New Drug Developments

Deferasirox—An Oral Agent for Chronic Iron Overload

Heidi E VanOrden and Tracy M Hagemann

OBJECTIVE: To review the available literature on the pharmacology, pharmacokinetics, efficacy, toxicology, adverse effects, drug
interactions, and dosage guidelines for deferasirox, an oral iron chelator, in Phase III trials.
DATA SOURCES: Reviewers searched the following databases for English-language studies: MEDLINE (1966–April 2006),
International Pharmaceutical Abstracts (1970–April 2006), and the Cochrane Library Database. Key search terms included iron
chelation, chelation, iron overload, deferasirox, and ICL670.
STUDY SELECTION AND DATA EXTRACTION: Data on efficacy, toxicology, adverse effects, and pharmacokinetics for deferasirox were
obtained from randomized, open-label, blinded clinical trials. Other information was obtained from the manufacturer, including
unpublished studies in abstract form as well as available data on deferasirox.
DATA SYNTHESIS: Deferasirox is an orally active iron chelator. In clinical trials, deferasirox demonstrated efficacy at dosages of 20
and 30 mg/kg/day in treating iron overload in patients with β-thalassemia. Deferasirox has been studied in patients older than 2
years and appears to be safe, with the most common adverse effects reported being mild, transient nausea, gastrointestinal
disturbances, and rash. There were no reports of serious adverse effects in trials to date.
CONCLUSIONS: Deferasirox represents a new approach to the management of chronic iron overload in patients with chronic anemias
who require blood transfusions. The available literature suggests that deferasirox is safe and as effective as the current standard of
therapy at dosages of 20–30 mg/kg/day for β-thalassemia. Further studies are needed to confirm its efficacy in other chronic
transfusion-requiring diseases.
KEY WORDS: chronic iron overload, deferasirox, Exjade, ICL670, β-thalassemia.

Ann Pharmacother 2006;40:1110-7.

Published Online, 30 May 2006, [Link], DOI 10.1345/aph.1G566
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-012-H01

ron overload is a serious and potentially life-threatening Iron accumulation can occur either through excessive
I complication of chronic anemias, which require multiple
transfusions over long periods of time. Conditions that typ-
absorption in the gastrointestinal tract (primary hemochro-
matosis) or exogenous administration via multiple transfu-
ically require chronic transfusions include β-thalassemia, sions of red blood cells. Normal body iron stores in the
sickle cell anemia, and myelodysplastic syndrome. The typical patient are 3– 4 g; an excess of iron of 20 g or more
detrimental effects of chronic iron overload can lead to can lead to organ damage.1 Each unit of transfused red
damage of the liver, heart, and endocrine glands, resulting blood cells averages 200–250 mg of iron. In iron overload,
in organ compromise and, eventually, death. the hepatocytes are the major cell of iron storage, with liv-
er iron closely approximating total body iron.2 Measure-
ment of serum ferritin is the most commonly used indirect
Author information provided at the end of the text. estimate of body iron stores, but it is not a reliable surro-

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gate marker of hepatic iron burden.2,3 Ferritin levels are af- of efficacy makes this an attractive option for patients re-
fected by infection, inflammation, liver disease, vitamin C quiring long-term iron chelation therapy.
deficiency, and hemolysis.4 While serum ferritin is general-
ly not a great marker of iron, it is useful as a rough esti- Data Sources
mate, with a threshold level of approximately 2500 µg/L.5
Liver biopsy is considered the gold standard for measure- Reviewers searched the following databases for En-
ment of direct and total body iron, but this invasive tech- glish-language studies: MEDLINE (1966–April 2006), In-
nique is not always practical or advised.6 Noninvasive ternational Pharmaceutical Abstracts (1970–April 2006),
measurement techniques are being developed, including and the Cochrane Library Database. An Internet search
magnetic susceptometry using a super conduction quan- was conducted using the key terms iron chelation, chela-
tum interference device (SQUID), which has been shown tion, iron overload, and deferasirox. The manufacturer was
in some studies to have good correlations with liver biop- contacted and unpublished information, including ab-
sy– determined iron concentration.7,8 Hepatic iron content stracts, was obtained along with approved prescribing in-
of 2–7 mg/g dry weight (dw) liver is a goal of chelation formation.
therapy. Levels above 15 mg/g dw have been linked to in-
creased complications, including cardiac dysfunction.9 Pharmacology and Pharmacodynamics
Phlebotomy or chelation therapy are the only means of
eliminating excess iron from the body.10 The elimination of Deferasirox is the first of a new class of oral iron chela-
excess iron is crucial for preserving organ function in pa- tors called bishydroxyphenyltriazoles. As a tridentate
tients for whom iron accumulation is a possibility. molecule containing 3 active binding sites for iron, it has a
For many years, the only iron-chelating agent available 2:1 binding ratio with ferric iron (Fe3+). Due to its relative-
in the US has been deferoxamine. Its 1:1 iron molecule ly small size (MW 373.4), it is well absorbed through the
binding ratio makes it an effective agent for the chelation gastrointestinal tract. It has demonstrated a two- to fivefold
of excess iron. In patients with β-thalassemia, iron chela- increased potency over deferoxamine for the mobilization
tion with deferoxamine has been shown to decrease and re- of iron from tissue both in vitro and in vivo.14 The selectiv-
tard liver disease, diabetes, and endocrine failure; normal- ity for iron is high, with low affinity for trace metals such
ize growth; and prevent cardiac insufficiency.11 However, as zinc or copper. At doses of 10, 20, and 40 mg/kg/day, a
the short half-life and lack of oral bioavailability require mean iron excretion value of 0.119, 0.329, and 0.445
that deferoxamine be given as a subcutaneous infusion mg/kg/day, respectively, was demonstrated.15 Deferasirox
over 8–12 hours, 5–7 days per week.12 This requirement, is marketed as a dispersible tablet that is administered once
as well as the potential for local adverse reactions, makes daily on an empty stomach.
adherence a challenge in long-term utilization.
In patients with iron overload requiring chelation thera- Toxicology
py, adherence correlates directly with decreased morbidity A 4 week oral toxicology study performed in normal
and mortality. Unfortunately, approximately one-third of (non–iron overloaded) rats demonstrated that most of the
patients are nonadherent to deferoxamine therapy.13 As treatment-related toxicities were a direct result of the phar-
iron chelation is a life-long component of therapy for these macologic effect of deferasirox, which correlates well with
patients, an orally active agent would greatly increase ad- the depletion of iron in the kidneys and liver.16 The vac-
herence and patient tolerability, thereby increasing benefi- uolization of the epithelium in the proximal tubules seen in
cial long-term outcomes. The oral iron chelator deferi- the normal rats was attributable to the decreased iron con-
prone is marketed in Europe for second-line treatment of tent of the kidneys. Hematologic toxicities included de-
iron overload, but it has a narrow therapeutic index and creased erythropoiesis, also due to a lack of iron. Myocar-
carries a risk of agranulocytosis. dial toxicities were also seen, including focal degeneration,
A newly developed iron-chelating agent has been grant- inflammation, and myocarditis at the highest dose of 100
ed Food and Drug Administration (FDA) approval for the mg/kg. The no-observed-adverse-effect level (NOAEL) in
treatment of chronic iron overload due to blood transfu- this study was 10 mg/kg. Trials performed in both iron-
sions in patients 2 years of age and older. Deferasirox overloaded and normal rats showed that the same toxicities
(ICL670, Exjade) is an orally active iron chelator that is were seen but were less pronounced in the iron-overloaded
quickly absorbed and has an extended half-life, allowing rats.17 Doses up to 400 mg/kg/day have been administered
for once-daily dosing. It is largely excreted in the feces, to iron-overloaded marmosets.18 The dose was well toler-
with less than 10% excreted in the urine. It has been shown ated and not associated with proximal tubule vacuoliza-
to be effective and well tolerated, with minimal adverse ef- tion, as seen in the normal animals. The NOAEL was
fects. The improvement in patient tolerability with no loss found to be 400 mg/kg in this study.

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HE VanOrden and TM Hagemann

Chronic toxicity studies were performed in non–iron METABOLISM

overloaded marmosets and rats with iron-supplemented and
Metabolism of deferasirox occurs primarily through
non-supplemented diets. Morbidity and mortality were noted
glucuronidation.20 Oxidative metabolism is of minor im-
at the highest doses (≤180 mg/kg) along with nephropathies,
portance, only accounting for roughly 8% of the dose. The
vacuolization of the adrenal medulla and hepatic bile duct
acyl glucuronide M3 is suspected to be the main metabo-
cells, and inflammation of the gallbladder. At lower doses of
lite present in the bile.20 It is likely that the drug may un-
80 mg/kg, cataracts, hematologic effects, glandular ulcera-
dergo enterohepatic recirculation.14 It is thought that the
tions, and an increase in kidney weight were noted. The
cytochrome P450 system’s role is inconsequential and,
NOAEL for these studies was found to be 30– 40 mg/kg.16
therefore, the potential for drug– drug interactions resulting
from this pathway will most likely be minimal. No induc-
Pharmacokinetics tion or inhibition of these enzymes has been observed at
therapeutic doses.
No pharmacokinetic studies have been performed in
non–iron overloaded human subjects due to the potential
ELIMINATION
for toxicity associated with the pharmacologic effect of the
drug as demonstrated in animal studies. Following is a The final step in the elimination of deferasirox, the
summary of the pharmacokinetic findings that are known chelated compound, and the metabolites is hepatobiliary
to date. anion transport. The half-life is between 8 and 16 hours,
supporting the once-daily dosing schedule proposed for
ABSORPTION further studies and recommended by the manufacturer. Ap-
proximately 84% of the dose is excreted in the feces, with
Deferasirox is available in 125, 250, and 500 mg tablets
only approximately 8% elimination through the urine.12,15
for oral suspension. The solubility of the tablets at a pH of
This would suggest that no dose adjustments would be
7.4 and 25 ˚C is 0.4 mg/mL with a pKa of 4.57 for the car-
needed for patients with mild-to-moderate renal insuffi-
boxylic acid group. The pKa values of the 2 hydroxyl
ciency. The clearance of the drug at steady-state is between
groups are 8.71 and 10.56, contributing to the product’s
0.103 and 0.144 L/h/kg.14
pH-dependent dissolution.16 Water, orange juice, and apple
juice have been approved by the FDA as acceptable disso-
Clinical Trials
lution agents. The tablets contain lactose as an inactive in-
gredient. Deferasirox is rapidly and well absorbed (70%), In a Phase I study, deferasirox was studied in 24 male
with dose accumulation up to steady-state. No continuing patients with transfusion-dependent β-thalassemia, using a
accumulation was seen past steady-state after repeated 2-period, randomized, double-blind, placebo-controlled
doses administered for 6 months.19 The time (tmax) to reach parallel-group design.14 All patients had previously re-
maximum concentration (Cmax) of deferasirox in plasma is ceived a mean daily dose of deferoxamine 20 –50 mg/kg
1.5– 4 hours.15 In the pediatric population, the drug demon- for at least 4 weeks prior to screening. Patients received
strates slower absorption, resulting in a tmax of 4 – 6 single oral doses ranging from 2.5 to 80 mg/kg to investi-
hours.10,14 Steady-state is reached after 3 days of adminis- gate the drug’s safety, tolerability, and pharmacokinetics.
tration, based on trough plasma concentrations.12 The Cmax After an initial 16 day run-in period, patients were ran-
and AUC directly correlate with the dose administered. domized to 1 of 3 study groups; each group received a sin-
The AUC at steady-state was higher than the AUC after gle low dose of deferasirox followed by a higher dose 7
the administration of the first dose by an accumulation fac- weeks later. Within each treatment period, 2 patients in
tor of 1.3–2.3.15 each group received placebo. Between treatment periods,
patients were permitted to return to their usual transfusion
DISTRIBUTION and deferoxamine therapy.
Group 1 started with 2.5 mg/kg, which was increased to
Deferasirox is highly protein bound (~99%), almost all 20 mg/kg, group 2 started with 5 mg/kg and was increased
of which is bound to albumin. The amount associated with to 40 mg/kg, and group 3 started with 10 mg/kg, which
red blood cells is approximately 5%.15 The volume of distri- was increased to 80 mg/kg. Efficacy was measured by uri-
bution ± SD at steady-state is 14.37 ± 2.69 L in adults.14,15 In nary iron excretion. Safety assessments included physical
several patients in one study, a bump-like second concen- examination, electrocardiogram (ECG), vital signs, au-
tration peak was observed during the elimination phase of diometry, clinical laboratory evaluations, and adverse
both the unbound ligand and the complex, suggesting that event monitoring, and took place up to 10 days after pa-
the drug may undergo enterohepatic recirculation.14 tients received the drug.14

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 Deferasirox—An Oral Agent for Chronic Iron Overload

The urinary excretion of deferasirox and its iron com- In a Phase II study conducted over 1 year, 71 β-thal-
plex was less than 0.1% of the dose given. The drug was assemia patients with transfusional iron overload were ran-
well tolerated, and adverse events were considered mild. domized to receive either deferasirox 10 or 20 mg/kg giv-
Nausea and diarrhea were noted in 3 of 8 patients in the 80 en once daily or deferoxamine 40 mg/kg/day given subcu-
mg/kg dose group. There were 6 reports of headache (1 in taneously 5 days a week.21 Liver iron content (LIC) was
the placebo group, 4 in the 2.5 mg/kg group, 1 in the 20 measured by SQUID every 3 months, and patients were
mg/kg group). There were single reports of joint pain, ver- monitored for any changes in hepatic, renal, cardiac, ocu-
tigo, and influenza, which were not dose related and were lar, and audiometric parameters. Total body iron elimina-
not considered to be drug related.14 tion rate was based on a calculation of the volume of red
Twenty-four patients over 16 years of age with β-thal- blood cells transfused and the change in total body iron
assemia and iron overload were enrolled in a randomized, stores extrapolated from the LIC. Preliminary results on 63
placebo-controlled, double-blind, dose escalation study patients after 6 months of therapy showed that the range of
completed over 12 days.12 All patients had serum ferritin total body iron elimination in deferasirox patients (7.7–
levels between 1000 and 8000 ng/mL at baseline and had 28.5 mg/day) was similar to what was seen in the deferox-
undergone liver biopsy within 3 months of enrollment. amine patients in the study, as well as values reported in
Three patients were not randomized due to issues that the literature for deferoxamine. In the deferasirox 10
arose on the first day of the study: 1 patient had a delayed mg/kg group, LIC decreased from baseline in 11 patients,
hemolytic reaction to a transfusion and 2 patients had cen- demonstrated no change in 5 patients, and increased from
tral line infections. Twenty-one patients were randomized baseline in 6 patients. For patients receiving deferasirox 20
to 1 of 3 groups: 10, 20, or 40 mg/kg once daily. In each mg/kg, LIC decreased from baseline in 12 patients, did not
cohort, 5 patients received deferasirox and 2 received change in 8 patients, and increased in 1 patient. In the de-
placebo. Patients consumed a diet with a prescribed iron feroxamine 40 mg/kg/day group, LIC decreased from
content for the 12 days of the study. There was no differ- baseline in 11 patients, did not change in 7 patients, and in-
ence in patient demographics at baseline with respect to creased in 2 patients. The mean ± SD absolute change was
age and weight. –0.6 ± 1.61 for deferasirox 10 mg/kg, –1.5 ± 2.24 for de-
All doses of deferasirox resulted in a positive net iron ferasirox 20 mg/kg, and –1.3 ± 1.8 for deferoxamine 40
excretion as measured by atomic absorption spectrometry mg/kg. Intermittent, mild nausea was the only adverse ef-
of dietary, urine, and fecal iron and calculated net iron ex-
fect reported, and it was seen more often in the 20 mg/kg
cretion. There was a dose-related increase in net iron ex-
deferasirox group.
cretion, with iron balance achieved with 20 mg/kg daily.
Deferasirox was evaluated in 184 patients with various
However, this was a very small sample size and a short
transfusion-dependent anemias (85 β-thalassemia, 47
course of administration. Skin rash was reported in 4 pa-
myelodysplastic syndrome, 30 Diamond–Blackfan syn-
tients receiving 20 and 40 mg/kg. Nine patients discontin-
drome, 22 other anemias, excluding sickle cell) in an open-
ued the study secondary to serious adverse events not sus-
label, noncomparative, multicenter study over 1 year.22
pected to be caused by the study drug including fever and
This study included pediatric patients (n = 35) between 2
hypotension, transfusion reaction, retinal infarct, central
line infection, elevated QT interval with hypocalcemia and and 16 years of age (19% of all pts.). LIC was assessed via
hypoparathyroidism, and rash. All patients were receiving SQUID in 35% of the patients. Doses of deferasirox 5, 10,
study drug except the patient exhibiting fever and hypoten- 20, and 30 mg/kg were assigned based on LIC at baseline.
sion. Of the 4 cases of rash, 3 were deemed to be related to There was a dose-dependent decreased effect on LIC, with
the study drug. The rash was erythematous and macu- overall success rates of 56.4% (95% CI 48.8 to 63.9).
lopapular; involved the trunk, arms, and legs; and tended There was a statistically significant decrease in LIC of 4.7
to occur 8–10 days after starting the 40 mg/kg dose. There ± 8.6 mg/g dw in patients with β-thalassemia and 3.7 mg/g
was no incidence of respiratory or hemodynamic compro- dw in all patients with other anemias (p < 0.001). A signif-
mise in conjunction with development of the rash. Other icant decrease in LIC was seen in all patients with a base-
adverse effects included increased transient transaminases line LIC of more than 7 mg/g dw treated with either 20 or
(n = 1), diarrhea (n = 4), moderate nausea (n = 1), and mild 30 mg/kg; there was a dose-dependent decrease of ferritin
abdominal pain (n = 1), and were seen in the groups re- in all groups. The number of blood transfusions was also
ceiving 20 and 40 mg/kg. The authors concluded that net similar across all groups.
iron excretion with deferasirox 20 mg/kg would prevent The most frequent adverse effects were mild transient
net iron accumulation equivalent to 0.3–0.5 mg/kg/day in gastrointestinal disturbances (~76%) and skin rash
most patients receiving transfusions of packed red blood (~10%). There were no cases of severe renal impairment
cells 12–15 mL/kg/month. The 20 mg/kg dose was or failure; however, increases of serum creatinine 33%
deemed to be the most safe and effective in this study.12 above baseline on 2 or more consecutive visits were ob-

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HE VanOrden and TM Hagemann

served in 40% of patients overall, most frequently in doses with LIC greater than 14 mg/g dw received either de-
above 30 mg/kg/day in those with rare anemias. The au- ferasirox 30 mg/kg or 50 mg/kg or more of deferoxamine
thors noted that serum creatinine levels stayed within the (group 4). LIC was measured by liver biopsy (84% of pa-
normal range despite the increases seen. Two patients, both tients) or by magnetic susceptometry using SQUID. Fifty-
in the 30 mg/kg dose group, were discontinued from the one percent of the patients in this study were 16 years of
study based on increased serum creatinine. No cases of age or younger (range 2–53).
agranulocytosis were reported in the patients with β-thal- The absolute reduction in LIC for all patients was –2.4
assemia. The study drug was discontinued in 10% of pa- ± 8.2 (deferasirox) and –2.9 ± 5.4 (deferoxamine), which
tients due to adverse event or death, mostly secondary to were each statistically significant from baseline (p <
complications of the underlying disease state (5 deaths in 0.001). However, all groups with baseline LIC less than 7
the other anemias group). Two patients older than 50 years mg/g dw showed marked differences in each group at the
were discontinued from the study secondary to continued end of 1 year (LIC 4 ± 3.8 with deferasirox, 0.13 ± 2.2
increases in serum creatinine and 1 was discontinued sec- with deferoxamine). Dosing by LIC category in the treat-
ondary to diarrhea. There were no reports of arthropathy, ment arms was disproportionate, which affected the non-
growth failure, or bone changes. Overall, deferasirox ex- inferiority analysis. There was a less than twofold differ-
hibited dose-dependent effects, which produced statistical- ence in the average daily dose of deferoxamine between
ly significant decreases in LIC. Doses of 20 and 30 mg/kg the highest and lowest dosing categories compared with a
produced stable or decreasing LIC over 1 year of therapy, fivefold difference in the deferasirox dosing categories,
while doses of 5 and 10 mg/kg were too low to produce which means that patients with baseline LICs less than 7
this effect.22 mg/g dw received lower doses of deferasirox (5–10 mg/kg),
The efficacy and safety of deferasirox were evaluated in while those in the deferoxamine comparator arm received
an open-label, multicenter, Phase II trial in 47 patients with correspondingly higher doses of deferoxamine. Success
myelodysplastic syndrome and iron overload.23 Patients criteria after 1 year of treatment were defined by an LIC
ranged in age from 20 to 81 years (mean 65.1) and re- from 1 to less than 7 mg/g dw for patients with a baseline
ceived 5, 10, 20, or 30 mg/kg depending on their baseline LIC of 10 mg/g dw or less, and a decrease by 3 mg/g dw
LIC, which was not reported. Overall, a dose-dependent or more for patients who had an LIC of 10 mg/g dw or
decrease in LIC of 5.7 ± 6.3 mg/g dw (mean ± SD) was higher at baseline.24
seen, as well as a dose-dependent decrease in serum fer- Overall success rates were 52.9% with deferasirox and
ritin (overall decrease of 267.6 ± 2053.1 µg/L). The medi- 66.4% with deferoxamine. Non-inferiority was achieved in
an number of transfusions per patient was 14 (range 6–26) patients with LICs of 7 mg/g dw or higher. Changes in LIC
over the year of the study. There were no cases of drug-in- from baseline to end of study (EOS) were significant and
duced neutropenia or arthralgia reported. Most adverse dose-dependent for both treatments. Deferasirox doses of
events were mild/moderate and involved transient, mild 20 and 30 mg/kg produced stable or decreasing LIC levels
gastrointestinal disturbances. There were 4 deaths, all of over 1 year (p < 0.001). Dose-dependent increases in LIC
which were related to the underlying diseases. Two pa- were found in patients receiving deferasirox 5 and 10
tients discontinued the study secondary to drug-related mg/kg. There was a dose-dependent effect on ferritin for
events, including mild emesis and mild increases in serum both treatment arms, which paralleled the changes in LIC.
creatinine levels. Serum ferritin levels at baseline and EOS, respectively, for
Cappellini et al.24 compared once-daily oral deferasirox group 1 were 1532 and 2532 µg/L for deferasirox and
with subcutaneous infusion of deferoxamine in a 1 year, 1232 and 836 µg/L for deferoxamine. In group 2, ferritin
open-label, multicenter, Phase III study in 586 patients levels were 1881 µg/L at baseline and 2543 µg/L at EOS
with β-thalassemia and transfusional hemosiderosis. The for deferasirox, and 1469 µg/L at baseline and 1518 µg/L
study investigated the hypothesis that deferasirox was non- at EOS for deferoxamine. For group 3, ferritin baseline
inferior to deferoxamine, based on the primary endpoint of and EOS levels, respectively, were 1954 and 2032 µg/L
maintenance or reduction of baseline LIC. Patients were for deferasirox and 2041 and 1845 µg/L for deferoxamine.
randomized 1:1, and LIC was used to assign the dose of ei- Group 4 had serum ferritin levels of 3318 µg/L at baseline
ther agent. Patients with LIC of 2–3 mg/g dw received ei- and 2069 µg/L at EOS for deferasirox and 2542 µg/L at
ther deferasirox 5 mg/kg or deferoxamine 20 –30 mg/kg baseline and 1920 µg/L at EOS for deferoxamine. Overall,
(group 1). Patients with LIC between 3 and 7 mg/g dw deferasirox doses of 5 and 10 mg/kg led to increasing
were randomized to receive deferasirox 10 mg/kg or defer- serum ferritin levels over time, 20 mg/kg doses led to sta-
oxamine 25–35 mg/kg (group 2). Patients with baseline ble ferritin levels, and doses of 30 mg/kg led to decreased
LIC of 7–14 mg/g dw received either deferasirox 20 ferritin levels. The number of blood transfusions was simi-
mg/kg or deferoxamine 35–50 mg/kg (group 3), and those lar in both groups.24

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 Deferasirox—An Oral Agent for Chronic Iron Overload

Of note, during the New Drug Application hearings, the trials to date. This is a chronic therapy, and long-term fol-
validity of SQUID was questioned in this study24; the LICs low-up of patients receiving deferasirox will be important
measured by SQUID in this trial were found to have varied to assess adverse effects that may occur with long-term
substantially among the study institutions. SQUID was use. Studies are planned to evaluate duration of use longer
found to have underestimated LIC by a factor of 2 com- than 1 year.
pared with LIC measured by liver biopsy.25 Novartis asked Drug-induced hepatitis confirmed by liver biopsy lead-
that patients whose LIC had been measured by SQUID ing to drug discontinuation has been seen in 2 patients in
(16%) be excluded from the efficacy analysis for FDA ap- one clinical trial.24 In this study, 25 additional patients had
proval. The rationale was that the initial deferasirox dose increased alanine aminotransferase (ALT) levels more than
was based on LIC and, because SQUID measurement un- 5 times the upper limit of normal at 2 or more post-base-
derestimated the LIC measured by biopsy, patients whose line visits. Two patients were discontinued from the study
dose was determined on this basis were apparently under- due to increased ALT levels. The increases in transaminas-
dosed. es did not appear to be dose related. Liver function tests
Generally, deferasirox was well tolerated, with the most should be performed monthly during deferasirox treatment
common adverse effects presenting as mild, transient gas- and dose adjustments should be considered for patients
trointestinal disturbances and skin rashes. There were no with persistent or severe elevations.15
findings of agranulocytosis, arthropathy, growth failure, Both ocular and auditory function were assessed in clin-
bone changes, or sensorineural toxicity. Four deaths (1 ical trials; disturbances, including high-frequency hearing
with deferasirox, 3 with deferoxamine) were considered loss, lens opacities, cataracts, and elevations in intraocular
unrelated to the study drugs. Three patients in the de- pressure, were reported at less than a 1% incidence overall.
ferasirox arm discontinued therapy due to moderate in- Ophthalmic and auditory tests are recommended before
creases in transaminase levels in association with increased starting treatment and at yearly intervals. If abnormalities
serum ferritin levels. Once-daily oral deferasirox taken for are found on examination, dose reduction or discontinua-
more than 1 year had a statistically significant decrease in tion should be considered.15
LIC similar to that seen with the use of deferoxamine; this In healthy volunteers, deferasirox has shown no effect
effect was dose-dependent, with a better response in pa- on the pharmacokinetics of digoxin.15 It is unknown at this
tients taking 20 and 30 mg/kg.24 time what the potential effects of digoxin on deferasirox
Several ongoing studies are evaluating the use of de- pharmacokinetics may be, as this has not been studied. Po-
ferasirox for iron overload in sickle cell disease and myelo- tential interactions with hydroxyurea, vitamin C, or alu-
dysplastic syndrome. Data are not yet available from these minum-containing antacids have not been evaluated. De-
studies. ferasirox has a lower affinity for aluminum than for iron; it
is recommended to avoid concomitant use of deferasirox
Adverse Drug Reactions and Drug Interactions with aluminum-containing antacids. To date, the only es-
tablished contraindication to deferasirox is prior hypersen-
From all trials to date, the most commonly reported ad- sitivity to the drug.15
verse effects with deferasirox were transient, including
nausea (10%), vomiting (9%), abdominal pain (14%), diar-
Special Populations
rhea (12%), and skin rash (8%).12,14,19,21-24,26 These effects
rarely caused discontinuation of the study drug. Skin rash Deferasirox has not been studied in women who are
was usually erythematous and maculopapular and tended pregnant or breast-feeding, or in pediatric patients younger
to occur about 1 week after starting high-dose therapy (40 than 2 years.
mg/kg).12 Some mild increases in serum creatinine levels Thirty patients 65 years of age and older have been in-
were observed; these appear to be dose-related. In patients cluded in clinical trials of deferasirox, with the majority (n
with β-thalassemia, 3% overall had serum creatinine val- = 27) having myelodysplastic syndrome. Caution should
ues that increased more than 33% above baseline but were be used in patients older than 65 years due to a greater fre-
still within normal range. In patients who exhibited these quency of decreases in hepatic, renal, or cardiac function.15
serum creatinine elevations, the daily dose was decreased Deferasirox has been studied in pediatric patients 2
by 10 mg/kg. In patients with rare anemias, such as Black- years of age and older with β-thalassemia. In an open-la-
fan–Diamond syndrome, this percentage increased to 16%. bel, 48 week, multicenter study of 40 pediatric patients, pa-
However, no cases of moderate-to-severe renal impair- tients were stratified by age into 2 groups: those aged from
ment or renal failure have been observed in any of the tri- 2 to less than 12 years of age, labeled “children,” and those
als to date. Also of note, there have been no cases of agran- 12–17 years of age, labeled “adolescents” (mean age for
ulocytosis, an effect that is associated with deferoxamine, all patients: 10.4 y).26 All patients initially received de-
seen in any patient who has taken deferasirox in any of the ferasirox 10 mg/kg, and the dose was increased after 12

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HE VanOrden and TM Hagemann

weeks if indicated by increases in LIC and serum ferritin serum ferritin is consistently less than 500 µg/L after start-
levels. Safety was monitored by assessing adverse effects, ing therapy, interruption of therapy should be considered.
hematology, blood and urine chemistry, vital signs, ECG, Doses of deferasirox greater than 30 mg/kg/day should be
ophthalmology and auditory tests, and growth parameters. used with caution.15
LIC was measured at baseline and at 4, 12, 24, 36, and 48
weeks by SQUID. Summary
While dose increases were allowed after week 12, only
21 patients (14 children, 7 adolescents) required an in- Deferasirox is a new drug within a class of agents that
crease. Three patients had dose increases before week 20, can now be given orally for the treatment of transfusion-re-
3 had increases between weeks 20 and 24, and the remain- lated iron overload in patients 2 years of age and older
ing patients had dose increases after 34 weeks. Only 1 sub- with chronic anemias that require multiple transfusions over
ject required a dose increase to 30 mg/kg. Serum ferritin long periods of time. Current data show deferasirox to be as
trends were similar in all patients. The amount of iron re- effective as the current treatment of choice, subcutaneous de-
moved by deferasirox at the doses used (10 –20 mg/kg) feroxamine administered over 8–12 hours, 5–7 days per
was too low to counterbalance iron intake, which was week. Adverse effects are relatively mild and transient and
close to the upper limit of standard transfusion requirements are most likely to include nausea, abdominal pain, diarrhea,
in β-thalassemia (0.46 mg/kg). Iron intake was marginally and skin rash. There are no cases reported to date of any de-
greater than calculated iron excretion. Deferasirox was well velopment of agranulocytosis with the use of deferasirox. Be-
tolerated, with mild, transient nausea reported in 2 adoles- cause deferasirox is administered once daily in an oral for-
cents and skin rash reported in 2 children, 1 of which led to mulation, patient adherence to this therapy may be improved
study drug discontinuation. One patient exhibited increased over that with use of long subcutaneous infusions.
transaminase levels, which normalized after dose interrup- Further studies are ongoing to assess the use of de-
tion and did not recur with continuation of the study drug. ferasirox in sickle cell disease patients and myelodysplas-
There were no reports of agranulocytosis, thrombocytope- tic syndrome patients with chronic iron overload. To date,
nia, arthralgia, increases in serum creatinine, or growth ab- no data exist on the effects of deferasirox in pregnancy,
normalities. This study used lower doses compared with lactation, hepatic insufficiency, or renal insufficiency. De-
previous data in adults, and the dose used (10 mg/kg) was ferasirox should be avoided with aluminum-containing
too low to maintain a negative iron balance.26 antacids. Other drug interactions have not been studied.
This initial starting dose for pediatric patients 2 years or Deferasirox represents a significant advancement in the
older is 20 mg/kg/day, and dose modifications are the same treatment of chronic iron overload and could help many
as for adult patients. patients who are unable to comply with the current stan-
dard of care.
Dosage and Administration
Heidi E VanOrden PharmD, Senior Clinical Pharmacist, Center
Deferasirox is an orally active iron chelator provided as for Cancer and Blood Disorders, Children’s Medical Center of Dallas,
125, 250, and 500 mg tablets that are to be dispersed in Dallas, TX
noncarbonated water, orange juice, or apple juice, and in- Tracy M Hagemann PharmD, Associate Professor, Department
of Pharmacy: Clinical and Administrative Sciences, College of Phar-
gested orally once daily. Doses less than 1 g should be dis- macy, University of Oklahoma, Oklahoma City, OK
persed in 3.5 ounces of liquid and doses more than 1 g Reprints: Dr. Hagemann, Department of Pharmacy: Clinical and
Administrative Sciences, College of Pharmacy, University of Okla-
should be dispersed in 7 ounces of liquid. Dispersion of the homa, 1110 N. Stonewall Ave., Oklahoma City, OK 73117-1223, fax
tablet typically takes approximately 3 minutes of manual 405/271-6430, Tracy-Hagemann@[Link]
stirring. After the suspension is swallowed, any remaining
residue should be resuspended in a small volume of liquid References
and swallowed. Deferasirox should be taken on an empty
1. Porter JB. Practical management of iron overload. Br J Haematol 2001;
stomach 30 minutes before eating.15 115:239-52.
The recommended starting dose is 20 mg/kg and should 2. Kushner JP, Porter JP, Oliveri NF. Secondary iron overload. Hematology
be rounded to the nearest available tablet strength. It is rec- (Am Soc Hematol Educ Program) 2001:47-61.
3. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complications
ommended that therapy begin when a patient has evidence of beta-thalassemia major in North America. Blood 2004;104:34-9.
of chronic iron overload, such as transfusion of approxi- 4. deVirgiliis S, Sanna G, Cornacchia G, et al. Serum ferritin, liver iron
mately 100 mL/kg of packed red blood cells and a serum stores, and liver histology in children with thalassemia. Arch Dis Child
1980;55:43-5.
ferritin level higher than 1000 µg/L. Serum ferritin should 5. Lo L, Singer ST. Thalassemia: current approach to an old disease. Pediatr
be monitored monthly, and the dose of deferasirox should Clin North Am 2002;49:1165-91.
be adjusted every 3– 6 months as needed. Dose adjust- 6. Porter JB, Davis BA. Monitoring chelation therapy to achieve optimal
outcome in the treatment of beta-thalassemia. Best Pract Res Clin
ments should be made in increments of 5–10 mg/kg. If Haematol 2002;15:329-68.

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 Deferasirox—An Oral Agent for Chronic Iron Overload

7. Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility FUENTES DE INFORMACIÓN: Los revisores buscaron en las bases de datos
measurement of human iron stores. N Engl J Med 1982;307:1671-5. de estudios en el idioma inglés utilizado el motor de búsqueda de
8. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of artículos MEDLINE (entre 1966 hasta abril de 2006), Extractos
thalassemia. Blood 1997;89:739-61. Farmacéuticos Internacionales (del 1970 hasta abril de 2006), y la base
9. Olivieri NF. The beta-thalassemias. N Engl J Med 1999;341:99-109. de datos de la biblioteca Cochrane. Los términos claves usados en la
10. Committee for Orphan Medicinal Products. Public summary of positive búsqueda incluyeron quelación de hierro, quelación, sobrecarga de
opinion for orphan designation of 4-(3,5-bis-(hydroxyl-phenyl)-1,2,4)tri- hierro, deferasirox, y ICL670.
azol-1-yl)-benzoic acid for the treatment of chronic iron overload requir- SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Los datos sobre la
ing chelation therapy. London: European Medicines Agency, 2003 Jan 8.
eficacia, toxicología, efectos adversos, y farmacocinética se obtuvo de
11. Nick H, Wong A, Acklin P, et al. ICL670A: preclinical profile. Adv Exp estudios clínicos aleatorio. Otra información se obtuvo de estudios no
Med Biol 2002;509:185-203.
publicados pero en disponibles como extractos (n = 4) con datos
12. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safety disponibles sobre deferasirox del manufacturero.
of ICL670 in iron-loaded patients with thalassaemia: a randomized, dou-
ble-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361: SÍNTESIS: Deferasirox es un quelante de hierro oral. En los estudios
1597-602. clínicos deferasirox demostró eficacia al tratar sobrecarga de hierro en
13. National Horizon Scanning Center. Deferasirox (ICL670) for iron over- pacientes con β-talasemia con dosis entre 20 y 30 mg/kg día. Se ha
load. Jan 2005. [Link]/publichealth/horizon (accessed estudiado en pacientes mayores de 2 años y aparenta ser seguro. Los
2005 Jun 20). efectos adversos mas comúnmente reportados son nausea, malestar
14. Galanello R, Piga A, Alberti D, et al. Safety, tolerability, and pharma- gastrointestinal, y sarpullido y estos son de leves y transitorios. No
cokinetics of ICL670, a new orally active iron-chelating agent in patients existen informes de reacciones adversas serias en estudios hasta el
with transfusion-dependent iron overload due to β-thalassemia. J Clin momento.
Pharmacol 2003;43:565-72. CONCLUSIONES: Deferasirox representa una nueva estrateguia en el
15. Package insert. Exjade (deferasirox). East Hanover, NJ: Novartis Phar- managejo de sobrecarga crónica de hierro en pacientes con anemia
maceuticals, November 2005. crónica que requieren transfusiones de sangre. La literatura disponible
16. Barton JC. Deferasirox (Novartis). Curr Opin Investig Drugs 2005;6: sugiere que deferasirox es tan segura y efectiva como la terapia estándar
327-35. en dosis de of 20–30 mg/kg/day for β-talasemia. Se recomiendan más
17. Hershko C, Konijin AM, Nick HP, et al. ICL670: a new synthetic oral investigaciones para confirmar su eficacia en otras enfermedades
chelator: evaluation in hypertransfused rats with selective radioiron crónicas que requieren transfusiones.
probes of hepatocellular and reticuloendothelial iron stores and in iron-
loaded rat heart cells in culture. Blood 2001;97:1115-22. Jorge R Miranda-Massari
18. Sergejew T, Forgiarini P, Schnebli HP. Chelator-induced iron excretion in
iron-overloaded marmosets. Br J Haematol 2000;110:985-92.
19. Cappellini M. Iron-chelating therapy with the new oral agent ICL670 RÉSUMÉ
(Exjade). Best Pract Res Clin Haematol 2005;18:289-98. OBJECTIF: Revoir la littérature disponible sur la pharmacologie, la
20. Novartis media release. Novartis files Exjade new drug applications for pharmacocinétique, l’efficacité, la toxicologie, les effets secondaires, les
treatment of chronic iron overload due to blood transfusions. May 3, interactions médicamenteuses, et les recommandations posologiques du
2005. [Link] (accessed 2005 May 14). deferasirox, un médicament en phase III d’investigation.
21. Piga A, Galanello R, Cappellini MD, et al. Phase II study of oral chelator
SOURCE DE L’INFORMATION: Une recherche informatisée sur les banques
ICL670 in thalassemia patients with transfusional iron overload: efficacy,
safety, pharmacokinetics and pharmacodynamics after 6 months of ther- de données MEDLINE (1966–avril 2006), International
apy (abstract). Blood 2002;100:5a. Pharmaceutical Abstracts (1970–avril 2006), et la Cochrane Library
22. Porter J, Vichinsky E, Rose C, et al. A Phase II study with ICL670 (Ex- Database a été effectuée. Les mots clés de recherche incluent: iron
jade), a once-daily oral iron chelator, in patients with various tranfusion- chelation, chelation, iron overload; deferasirox, et ICL670.
dependent anemias and iron overload (abstract). Blood 2004;104:3193. SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les données sur l’efficacité,
23. Gattermann N, Cazzola M, Greenberg P, et al. The efficacy and tolerabil- la toxicité, les effets secondaires, et la pharmacocinétique furent
ity of ICL670, a once-daily oral iron chelator, in patients with myelodys- obtenues à partir des études randomisées ouvertes ou à double-insu. Des
plastic syndrome (MDS) and iron overload (abstract). Leuk Res 2005; informations supplémentaires furent obtenues d’études publiées sous
29(suppl 1):S67. forme d’abrégé (n = 4) ainsi que du manufacturier.
24. Cappellini M, Bejaoui M, Perrotta S, et al. Phase III evaluation of once- RÉSUMÉ: Le deferasirox est un chélateur de fer actif par voie orale. Dans
daily, oral therapy with ICL670 (Exjade) versus deferoxamine in patients
les études cliniques, le deferasirox a été démontré efficace dans le
with β-thalassemia and transfusional hemosiderosis (abstract). Blood
2004;104:3619.
traitement de la surcharge de fer chez les patients avec β-thalassémie à
des doses de 20 et 30 mg/kg. Il a été étudié chez les patients âgés de plus
25. Food and Drug Administration. NDA 21-882. Exjade Advisory Committee
Summary. [Link]/ohrms/dockets/ac/05/briefing/2005-4177B1_02_a.
de 2 ans et semble sécuritaire. Les effets secondaires les plus fréquents
pdf (accessed 2006 Jan 24). étaient légers et impliquaient des nausées transitoires, des désordres
26. Piga A, Galanello R, Foschini ML, et al. Once-daily treatment with the
gastrointestinaux, et un rash cutané. Aucun rapport d’effets secondaires
oral iron chelator ICL670 (Exjade): results of a Phase II study in pedi- sérieux n’existe à ce jour.
atric patients with β-thalassemia major (abstract). Blood 2004;104:3614. CONCLUSIONS: Le déferasirox représente une nouvelle approche dans le
traitement de la surcharge chronique en fer chez des patients souffrant
d’anémie chronique et requerrant des transfusions sanguines. La
littérature suggère que le deferasirox est sécuritaire et aussi efficace que
le traitement standard à des doses de 20 à 30 mg/kg/jour pour la β-
EXTRACTO thalassémie. Des études supplémentaires seront nécessaires pour
OBJETIVO: Revisar la literatura disponible sobre la farmacología, confirmer l’efficacité auprès d’autres maladies requerrant régulièrement
farmacocinética, eficacia, toxicología, efectos adversos, interacciones de des transfusions sanguines
drogas, y guías de dosificación para deferasirox, un producto en estudios
Marc M Perreault
fase III.

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