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Special Article

Deferasirox : Oral, Once Daily Iron Chelator - An Expert

M.B. Agarwal

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

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:

Key words: Chelation; Deferasirox; Iron; Thalassemia

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

Indian Journal of Pediatrics, Volume 77February, 2010 185

M.B. Agarwal

Unmet Medical Need/ Therapy Gap in Clinical Practice the synthesis of the tridentate desferrithiocin, whose
activity via oral administration have raised a hope.
In 1963, the introduction of Deferoxamine (DFO), a
However, animal studies confirmed the compound to be
hexadentate chelator marked a breakthrough in the
toxic. The discovery of bishydroxyphenyltriazoles, a new
management of iron overload. However, Deferoxamine
chemical class of iron chelators, renewed the pursuit of a
requires subcutaneous or intravenous infusions.
safe tridentate chelator.10
Moreover, patients with severe anemia cannot achieve
iron depletion by the periodic removal of blood A combination of rational design, intuition and
(therapeutic phlebotomy), because they cannot tolerate experience paved the way for the discovery of the basic
exacerbation of anemia that occurs as an unavoidable structure of this completely new chemical class of iron
consequence of therapeutic phlebotomy7. Clearly, the chelators. More than forty derivatives of the triazole series
removal of excess body iron is vital to improve morbidity were synthesized at Novartis. After screening more than
and mortality in patients with transfusional 700 chelators from various chemical classes, Deferasirox
hemosiderosis. Table 1 compares deferasirox with existing emerged as a bishydroxyphenyltriazole entity, which best
iron chelators i.e., deferoxamine and deferiprone. combined high oral potency and tolerability in animals.10
Goals of Chelation therapy Stucture Activity Relationship (SAR)

In clinical practice, key goal of chelation therapy is Deferasirox is a bis-hydroxyphenyl-triazole benzoic acid
prevention of iron accumulation, as this will prevent a rise derivative (Fig. 1). 1,2,4-triazoles can be regarded as
in liver iron concentration and the secondary condensation products of imides with hydrazines.
redistribution of iron to other organs, including the Thionylchloride mediated condensation of salicylic acid
pituitary, endocrine glands and the heart. In order to with salicylic amide results in the formation of a
achieve an iron balance, two key iron pools need to be hydroxyphenylbenzoxazinone, a derivative form of the
accessed by chelators. imide. This intermediate is ideally activated to react with
hydrazines, forming bishydroxyphenyl-triazoles in just
(i) Intracellular labile iron pool (LIP) two steps from salicylic acid.10

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
Fig. 1. Chemical structure of Deferasirox
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 Pharmacodynamics
24 hr a day; called as protection time.9
Deferasirox is an orally active chelator that is highly
Discovery of a novel chelator: From desferrithiocin to selective for iron. It is a tridentate chelator that mobilizes
Deferasirox iron stores by binding selectively to the ferric (Fe3+) form
of iron. 11 Tridentate chelators require two ligand
Several efforts have been made over the past four to five molecules to bind one iron atom. The selectivity for iron
decades, to synthesize orally active iron chelators. is high, with low affinity for trace metals, such as zinc or
Ferferrithiocin was first discovered in 1980, followed by copper.12

TABLE 1. Comparison of Deferasirox with Existing Iron Chelators28

Feature Deferrioxamine Deferiprone Deferasirox

Iron binding efficiency (drug : iron) 1:1 3:1 2 :1

Iron selectivity Highly selective Zinc is also excreted Highly selective
Regimen SC or IV infusion Oral, 3 times a day Oral, once a day
Tolerability issues Local reactions Joint problems Skin rashes
Long-term safety profile Proven Severe neutropenia Emerging

186 Indian Journal of Pediatrics, Volume 77February, 2010

Deferasirox : Oral, Once Daily Iron Chelator - An Expert Opinion

Deferasirox readily enters most of the cells and Clinical trials evaluating effect of Deferasirox in iron
efficiently reaches the major intracellular sites of iron overloaded patients have proved that Deferasirox chelates
accumulation.13 cardiac iron without affecting the left ventricular ejection
fraction (LVEF). The effects of Deferasirox on myocardial
Hepatic iron iron, in a subset of patients enrolled in two clinical studies,
were recently reported. In a subgroup of 23 patients
Radiolabelled iron probes have been used to investigate
(mean age, 24.6 yr; range, 9-50 yr), who received
the source of iron chelated by Deferasirox, in vivo. 14
Deferasirox appeared to be four to five times more Deferasirox 10-30 mg/kg/day, at a single center for a
effective than parenterally administered Deferoxamine in mean S.D. of 13.1 0.78 months, the mean myocardial
promoting the excretion of chelatable iron from T2*, a cardiovascular magnetic resonance imaging (MRI)
hepatocellular iron stores. This suggests that Deferasirox measurement inversely related to myocardial iron
chelates excess iron that enters the reticuloendothelial content, significantly increased into the normal range (p =
system as insoluble ferritin rather than iron required for 0.013). Likewise, eight patients who received Defero-
enzyme activity, which may explain the lack of enzyme- xamine had increases in mean cardiac T2*, although these
related adverse effects seen with Deferasirox treatment. In changes were small and did not achieve statistical
addition, the iron complex of Deferasirox appears inert significance (p = 0.11). Deferasirox treatment led to
enough to be excreted to a large extent in the faeces, rather significant reductions from baseline in mean S.D. serum
than being redistributed.15 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
Labile plasma iron (LPI) 1.49 mg iron/g dw, p = 0.0002), while no changes in LVEF
Iron loading may lead to excessive cellular accumulation were noted.18
of labile iron in susceptible parenchymal tissue, such as One study monitored cardiac siderosis using T2 MRI in
the liver, heart and endocrine system. This labile iron may a cohort of 19 heavily iron-overloaded patients with -
prove to be a key mediator of iron toxicity due to its thalassemia major, receiving iron chelation therapy with
ability to catalyze production of reactive oxygen species Deferasirox over an 18-month period. Deferasirox therapy
(ROS), such as free radicals. significantly improved mean standard deviation cardiac
A subgroup analysis of the 1-yr ESCALATOR trial T2 from a baseline of 17.210.8 to 21.512.8 ms (+25.0%;
evaluated the effect of Deferasirox in reducing LPI, in P=0.02). A concomitant reduction in median serum
heavily iron-overloaded -thalassaemia patients, all of ferritin from a baseline of 5,497 to 4,235 ng/mL (23.0%;
whom had achieved inadequate chelation with P=0.001), and mean liver iron concentration from 24.29.0
Deferoxamine or deferiprone. Deferasirox 20-30 mg/kg/ to 17.6 12.9 mg Fe/g dry weight (27.1%; P=0.01) was
day significantly reduced levels of toxic LPI and also seen. Improvements were seen in patients with
maintained them within normal limits, despite a high various degrees of cardiac siderosis, including those
baseline iron burden. Deferasirox daily trough levels were patients with a baseline cardiac T2 of <10 ms, indicative of
within the therapeutic range, which indicated a constant high cardiac iron burden.19
24-hr chelation coverage. Decreases in LPI were also Thus, the available data show promising results on the
associated with decreases in mean LIC and SF, indicating effect of Deferasirox on cardiac iron. Further trials are
effective iron removal by Deferasirox. The results of the ongoing, to elucidate the effect of Deferasirox on cardiac
ESCALATOR study highlight the importance of timely iron and function.
Deferasirox dose adjustments, based on serum ferritin
levels and transfusional iron intake to ensure patients Pharmacokinetics
achieve their therapeutic goal of maintenance or reduction
in iron burden.16 Due to its relatively small size (MW 373.4), Deferasirox is
well absorbed through the gastrointestinal tract. The
Myocardial iron median time to maximum plasma concentration (Tmax) is
about 1.5 to 4 hr and an absolute bioavailability (AUC) of
In vitro and in vivo preclinical data have demonstrated that about 70%. Deferasirox is highly (99%) protein bound to
Deferasirox has the ability to enter myocardial cells and plasma proteins, almost exclusively serum albumin and
chelate iron from these cells. It was also observed from
has a volume of distribution of approximately 14 L in
studies in myocyte cultures that Deferasirox rapidly
adults. Deferasirox plasma levels persisted at a detectable
gained entry in the myocytes and bound to labile
level for at least 24 hr after single and multiple doses of 10
intracellular iron, leading to decreased free radical
and 20 mg/kg.20
production. Effective cardiac iron removal has also been
demonstrated by Deferasirox in an iron-loaded gerbil Glucuronidation is the main metabolic pathway for
model. In this study Deferasirox removed more hepatic Deferasirox, with subsequent biliary excretion. No
iron than deferiprone, for a given cardiac iron burden.17 evidence for induction or inhibition of enzymes at

Indian Journal of Pediatrics, Volume 77February, 2010 187

M.B. Agarwal

Deferasirox 10 mg/kg/day 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
Deferasirox concentration (

pharmacokinetics of long term administration of

80 Deferasirox in adult -thalassemia patients. The study
compared two doses of Deferasirox (10 mg/kg/day and
60 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
40 concentration (LIC) were comparable in the Deferasirox
20 mg/kg/day and Deferoxamine groups (baseline
20 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
0 4 8 12 16 20 24
Deferasirox 20 mg/kg given orally, once daily was as
Time (hours)
effective and well-tolerated as Deferoxamine 40 mg/kg
Fig. 2. Mean steady-state plasma concentrations (+SD) of Defera- given by sc infusions for 5 days each wk.23
sirox following a dose of 10 or 20 mg/kg/day.
In a comparative phase III trial, patients with -
Thalassaemia major were randomized to receive either
Deferasirox (296 patients) or Deferoxamine (290 patients),
therapeutic doses has been observed. The mean
dosed according to their baseline LIC. A Deferasirox dose
elimination half-life (t1/2) ranges from 8 - 16 hr
of 30 mg/kg/day reduced serum ferritin by about 1,200
supporting the once-daily dosing schedule. The
mg/L and achieved negative iron balance, with a fall in
pharmacokinetics of Deferasirox were not influenced by
LIC of 8.9 mg/g dry weight over 1 year. Over 90% of
liver transaminase levels up to 5 times the upper limit of
patients treated with Deferasirox reported that their
the normal range. In children younger than 6 yr old,
treatment was convenient significantly more than patients
exposure was about 50 % lower than in adults.
treated with Deferoxamine (only 11 21%) and nearly 97%
Deferasirox and its metabolites are primarily excreted in
reported a preference for Deferasirox over
the faeces (84% of the dose). Renal excretion of
Deferasirox and its metabolites is minimal (8% of the
dose). Sickle Cell Anemia
Achieving an effective, well tolerated and convenient
Deferasirox has been evaluated in a randomized open-
therapy that provided 24-hr chelation coverage, has
label, phase II trial in iron overloaded patients with sickle
proved difficult with previous therapies so far, thus
cell anemia, the primary objective of this trial being
making patients vulnerable to organ loading between the
comparison of safety and tolerability of Deferasirox with
doses of chelator. The protection time of 24 hr offered Deferoxamine in this population. A total of 195 adult and
by Deferasirox can make it an ideal chelator. pediatric patients received Deferasirox (n = 132) or
Clinical Efficacy of Deferasirox Deferoxamine (n = 63). Over 1 yr, similar dose-dependent
LIC reductions were observed with Deferasirox and
Deferasirox has been studied in adult as well as pediatric Deferoxamine. Adverse events associated with
patients who had transfusion-related iron overload and Deferasirox were mild. Once-daily oral Deferasirox had
underlying thalassemia, sickle cell anemia, acceptable tolerability and similar efficacy to
myelodysplastic syndrome, DiamondBlackfan Deferoxamine, in reducing iron burden in transfused
syndrome, or other rare anemias. 20,21 patients with sickle cell disease.24

Thalassemia Myelodysplastic Syndrome (MDS)

The first phase I dose escalation study concluded that The efficacy of Deferasirox has been evaluated in a 1-yr
Deferasirox in doses of 20-30 mg/kg/day could phase II trial in regularly transfused patients with
effectively reduce iron burden in iron-overloaded patients myelodysplastic syndromes, -thalassaemia, Diamond
with -thalassemia. Hence, the recommended starting Blackfan anaemia and other rare anaemias. In patients
dose of Deferasirox for most patients is 20 mg/kg/day. with baseline LIC 7 mg FeD g dw, Deferasirox initiated

188 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 cause of anemia. Iron chelation therapy is recommended
decreases in LIC (P < 0.001). Chelation efficiency and iron for patients requiring frequent blood transfusions,
excretion did not differ significantly between disease including those with -thalassemia, sickle cell disease or
groups, hence the differences in LIC changes are myelodysplastic syndrome.28
consistent with mean transfusional iron intake.
Deferoxamine has been used as a iron chelation
Deferasirox had a safety profile compatible with long-
therapy for the past 40 yr. However, chelation therapy
term use. There were no disease-specific safety or
with Deferoxamine requires slow, subcutaneous infusions
tolerability effects, the most common adverse events were
for a period of 812 hr, 57 times each wk, which results
gastrointestinal disturbances, skin rash. 25,26
in poor patient compliance. The efficacy of a chelation
Therapeutic Indications therapy is dependent on good compliance.
Deferasirox is indicated for the treatment of chronic iron Randomized, comparative clinical trials have
overload due to blood transfusions (transfusional demonstrated Deferasirox 20-30 mg/kg/day to be as
hemosiderosis) in adult and pediatric patients (aged 2 yr effective as Deferoxamine in reducing iron burden in iron-
and over). 12, 27 overloaded patients with -thalassemia, sickle cell anemia
Dosage and administration and myelodysplastic anemia.20-25 Thus, the availability of
Deferasirox, an easily administered iron chelator provides
Deferasirox therapy should be started when a patient has an effective alternative to Deferoxamine in treatment of
evidence of chronic iron overload, such as the transfusion transfusional hemosiderosis. This improvement in
of approximately 100 ml/kg of packed red blood cells compliance with Deferasirox as compared to
(approximately 20 units for a 40 kg patient) and a serum Deferoxamine, could translate into a long-term health
ferritin consistently greater than 1000mcg/l. The related benefits and reduced healthcare costs.
recommended starting daily dose is 20 mg per kg body
weight. Serum ferritin should be monitored monthly and It has been shown that Deferasirox maintains constant
the dose adjusted if necessary every 3-6months based on 24 hr levels within the plasma, thus it exerts a sustained
serum ferritin trends and attainment of clinical goals. reduction in toxic plasma labile iron.20 In vivo studies have
Dose adjustments should be made in increments of 5 or proved that Deferasirox is more effective than
10mg/kg. If the serum ferritin consistently falls below 500 parenterally administered Deferoxamine in promoting the
mcg/l, temporary interruption of therapy should be excretion of chelatable iron from hepatocellular iron
considered. Deferasirox should be taken once daily on an stores. 14 Likewise Deferasirox is capable of chelating
empty stomach at least 30 minutes prior to food, myocardial iron as demonstrated by in vivo studies and
preferably at the same time each day.28 preliminary trial reports. 17,18,19 Long term studies have
reported Deferasirox to have a clinically manageable
Safety profile
tolerability profile with regular patient monitoring.24
In clinical trials, Deferasirox was generally well tolerated
In a retrospective analysis, which investigated the
with clinically manageable safety profile with regular
efficacy and safety of Deferasirox >30 mg/kg per day in
patient monitoring, and the most common adverse events
adult and paediatric patients with transfusion-dependent
were usually mild and/or transient in nature and
anemias, 264 patients pooled from four clinical trials
resolved spontaneously.29 The most frequent reactions
received doses of >30 mg/kg per day. The median
reported during treatment with Deferasirox in adult and
exposure to Deferasirox >30 mg/kg per d was 36 wk. In
pediatric patients included gastrointestinal disturbances
the overall population there was a statistically significant
in about 26% of patients (mainly nausea, vomiting,
median decrease in serum ferritin of 440 g/L (P < 00001)
diarrhea, or abdominal pain), and skin rash in about 7% of
from pre-dose-escalation to the time-of-analysis. The
patients. These reactions were dose-dependent, mostly
mild to moderate, generally transient and mostly resolved adverse event profile in patients who received Deferasirox
even if treatment was continued.30 doses of >30 mg/kg per day was consistent with
previously published data. This has important
Mild, non-progressive increases in serum creatinine, implications for patients who are heavily transfused and
mostly within the normal range, occurred in about 36% of may require higher doses to reduce body iron burden.31
patients. These were dose-dependent, often resolved
spontaneously and were sometimes alleviated by In view of inadequate iron chelation, Indian subjects of
reducing the dose. Elevations of liver transaminases were transfusion-dependent anemia are heavily iron loaded.
reported in about 2% of patients. The median serum ferritin (pre-therapeutic) was 4230
1580 (ng/ml). Forty four subjects (thalassaemia major : 39,
Place of Deferasirox in Transfusional Hemosiderosis sickle cell disease : 3, MDS : 2) received Deferasirox in
Iron overload is an undesirable and unavoidable effect of varied dose (from 10 to 40 mg/k/d). Median duration of
ongoing transfusion therapy, regardless of the underlying treatment was 7.3 months. After a median of 7.3 months,

Indian Journal of Pediatrics, Volume 77February, 2010 189

M.B. Agarwal

22 subjects with 40 mg/k/d had drop in serum ferritin 10. Nick H, Acklin P, Lattmann R et al. Development of tridentate
level, which was proportionate to the duration of therapy. iron chelators: from desferrithiocin to ICL670. Curr Med Chem
2003; 10: 1065-1076.
The adverse events with high-dose Deferasirox were
11. Stumpf JL. Deferasirox. Am J Health Syst Pharm 2007; 64: 606-
similar to the standard dose.32 616.
12. Vanorden HE, Hagemann TM. Deferasirox--an oral agent for
In patients, not adequately controlled with doses of 30
chronic iron overload. Ann Pharmacother 2006; 40: 1110-1117.
mg/kg (e.g. serum ferritin levels persistently above 2500 13. Glickstein H, El RB, Shvartsman M, Cabantchik ZI.
mcg/L and not showing a decreasing trend over time), Intracellular labile iron pools as direct targets of iron chelators:
doses of up to 40 mg/kg may be considered. Doses above a fluorescence study of chelator action in living cells. Blood
40 mg/kg are not recommended.33 2005; 106: 3242-3250.
14. Hershko C, Konijn AM, Nick HP, Breuer W, Cabantchik ZI,
Thus, convenient, effective and tolerable chelation Link G. ICL670A: a new synthetic oral chelator: evaluation in
therapy with oral Deferasirox, is likely to be a significant hypertransfused rats with selective radioiron probes of
development in the treatment of transfusional iron hepatocellular and reticuloendothelial iron stores and in iron-
loaded rat heart cells in culture. Blood 2001; 97: 1115-1122.
overload due to its ability to provide constant chelation 15. Nick H, Wong A, Acklin P et al. ICL670A: preclinical profile.
coverage and the potential to improve compliance. Adv Exp Med Biol 2002; 509: 185-203.
16. Taher A, El-Beshlawy A, Elalfy MS et al. Efficacy and safety of
Deferasirox, an oral iron chelator, in heavily iron-overloaded
CONCLUSION patients with -thalassaemia: the ESCALATOR study. Eur J
Haematol 2009; 82:458-465.
17. Wood JC, Otto-Duessel M, Gonzalez I et al. Deferasirox and
Deferasirox is the only orally active, FDA-approved iron deferiprone remove cardiac iron in the iron-overloaded gerbil.
chelator on the U.S. market. The 24-hr chelation coverage Transl Res 2006; 148 : 272-280.
by Deferasirox allows once daily dosing, which may help 18. Neufeld EJ. Oral chelators Deferasirox and deferiprone for
improve compliance in the management of chronic transfusional iron overload in thalassemia major: new data,
transfusion-related iron overload. Clinical data have new questions. Blood 2006; 107: 3436-3441.
19. Pathare A, Taher A, Daar S. Deferasirox (Exjade(R))
shown that it is important to adjust the dose of significantly improves cardiac T2* in heavily iron-overloaded
Deferasirox based on iron intake to achieve the patients with -thalassemia major. Ann Hematol 2009 Oct 2.
therapeutic goal of maintenance or reduction of iron [Epub ahead of print]
burden. The long-term efficacy and safety of Deferasirox 20. Stumpf JL. Deferasirox. Am J Health Syst Pharm 2007; 64 : 606-
for up to 5 yr of treatment have now been established.34 616.
On the basis of published data to date, Deferasirox indeed 21. Cappellini MD. Long-term efficacy and safety of Deferasirox.
Blood Rev 2008; 22 : S35-S41.
appears promising for an effective oral iron chelator 22. Nisbet-Brown E, Olivieri NF, Giardina PJ et al. Effectiveness
suitable for long term use. and safety of ICL670 in iron-loaded patients with
thalassaemia: a randomised, double-blind, placebo-controlled,
dose-escalation trial. Lancet 2003; 361: 1597-1602.
REFERENCES 23. Piga A, Galanello R, Forni GL et al. Randomized phase II trial
of Deferasirox (Exjade, ICL670), a once-daily, orally-
1. Porter JB. Practical management of iron overload. Br J administered iron chelator, in comparison to Deferoxamine in
Haematol 2001; 115: 239-252. Thalassemia patients with transfusional iron overload.
2. Taher A. Iron overload in thalassemia and sickle cell disease. Haematologica 2006; 91:873-880.
Semin Hematol 2005; 42: S5-S9. 24. Vichinsky E, Onyekwere O, Porter J et al. Deferasirox in Sickle
3. Olivieri NF, Brittenham GM. Iron-chelating therapy and the Cell Investigators. A randomised comparison of Deferasirox
treatment of thalassemia. Blood 1997; 89 : 739-761. versus Deferoxamine for the treatment of transfusional iron
4. Thakerngpol K, Fucharoen S, Boonyaphipat P et al. Liver overload in sickle cell disease. Br J Haematol 2007; 136: 501-508.
injury due to iron overload in thalassemia: histopathologic 25. Porter J, Galanello R, Saglio G et al. Relative response of
and ultrastructural studies. Biometals 1996; 9: 177-183. patients with myelodysplastic syndromes and other
5. Olivieri NF. Progression of iron overload in sickle cell disease. transfusion-dependent anaemias to Deferasirox (ICL670): a 1-
Semin Hematol 2001; 38: 57-62. yr prospective study. Eur J Haematol 2008; 80 :168-176.
6. Kontoghiorghes GJ. Future chelation monotherapy and 26. Jabbour E, Garcia-Manero G, Taher A, Kantarjian HM.
combination therapy strategies in thalassemia and other Managing iron overload in patients with myelodysplastic
conditions. comparison of deferiprone, Deferoxamine, syndromes with oral Deferasirox therapy. Oncologist 2009; 14:
ICL670, GT56-252, L1NAll and starch Deferoxamine 489-496. Epub 2009 Apr 13.
polymers. Hemoglobin 2006; 30: 329-347. 27. Cappellini MD, Taher A. Long-term experience with
7. Barton JC. Deferasirox Novartis. Curr Opin Investig Drugs Deferasirox (ICL670), a once-daily oral iron chelator, in the
2005; 6: 327-335. treatment of transfusional iron overload. Expert Opin
8. Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Pharmacother 2008; 9: 2391-2402.
Hematology Am Soc Hematol Educ Program 2001: 47-61. 28. Yang LP, Keam SJ, Keating GM. Deferasirox : a review of its
9. Porter JB. Deferasirox: An effective once-daily orally active use in the management of transfusional chronic iron overload.
iron chelator. Drugs Today (Barc) 2006; 42: 623-637. Drugs 2007; 67: 2211-2230.

190 Indian Journal of Pediatrics, Volume 77February, 2010

Deferasirox : Oral, Once Daily Iron Chelator - An Expert Opinion

29. Agarwal MB. Exjade (ICL 670): A new oral iron chelator. J 32. Agarwal MB, Rathi SS, Agarwal UM et al. High-dose (>30
Assoc Physicians India 2006; 54: 214-217. mg/k/d) Deferasirox (Asunra, Desirox) therapy is effective
30. Cappellini MD, Pattoneri P. Oral iron chelators. Annu Rev Med and safe in heavily iron loaded patients - An Indian study.
2009;60: 25-38. Presented at The Annual Conference of Mumbai Haematology
31. Taher A, Cappellini MD, Vichinsky E et al. Efficacy and safety Group, Mumbai, March 2009
of Deferasirox doses of >30 mg/kg per d in patients with 33. Exjade. Prescribing Information. April 2009
transfusion-dependent anaemia and iron overload. Br J 34. Taher A, Cappellini MD. Update on the use of Deferasirox in
Haematol 2009; 147: 752-759. the management of iron overload. Ther Clin Risk Manag 2009;
5: 857-868.

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