 14 Likewise Deferasirox is capable of chelating
myocardial iron as demonstrated by in vivo studies and
preliminary trial reports. 17,18,19 Long term studies have
reported Deferasirox to have a clinically manageable
tolerability profile with regular patient monitoring.24
In a retrospective analysis, which investigated the
efficacy and safety of Deferasirox >30 mg/kg per day in
adult and paediatric patients with transfusion-dependent
anemias, 264 patients pooled from four clinical trials
received doses of >30 mg/kg per day. The median
exposure to Deferasirox >30 mg/kg per d was 36 wk. In
the overall population there was a statistically significant
median decrease in serum ferritin of 440 g/L (P < 00001)
from pre-dose-escalation to the time-of-analysis. The
adverse event profile in patients who received Deferasirox
doses of >30 mg/kg per day was consistent with
previously published data. This has important
implications for patients who are heavily transfused and
may require higher doses to reduce body iron burden.31
In view of inadequate iron chelation, Indian subjects of
transfusion-dependent anemia are heavily iron loaded.
The median serum ferritin (pre-therapeutic) was 4230
1580 (ng/ml). Forty four subjects (thalassaemia major : 39,
sickle cell disease : 3, MDS : 2) received Deferasirox in
varied dose (from 10 to 40 mg/k/d). Median duration of
treatment was 7.3 months. After a median of 7.3 months,
189
 M.B. Agarwal
22 subjects with 40 mg/k/d had drop in serum ferritin
level, which was proportionate to the duration of therapy.
The adverse events with high-dose Deferasirox were
similar to the standard dose.32
In patients, not adequately controlled with doses of 30
mg/kg (e.g. serum ferritin levels persistently above 2500
mcg/L and not showing a decreasing trend over time),
doses of up to 40 mg/kg may be considered. Doses above
40 mg/kg are not recommended.33
Thus, convenient, effective and tolerable chelation
therapy with oral Deferasirox, is likely to be a significant
development in the treatment of transfusional iron
overload due to its ability to provide constant chelation
coverage and the potential to improve compliance.
CONCLUSION
Deferasirox is the only orally active, FDA-approved iron
chelator on the U.S. market. The 24-hr chelation coverage
by Deferasirox allows once daily dosing, which may help
improve compliance in the management of chronic
transfusion-related iron overload. Clinical data have
shown that it is important to adjust the dose of
Deferasirox based on iron intake to achieve the
therapeutic goal of maintenance or reduction of iron
burden. The long-term efficacy and safety of Deferasirox
for up to 5 yr of treatment have now been established.34
On the basis of published data to date, Deferasirox indeed
appears promising for an effective oral iron chelator
suitable for long term use.
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