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Review of Oral Iron Chelators

(Deferiprone and Deferasirox)


for the Treatment of Iron Overload in Pediatric Patients

D. Adam Algren, MD
Assistant Professor of Pediatrics and Emergency Medicine
Division of Pediatric Pharmacology and Medical Toxicology
Departments of Pediatrics and Emergency Medicine
Children’s Mercy Hospitals and Clinics/Truman Medical Center
University of Missouri-Kansas City School of Medicine

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PROPOSAL

The World Health Organization Model List of Essential Medicines and Model
Formulary 2010 list deferoxamine (DFO) as the treatment of choice for both acute and
chronic iron poisoning. The Model Formulary currently does not designate any orally
administered agents for the chelation of iron. It is proposed that deferasirox be
considered the oral chelator of choice in the treatment of chronic iron overload.
Deferasirox is widely available recent evidence support that it is both safe and
efficacious.

INTRODUCTION
Acute iron poisoning and chronic iron overload result in significant morbidity
and mortality worldwide. Treatment of acute iron poisoning and chronic iron
overload can be challenging and care providers are often confronted with management
dilemmas. Oral iron supplements are commonly prescribed for patients with iron
deficiency anemia. The wide availability of iron supplements and iron-containing
multivitamins provide easy accessibility for both adults and children. The approach to
treatment of acute iron toxicity involves providing adequate supportive care,
optimizing hemodynamic status and antidotal therapy with IV deferoxamine, when
indicated.1 Early following an acute ingestion gastrointestinal (GI) decontamination
can be potentially beneficial. Multiple options exist including: syrup of ipecac,
gastric lavage, and whole bowel irrigation (WBI). Although definitive evidence that
GI decontamination decreases morbidity and mortality is lacking it is often considered
to be beneficial. The decision to initiate GI decontamination should be made on an
individual case basis. In addition to conventional GI decontamination other methods
to prevent absorption have been investigated. Likewise, several small studies have
investigated the use of other oral agent/chelators for the treatment of acute iron
poisoning.
Chronic iron overload associated with red cell disorders (i.e. sickle cell anemia
and thalassemia) and other myelodysplastic syndromes affect a significantly larger
number of individuals. The body does not have an efficient mechanism to excrete
iron. Thus, in those patients requiring multiple transfusions iron accumulates and is
deposited into multiple organ systems. The long term consequences of chronic iron
overload include multiple organ dysfunction (heart, liver, and endocrine) and/or
failure.2-5
Therefore. iron chelation is necessary to prevent organ failure and decrease mortality.
Deferoxamine was the first iron chelator introduced into clinical practice.
Although effective, there are significant challenges associated with its use that can
result in non-compliance. Deferiprone and deferasirox, oral iron chelators, are
increasingly available and evidence supports their use in the treatment of chronic iron
overload. A perfect oral iron chelator does not exist; although, both deferiprone and
deferasirox are effective they have differences including different pharmacokinetics
and adverse effect profiles. These differences are both advantageous and/or
problematic. These advantages and disadvantages will be reviewed and a
recommendation for a chelator of choice will be made based on these considerations.

This review will summarize the available evidence regarding:

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a) Efficacy of deferoxamine in the treatment of chronic iron overload and the
challenges associated with its use.
b) Efficacy and safety of deferiprone
c) Efficacy and safety of deferasirox
d) Formulation, dosing recommendation, and cost comparison between deferiprone
and deferasirox.

LITERATURE REVIEW
The studies for this review were identified by performing a search of the
PubMed using the search terms: “iron poisoning”, “iron toxicity”, “iron chelation”,
“deferoxamine”, “deferiprone”, and “deferasirox”. The dates included 1966-2010.
The Cochrane Database for Systematic Reviews was also searched and pertinent
reviews were identified.6-8 The bibliographies of selected articles were also reviewed
to identify any relevant studies not found by the original literature search.

CURRENT LISTING
WHO 2010 Model Formulary for Children:
Deferoxamine. Acute Iron Poisoning. Neonate, Infant, Child. 15mg/kg/he reduced
after 4-6 hours so that total dose does not exceed 80mg/kg in 24 hours. Maximum
dose 6 grams/day. IM: 50mg/kg/dose every 6 hours. Maximum dose 6 grams/day.
The preferred route is IV. Chronic Iron Overload: SC or IV infusion in an infant or
child: 30mg/kg over 8-12 hours on 3-7 days/week. For established iron overload the
dose is usually 20-50mg/kg daily. The dose should reflect the degree of iron
overload. Use the lowest effect dose. Diagnosis of iron overload: 500mg IM.

EFFICACY AND SAFETY


ACUTE IRON POISONING-
Several different methods to prevent iron absorption following acute
ingestions have been investigated. GI decontamination involves removing the
compound from the GI tract prior to its absorption or administering an agent that is
capable of binding the compound so that it is not available for systemic absorption.
Syrup of ipecac traditionally had been recommended to induce vomiting in
order to facilitate removal of a substance from the GI tract. There is scant evidence to
support or refute the use of ipecac and therefore a recent international position
statement recommended against routine use of ipecac in the poisoned patient.9 The
available evidence does suggest that efficacy decreases dramatically beyond 30-60
minutes following ingestion. The generalizability of these recommendations to
developing nations is not clear. In locations with limited medical resources ipecac
administration may be the best GI decontamination option due to the fact that it is not
resource or labor intensive.
Physical removal of iron from the stomach may also be accomplished by
gastric lavage. There are no studies that specifically address its use in those with
acute iron ingestions. A consensus position statement also does not endorse its
routine use in poisoned patients.10 Available evidence suggests that it is most
effective if performed within 1 hour. Performing gastric lavage with different lavage

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solutions has also been investigated. Intuitively it would make sense that lavage
solutions could complex with the iron to form insoluble iron compounds. Hypertonic
phosphate solutions were not effective quickly abandoned due to morbidity from
associated electrolyte abnormalities that it induced.11-14 Although there is some
evidence to support the efficacy of magnesium hydroxide to prevent absorption of
iron it is generally not recommended for several reasons.15-17 An un-realistically large
volume would have to be administered and patients would be at risk for developing
electrolyte abnormalities.
Activated charcoal has become the method of choice among healthcare
providers for GI decontamination. However, iron does not adsorb well to charcoal
and therefore its use should be limited to those situations involving co-ingestants that
charcoal is deemed necessary.18
Whole bowel irrigation consists of the administration of polyethylene glycol
electrolyte solution to promote intestinal evacuation prior to systemic absorption.
WBI should be considered in cases of significant iron ingestion as there are limited
options for GI decontamination in iron poisoning.19 However, this procedure can be
labor intensive as it requires the ingestion of a large amount of polyethylene glycol
solution over a relatively brief time course. Although commonly recommended there
is limited evidence to support its use.
Several investigators have examined the utility of oral iron chelation in the
setting of an acute iron overdose. Animal studies initially suggested that oral
deferoxamine decreased iron absorption and could potentially be of benefit.20
Subsequent investigations failed to confirm decreased absorption in deferoxamine
treated swine and dogs.21-23 The literature regarding the efficacy of oral DFO in
humans is limited. A small volunteer study that assessed its ability to bind iron failed
to demonstrate decreased absorption.24 However, another volunteer study that used a
larger dose of DFO was able to show decreased iron absorption.25 Clinical experience
with oral DFO in overdose patients is limited. Early studies examining the efficacy of
DFO suggested that it likely does not prevent iron absorption and could in fact
contribute to toxicity by facilitating production and absorption of the toxic metabolite
ferrioxamine.22-23 The utility of other oral iron chelators for acute iron poisoning is
unknown. A rat model administered oral deferiprone following administration of an
LD50 dose of iron. Deferiprone decreased mortality in the treatment group,
especially in those that received a follow up dose.26 There are no human studies
addressing its use.

CHRONIC IRON OVERLOAD

Deferoxamine was introduced in the 1960’s and was the first iron chelator
used for the treatment of chronic iron overload. Several of the studies addressed in
this review have combined the use of DFO with an oral chelator. Although it is
administered parenterally, a review of evidence supporting its use will provide
background regarding chelation therapy for chronic iron overload. Even though there
is significant clinical experience with DFO a majority of the literature is retrospective
or observational.
DFO is derived from Streptomyces pilosus and is administered parenterally
given its poor oral bioavailability.27 DFO has a short half life and must be
administered by intravenous (IV) or subcutaneous injections/infusions.28-29 IV and
subcutaneous administration were shown to be more efficacious at improving iron
excretion compared to intramuscular administration.30-32 An intermittent subcutaneous

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injection schedule was shown to be as efficacious in promoting iron excretion as a
continuous 12 hour subcutaneous injection.33 Increasing the dose of DFO
administered generally results in higher iron excretion, especially in those with
patients with more significant iron overload.34 Urinary excretion of iron increases
within hours of administration.
Different clinical parameters are used to assess body iron burden and response
to therapy. Serum ferritin levels are the laboratory parameter most often used. In
general, sustained ferritin levels greater than 2500 mcg/L are associated with organ
toxicity and death.35 Most chelation regimens attempt to achieve the goal of lower
ferritin below 2500 mcg/L. DFO has demonstrated efficacy in decreasing morbidity
associated with iron overload. Other methods of determining body iron burdens
include: liver biopsy and liver/cardiac magnetic resonance imaging.2
Deferoxamine has long term data to support its use as a chelation agent in
chronic iron overload in both adult and children. Following the introduction of
deferoxamine survival rates for thalassemia patients increased substantially within a
decade.36 Morbidity from organ system toxicity as decreased significantly as well.
Cardiac disease has been reversed in multiple trials. Thalassemia patients (mean ages
9-15 years old) treated with 12 hour subcutaneous deferoxamine infusions that
resulted in well controlled serum ferritin levels had estimated 10 year survival of
100% without cardiac disease.35 Additional work demonstrated significant reduction
in mortality and incidence of heart failure in thalassemia patients treated with DFO.37-
38

Long-term morbidity associated with other organ system dysfunction was


prevented using a subcutaneous infusion regimen.39 Further studies also support the
clinical equivalence of IV and intermittent subcutaneous DFO infusion.30,40-42
Additional trials support the use of 12 hour continuous subcutaneous infusions in
pediatric patients.43-44 Other investigators have combined both intravenous and
subcutaneous dosing to avoid daily DFO administration. This protocol was effective
at lowering serum ferritin after 1 year of therapy and resulted in further reduction at
the end of the second year of treatment.45 A 24 hour infusion regimen was successful
in lowering ferritin levels and reversing cardiac complications; however mortality at
the end of the follow up period was equivalent to that of intermittent DFO protocols.46
Deferoxamine is effective in reversing hepatic iron overload. Early trials in
children demonstrated intermittent DFO infusions were effective in decreasing liver
iron stores and prevent progression of hepatic fibrosis.47 Intensive chelation
significantly reduced liver iron stores in four children within 52-83 months of DFO
initiation.48 Active liver disease may necessitate adjustment of the DFO dose that is
administered.49
The data to support deferoxamine use in other disorders associated with iron
overload is limited. Deferoxamine appears capable of increasing iron excretion in
sickle cell patients.50 Intermittent IV DFO infusions were effective in decreasing liver
iron concentrations in two small cohorts of sickle cell anemia patients.51-52
While effective deferoxamine administration can result in systemic toxicity
and it is resource and labor intensive. It those cases where it is administered
intravenously it requires the patient to have semi-permanent intravenous access.
Given its short half life it requires frequent administration, typically 5-7 days/week.
Long term intravenous access is associated with complications.46 Subcutaneous
administration avoids some risks associated with IV administration, but is more
painful. Both routes of administration require prolonged infusion times affecting
quality of life and risk non-compliance with therapy.53-54 Early and aggressive DFO

5
administration can adversely affect skeletal maturation and result in growth
retardation.55 The cumbersome nature and complications associated with DFO
therapy pushed investigators to identify oral agents that would suitable for long-term
chelation in those with chronic iron overload.
Deferiprone was initially introduced in Europe in the 1980’s and was the first
oral chelator to be used for the treatment of iron overload (Table). It is a bidentate
hydroxypyridone with a small molecular weight (139). Peak plasma levels occur
within 1 hour. It forms a stable complex with iron that is then excreted in the urine.56
It is metabolized by glucuronidation in the liver and has a relatively short half-life of
47-134 minutes necessitating multiple daily dosing.57-58 Early animal data
demonstrated good iron mobilization using deferiprone.59-60 The scientific data
regarding deferiprone is derived mostly from observational, retrospective, or
combination chelator studies. The lack of traditional safety and efficacy trials
comparing deferiprone to deferoxamine has prevented approval in the United States;
however it is used in Europe (under specific conditions) and other countries.
Several decades of experience with deferiprone have been reported. Initial
studies demonstrated comparable amounts of iron excretion when deferiprone was
compared to deferoxamine.61-62 However, DFO appears to results in slightly higher
net iron excretion as a result of fecal loss. Deferiprione results in more significant
reduction in iron levels in those with a higher iron burden.63 It may not be as helpful
for those less significant iron overload. However, this problem can be overcome by
increasing the amount of deferiprone administered from 75 to 100 mg/kg/day.63
Multiple studies have examined the deferiprone’s ability to lower serum
ferritin concentrations. These studies are mostly retrospective and observational and
include both adult and pediatric patients. A majority of the trials followed patients for
at least 1 year with several trails following patients for 3 or more years. The most
common dose administered in the trails was 75 mg/kg/day. The number of subjects in
each trial is small, typically numbering less than 40. However, several series with a
larger number of subjects have been published.
The effectiveness of deferiprone was reported by Cohen and colleagues in a 4
year observational trial.64 It included 187 patients with a mean age of 18 (range 10-
41). Deferiprone was quite effective in lowering serum ferritin over the study period.
In those patients with more severe iron overload the ferritin level dropped from 3661
± 1862 mcg/L to 2630 ± 1708 mcg/L. Patients with lower initial ferritin levels had
less dramatic results. There were 47 patients that discontinued therapy as a result of
increasing ferritin levels. The reasons for decreased effectiveness in this subset of
patients were not clear. They did not differ significantly from the study population
except they were less likely to have undergone splenectomy.64 Goel and collegues
examined their 3 year experience with deferiprone in 58 thalassemia patients (mean
age 11.9 years).65 They demonstrated that those patients that entered the trial with
higher mean serum ferritin concentrations (mean 4745 ± 1873 ng/ml) tended to have
the best response to therapy. Deferiprone was not uniformally successful in lower
ferritin concentrations as 17 patients finished in the study with higher concentrations
A smaller study of 21 patients evaluated deferiprone in thalassemia patients.66
The mean age of patients was 22 (range 7.5-31 years). Follow up at 3 years
demonstrated significant decreases in hepatic iron and serum ferritin concentrations.
Although the mean serum ferritin decreased from 3975 ± 766 mcg/L to 2546 ± 381
mcg/L those patients with more severe iron overload were only able to achieve ferritin
concentrations of 3273 ± 568 mcg/L.66 Similarly, the same authors examined
deferiprone effectiveness in 18 patients treated for a mean of 4.6 years.67 The mean

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age of the patients was 18.2 (range 10.5-23.7 years). Hepatic iron concentrations
remained elevated in 7 of18 patients. Five of these patients had biopsy documented
progression of liver fibrosis. Even though there was significant improvement in
serum ferritin levels, 9 of17 patients had levels that remained greater than 2500
mcg/L.67 More recent trials have assessed the efficacy of deferiprone in young
children. El Alfy and colleagues reviewed its use in 100 children (mean age 5.1 ± 2.4
years) with thalassemia or sickle cell disease.68 At the end of the 6 month treatment
period there was a significant drop in mean serum ferritin levels from 2532 ± 1463
ng/L to 2176 ± 1144 ug/L (p<0.05). Similar results were reported in another trial of
pediatric patients (median age 10.6 years).69 Mean serum ferritin levels decreased
from a mean of 4,677 ± 1,130 ng/L at baseline to 3,363 ± 1,149 ng/L following a
median treatment duration of 11.4 months (range 1.4-39.6 months).
Preventing iron burden of organs such as the heart and liver is crucial in
decreasing morbidity and mortality associated with chronic iron overload. Liver iron
concentrations more than 15mg/gram dry weight are associated with increased
mortality.39 Thus, several studies have examined deferiprone’s ability to lower liver
iron concentrations in thallasemia patients.66-67,70-73 . These studies involve small
numbers of patients followed for 1-5 years. Although deferiprone appears to be
effective in lower serum iron concentrations in some patients a majority of the trials
did not demonstrate significant improvement.
Multiple studies have looked at combination therapy involving the use of
deferiprone and deferoxamine.74-91 Although many of the studies suffer from
methodological issues including small patient numbers, short-follow up, and/or other
confounding variables they typically demonstrate the combining deferiprone with
deferoxamine is associated with improved outcomes. Deferiprone is less effective in
those with lower initial serum ferritin elevations. However, the use of this
combination is often more efficacious than use of either as a single agent as the
addistion of deferoxamine to deferiprone is synergestic. This is likely a result of
deferiprone’s ability to enter cells and chelate intracellular iron.56 Deferoxamine can
serve as adjunctive therapy in those patients with marginal responses to deferiprone.92
The largest trial comparing deferiprone monotherapy to combination therapy
was recently published. Maggio and colleagues assessed efficacy of deferiprone
versus combination therapy in a randomized trial involving 213 thalassemia patients
(mean age 23 years).74 Patients were followed for 5 years. The results demonstrated
that combination of deferiprone with subcutaneous deferoxamine was more effective
in lower serum ferritin. The ferritin concentration in the combination group was 1369
± 816 mcg/L versus 1588 ± 1217 mcg/L in the deferiprone group (p<0.05). There
was not statistically significant differences in mortality or cost between the groups.74
Daar and Pathare reviewed use of deferiprone/deferoxamine combination therapy in
55 thalassemia patients (mean age 15 ± 5.8 years).75 Combination therapy was
associated with a significant improvement in serum ferritin levels and
echocardiographic paramaters over the mean follow up period of 22 months. Similar
results were reported by Origa and collegues.76 They enrolled 79 patients (mean age
23 ± 5 years). Over the 12-24 month follow up period there was a statistically
significant improvement in serum ferritin and cardiac function in combination
deferiprone/deferoxamine group when compared to deferoxamine monotherapy.
A recent Cochrane review addressed deferiprone use in thalassemia patients.6
The reviewers concluded that although there was significant heterogeneity in study
data that they reviewed. Both deferiprone and deferoxamine resulted in iron
excretion; however, there was little consistency regarding the effectiveness of these

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chelators. Given that combination therapy appeared to result in greater iron excretion
and that deferiprone was associated with a higher incidence of adverse effects the
reviewers concluded that deferiprone should be reserved for those patients in whom
deferoxamine therapy is contraindicated or inadequate.6
Deferiprone is associated with several adverse effects. The most concerning is
agranulocytosis. In clinical trials neutropenia has been reported in up to 5% with
agranulocytosis typically reported in < 1%. Patients that develop agranulocytosis
typically do so during the first year of therapy, but it has been reported up to 19
months after deferiprone initiation.56,93 Combination therapy with deferoxamine and
and/or an intact spleen place patients at higher risk.73 Neutropenia is typically
reversible upon discontinuation of the drug, but can reoccur if deferiprone is
reintroduced.94-95 It has yet to be elucidated if the neutropenia and agranulocytiosis is
an idiosyncratic reaction or a dose-related direct myelotoxicty.56,93 Frequent
monitoring of white blood cell counts is recommended.96 Consideration should be
given to avoiding deferiprone in patients with myeloproliferative disorders.
Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain have
been reported in up to 33% of patients.94,97 These are usually mild and typically do
not result in drug discontinuation. Elevations of liver transaminases have been
reported during deferiprone treatment. An early trial suggested that deferiprone was
associated with progressive liver fibrosis.67 This was a small trial involving 19
patients of which 5 were considered to have progression of liver fibrosis. Subsequent
trials involving larger numbers of patients have not demonstrated liver toxicity.94,98-100
Liver enzyme elevations tend to be mild and reversible. In a recent pediatric trial
12% of patients experienced a mild elevation in ALT.68 Only 1 patient had an
elevation greater than twice the upper limit of normal at 3 and 6 months. Deferiprone
was continued in all patients without incident. The contribution of deferiprone to
worsening liver disease is often difficult to determine because of the natural
progression associated with chronic iron overload. Other co-existing diseases, such as
hepatitis, or other medications associated with hepatotoxicity contribute to the
difficulty of assigning culpability to deferiprone.
Arthralgias and arthritis have been associated with deferiprone. Although it
has been reported to occur in 30-40% of patients in some studies large trials have
reported a much lower incidence of 4%.56,64,101-2 Large joint, such as the knees, are
more commonly affected. 50% of cases develop with the first year of therapy.
Symptoms are typically mild and resolve with discontinuation.
Deferasirox is the most recent oral chelator to be used for the management of
chronic iron overload (Table). Unlike deferiprone, deferasirox was developed and
studied under more rigorous scientific scrutiny. Although there is less long-term
outcome data available, multiple studies have or are currently addressing its efficacy
and safety.
Iron chelation occurs when 2 molecules of deferasirox bind to 1 molecule of
103
iron. Peak plasma concentrations occur within 1-2 hours of administration. It is
highly protein bound (99%) and is metabolized by the liver with subsequent fecal
excretion.104 The eliminations half life is 7-18 hours.105 This relatively long
elimination facilitates once daily dosing. The tablets may be dissolved in water or
juice without altering the bioavailability.96
Initial data suggests that deferasirox has the capacity to gain access to
intracellular iron similar to deferiprone. Laboratory and animal studies confirm its
ability to chelate cardiac iron.106-107 Recent data regarding deferasirox’s ability to
treat cardiac iron overload initial human studies are promising. Multiple studies have

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shown deferasirox is effective in decreasing cardiac iron burden; however, the results
regarding if it is effective in removing cardiac iron in cases of severe iron overload are
conflicting.108-110 More recently a large trial of 192 thalassemia patients investigated
the efficacy of deferasirox in reducing cardiac iron overload as well as preventing
cardiac iron accumulation.111 One third of the patients were less than 16 years old.
The mean deferasirox dose administered over the 1 year treatment period was 32.6
mg/kg/day. A statistically significant decrease in cardiac iron, as demonstrated by
cardiac magnetic resonance imaging, was observed. Deferasirox was also beneficial
in preventing accumulation of cardiac iron.111
Deferasirox is effective in lowering serum ferritin levels and decreasing
overall iron burden. An early trial that evaluated the dose-response relationship
demonstrated that 20mg/kg/day effectively chelated iron. However, net iron excretion
only occurred at a dose of 40 mg/kg/day.112 Yet, in another trial 20 mg/kg/day
decreased liver iron concentrations in 71 adult thalassemia patients.113 A larger trial
compared deferasirox (132 patients) to deferoxamine (63 patients) for the treatment of
iron overload in patients with sickle cell anemia. The median age of the deferasirox
treatment group was 15 years. At the end of 1 year deferasirox (10-30 mg/kg/day)
was equivalent to deferoxamine in lowering liver iron concentrations.114 Likewise,
Cappellini and colleagues assessed the efficacy of deferasirox versus deferoxamine in
pediatric thalassemia patients.115 The mean age of the 296 patients that received
deferasirox was 17 (± 9.4 years). The mean daily dose of deferasirox varied between
6.2mg and 28.2mg depending on baseline liver iron concentrations. Across all
treatment groups noninferiority of deferasirox was not demonstrated. This was likely
related to underdosing of deferasirox in a significant number of patients. Further
analysis demonstrates that deferasirox was not inferior to deferoxamine in those
patients that received 20-30mg/kg/day. At the higher 30mg/kg/day dose a decrease in
serum ferritin and liver iron concentrations were observed.115 Taher and colleagues
assessed the utility of deferasirox in heavily iron-overloaded thalassemia patients.116
This was a prospective trial that followed 237 patients (162 were between 2 and 16
years of age) for 1 year. A majority of patients completed the trial on 30 mg/kg/day.
Deferasirox was effective and resulted in statistically significant decreases in liver
iron concentrations and serum ferritin levels.116 Recently, the largest trial to date
assessing deferasirox was published. It was a 1 year, prospective study of 1,744
patients with transfusion-associated iron overload.117 The mean age of all patients
was 30.6 years (range 2-89 years). Similar to other trials the initial deferasirox dose
varied and dose adjustments occurred throughout the trial. At the conclusion of the
study 51% of patient were receiving greater than 30 mg/kg/day and 39.6% were
receiving between 20-30 mg/kg/day. There was a statistically significant reduction in
serum ferritin from baseline.117 Although a majority of deferasirox studies have
enrolled thalassemia patients it has shown efficacy in treatment of other conditions
associated with iron overload.114,118
A Cochrane review addressed the use deferasirox for the treatment of iron
overload. In assessing its use in sickle cell anemia patients the reviewers concluded
that deferasirox was as effective as deferoxamine in reducing iron overload.7 They
cautioned however that long-term outcome data does not exist and further study is
needed to assess its efficacy and safety. Although the same authors reviewed
deferasirox use in patients with myelodysplastic syndromes they were not able to
identify any trials that met their inclusion criteria.8 Additionally, a review of
deferasirox for the treatment of thalassemia patients is currently in progress.

9
Deferasirox is generally well tolerated. Adverse effects associated with its use
are for the most part mild and self-limiting. The development of adverse effects
seems to be idiosyncratic and not dose dependent.119 Gastrointestinal symptoms, such
as nausea, vomiting, and abdominal pain, as common and have been reported in up to
1/3 of patients.96,111,116,117,120 These symptoms are often mild, self-resolving, and
typically do not necessitate discontinuing therapy. Skin rashs (maculopapular) are
another common adverse effect that is reported in up to 10% of patients.114-117,121
Again, these rashes are mild and resolve with drug discontinuation.
The most concerning adverse effect is acute renal insufficiency. This has been
reported in up to 1/3 of patients in trials.111,113-116,121 Generally the elevations are mild
and transient, however up to 10% of patients can have an increase greater than 33%
above baseline117. These abnormalities almost always resolve following drug
discontinuation.
A significant number of pediatric patients have been included in deferasirox
trials to date.114,115,121 The adverse effect profile in children is similar to that seen in
adults. Likewise, no effects on growth and sexual development have been reported to
date.

FORMULATION, DOSING, COST


Deferiprone is available as a 500mg tablet and an oral solution (100mg/0.4ml).
The recommended dose is 75 mg/kg/day divided into 3 doses.122
Deferasirox is available in 125 mg, 250 mg, and 500 mg dissolvable oral
tablets. The tablets are to be completely dissolved in water or juice and taken on an
empty stomach.123 The recommended dose is 20-30 mg/kg/day given in a single daily
dose. Subsequent dosing should be based on periodic serum ferritin monitoring.
A cost comparison between deferiprone and deferasirox has to account for
multiple variables including: drug cost, laboratory monitoring cost, cost associated
with treating adverse effects and/or worsening of underlying disease as a result of
non-compliance. A true, unbiased cost comparison between deferiprone and
deferasirox has not been published. It has been estimated that the cost of treating a
child with deferiprone could be twice the cost of deferoxamine. Whereas, the
deferasirox could cost 2-3 times as much as deferoxamine.124 Thus a rough pricing
order would be: deferasirox> deferiprone> deferoxamine. However, this could vary
from country to country. Several recent reports suggest that deferasirox therapy is
more cost effective than traditional deferoxamine therapy.125,126

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Table. Comparison of iron chelators
Property Deferoxamine Deferiprone Deferasirox
Chelator: iron 1:1 3:1 2:1
binding
Route of Subcutaneous or Oral Oral
administration intravenous
Usual dosage 25-50 mg/kg per 75 mg/kg per day 20-30 mg/kg per
day day
Schedule Administered Three times a day Daily
over 8-24 hours,
5-7 days per
week
Adverse effects Local reactions Agranuloctyosis/neutropenia Gastrointestinal
Ophthalmologic Arthralgias/Arthritis disturbances
Auditory Renal
Pulmonary Insufficiency
Neurologic
Infectious
Advantages Long-term data May be superior in removal Once daily
available of cardiac iron administration
Only oral
chelator licensed
for use in US
Disadvantages Toxicity Not licensed for use in Long-term data
Compliance United States. lacking
problems Frequent blood count
monitoring required
Drug Cost $ $$ $$$

Adapted from Reference 103. Kwiatkowski JL. Pediatr Clin N Am. 2008;55:461-82.

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SUMMARY
Acute iron poisoning continues to occur resulting in morbidity and mortality.
Treatment of acute iron poisoning should focus on providing supportive care and
administering deferoxamine parenterally. Oral iron chelators have not been widely
studied in human, acute iron poisoning and are therefore not recommended.
Worldwide many individuals with red cell disorders and myelodysplasia
develop transfusion-associated chronic iron overload. Significant morbidity and
mortality are associated with iron overload. Historically, deferoxamine was the only
iron chelator available. Deferoxamine therapy is inconvenient, time-consuming, and
associated with undesirable adverse effects resulting in non-compliance. Over the last
couple of decades significant evidence has emerged supporting the use of the oral iron
chelators deferiprone and deferasirox. Although both are effective at decreasing iron
burden several characteristics favor deferasirox. The once daily dosing requirement
for Deferasirox permits relative ease of administration and would be expected to
positively contribute to treatment adherence. It also has a favorable adverse effect
profile when compared to deferiprone which requires frequent blood count
monitoring. Although more research and long-term follow up studies are needed for
both oral chelators it is proposed that deferasirox be considered the oral chelator of
choice in pediatric patients with transfusion-associated chronic iron overload.

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