deferasirox--an oral agent for chronic iron overload

1110 n The Annals of Pharmacotherapy n 2006 June, Volume 40 www.theannals.com

Iron overload is a serious and potentially life-threateningcomplication of chronic anemias, which require multiple

transfusions over long periods of time. Conditions that typ-ically require chronic transfusions include β-thalassemia,sickle cell anemia, and myelodysplastic syndrome. Thedetrimental effects of chronic iron overload can lead todamage of the liver, heart, and endocrine glands, resultingin organ compromise and, eventually, death.

Iron accumulation can occur either through excessiveabsorption in the gastrointestinal tract (primary hemochro-matosis) or exogenous administration via multiple transfu-sions of red blood cells. Normal body iron stores in thetypical patient are 3– 4 g; an excess of iron of 20 g or morecan lead to organ damage.1 Each unit of transfused redblood cells averages 200–250 mg of iron. In iron overload,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 indirectestimate of body iron stores, but it is not a reliable surro-

Deferasirox—An Oral Agent for Chronic Iron Overload

Heidi E VanOrden and Tracy M Hagemann

New Drug Developments

Author information provided at the end of the text.

OBJECTIVE: To review the available literature on the pharmacology, pharmacokinetics, efficacy, toxicology, adverse effects, druginteractions, 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 ironchelation, chelation, iron overload, deferasirox, and ICL670.

STUDY SELECTION AND DATA EXTRACTION: Data on efficacy, toxicology, adverse effects, and pharmacokinetics for deferasirox wereobtained from randomized, open-label, blinded clinical trials. Other information was obtained from the manufacturer, includingunpublished 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 20and 30 mg/kg/day in treating iron overload in patients with β-thalassemia. Deferasirox has been studied in patients older than 2years and appears to be safe, with the most common adverse effects reported being mild, transient nausea, gastrointestinaldisturbances, 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 anemiaswho require blood transfusions. The available literature suggests that deferasirox is safe and as effective as the current standard oftherapy at dosages of 20–30 mg/kg/day for β-thalassemia. Further studies are needed to confirm its efficacy in other chronictransfusion-requiring diseases.

KEY WORDS: chronic iron overload, deferasirox, Exjade, ICL670, β-thalassemia.

Ann Pharmacother 2006;40:1110-7.

Published Online, 30 May 2006, www.theannals.com, DOI 10.1345/aph.1G566

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gate marker of hepatic iron burden.2,3 Ferritin levels are af-fected by infection, inflammation, liver disease, vitamin Cdeficiency, and hemolysis.4 While serum ferritin is general-ly not a great marker of iron, it is useful as a rough esti-mate, with a threshold level of approximately 2500 µg/L.5

Liver biopsy is considered the gold standard for measure-ment of direct and total body iron, but this invasive tech-nique is not always practical or advised.6 Noninvasivemeasurement techniques are being developed, includingmagnetic susceptometry using a super conduction quan-tum interference device (SQUID), which has been shownin some studies to have good correlations with liver biop-sy– determined iron concentration.7,8 Hepatic iron contentof 2–7 mg/g dry weight (dw) liver is a goal of chelationtherapy. Levels above 15 mg/g dw have been linked to in-creased complications, including cardiac dysfunction.9

Phlebotomy or chelation therapy are the only means ofeliminating excess iron from the body.10 The elimination ofexcess iron is crucial for preserving organ function in pa-tients for whom iron accumulation is a possibility.

For many years, the only iron-chelating agent availablein the US has been deferoxamine. Its 1:1 iron moleculebinding ratio makes it an effective agent for the chelationof excess iron. In patients with β-thalassemia, iron chela-tion with deferoxamine has been shown to decrease and re-tard liver disease, diabetes, and endocrine failure; normal-ize growth; and prevent cardiac insufficiency.11 However,the short half-life and lack of oral bioavailability requirethat deferoxamine be given as a subcutaneous infusionover 8–12 hours, 5–7 days per week.12 This requirement,as well as the potential for local adverse reactions, makesadherence a challenge in long-term utilization.

In patients with iron overload requiring chelation thera-py, adherence correlates directly with decreased morbidityand mortality. Unfortunately, approximately one-third ofpatients are nonadherent to deferoxamine therapy.13 Asiron chelation is a life-long component of therapy for thesepatients, an orally active agent would greatly increase ad-herence and patient tolerability, thereby increasing benefi-cial long-term outcomes. The oral iron chelator deferi-prone is marketed in Europe for second-line treatment ofiron overload, but it has a narrow therapeutic index andcarries a risk of agranulocytosis.

A newly developed iron-chelating agent has been grant-ed Food and Drug Administration (FDA) approval for thetreatment of chronic iron overload due to blood transfu-sions in patients 2 years of age and older. Deferasirox(ICL670, Exjade) is an orally active iron chelator that isquickly absorbed and has an extended half-life, allowingfor once-daily dosing. It is largely excreted in the feces,with less than 10% excreted in the urine. It has been shownto be effective and well tolerated, with minimal adverse ef-fects. The improvement in patient tolerability with no loss

of efficacy makes this an attractive option for patients re-quiring long-term iron chelation therapy.

Data Sources

Reviewers searched the following databases for En-glish-language studies: MEDLINE (1966–April 2006), In-ternational Pharmaceutical Abstracts (1970–April 2006),and the Cochrane Library Database. An Internet searchwas conducted using the key terms iron chelation, chela-tion, iron overload, and deferasirox. The manufacturer wascontacted and unpublished information, including ab-stracts, was obtained along with approved prescribing in-formation.

Pharmacology and Pharmacodynamics

Deferasirox is the first of a new class of oral iron chela-tors called bishydroxyphenyltriazoles. As a tridentatemolecule containing 3 active binding sites for iron, it has a2:1 binding ratio with ferric iron (Fe3+). Due to its relative-ly small size (MW 373.4), it is well absorbed through thegastrointestinal tract. It has demonstrated a two- to fivefoldincreased potency over deferoxamine for the mobilizationof iron from tissue both in vitro and in vivo.14 The selectiv-ity for iron is high, with low affinity for trace metals suchas zinc or copper. At doses of 10, 20, and 40 mg/kg/day, amean iron excretion value of 0.119, 0.329, and 0.445mg/kg/day, respectively, was demonstrated.15 Deferasiroxis marketed as a dispersible tablet that is administered oncedaily on an empty stomach.

Toxicology

A 4 week oral toxicology study performed in normal(non–iron overloaded) rats demonstrated that most of thetreatment-related toxicities were a direct result of the phar-macologic effect of deferasirox, which correlates well withthe depletion of iron in the kidneys and liver.16 The vac-uolization of the epithelium in the proximal tubules seen inthe normal rats was attributable to the decreased iron con-tent of the kidneys. Hematologic toxicities included de-creased erythropoiesis, also due to a lack of iron. Myocar-dial toxicities were also seen, including focal degeneration,inflammation, and myocarditis at the highest dose of 100mg/kg. The no-observed-adverse-effect level (NOAEL) inthis study was 10 mg/kg. Trials performed in both iron-overloaded and normal rats showed that the same toxicitieswere seen but were less pronounced in the iron-overloadedrats.17 Doses up to 400 mg/kg/day have been administeredto iron-overloaded marmosets.18 The dose was well toler-ated and not associated with proximal tubule vacuoliza-tion, as seen in the normal animals. The NOAEL wasfound to be 400 mg/kg in this study.

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Chronic toxicity studies were performed in non–ironoverloaded marmosets and rats with iron-supplemented andnon-supplemented diets. Morbidity and mortality were notedat the highest doses (≤180 mg/kg) along with nephropathies,vacuolization of the adrenal medulla and hepatic bile ductcells, and inflammation of the gallbladder. At lower doses of80 mg/kg, cataracts, hematologic effects, glandular ulcera-tions, and an increase in kidney weight were noted. TheNOAEL for these studies was found to be 30–40 mg/kg.16

Pharmacokinetics

No pharmacokinetic studies have been performed innon–iron overloaded human subjects due to the potentialfor toxicity associated with the pharmacologic effect of thedrug as demonstrated in animal studies. Following is asummary of the pharmacokinetic findings that are knownto date.

ABSORPTION

Deferasirox is available in 125, 250, and 500 mg tabletsfor oral suspension. The solubility of the tablets at a pH of7.4 and 25 ˚C is 0.4 mg/mL with a pKa of 4.57 for the car-boxylic acid group. The pKa values of the 2 hydroxylgroups are 8.71 and 10.56, contributing to the product’spH-dependent dissolution.16 Water, orange juice, and applejuice have been approved by the FDA as acceptable disso-lution agents. The tablets contain lactose as an inactive in-gredient. Deferasirox is rapidly and well absorbed (70%),with dose accumulation up to steady-state. No continuingaccumulation was seen past steady-state after repeateddoses administered for 6 months.19 The time (tmax) to reachmaximum concentration (Cmax) of deferasirox in plasma is1.5– 4 hours.15 In the pediatric population, the drug demon-strates slower absorption, resulting in a tmax of 4–6hours.10,14 Steady-state is reached after 3 days of adminis-tration, based on trough plasma concentrations.12 The Cmax

and AUC directly correlate with the dose administered.The AUC at steady-state was higher than the AUC afterthe administration of the first dose by an accumulation fac-tor of 1.3–2.3.15

DISTRIBUTION

Deferasirox is highly protein bound (~99%), almost allof which is bound to albumin. The amount associated withred blood cells is approximately 5%.15 The volume of distri-bution ± SD at steady-state is 14.37 ± 2.69 L in adults.14,15 Inseveral patients in one study, a bump-like second concen-tration peak was observed during the elimination phase ofboth the unbound ligand and the complex, suggesting thatthe drug may undergo enterohepatic recirculation.14

METABOLISM

Metabolism of deferasirox occurs primarily throughglucuronidation.20 Oxidative metabolism is of minor im-portance, only accounting for roughly 8% of the dose. Theacyl glucuronide M3 is suspected to be the main metabo-lite present in the bile.20 It is likely that the drug may un-dergo enterohepatic recirculation.14 It is thought that thecytochrome P450 system’s role is inconsequential and,therefore, the potential for drug– drug interactions resultingfrom this pathway will most likely be minimal. No induc-tion or inhibition of these enzymes has been observed attherapeutic doses.

ELIMINATION

The final step in the elimination of deferasirox, thechelated compound, and the metabolites is hepatobiliaryanion transport. The half-life is between 8 and 16 hours,supporting the once-daily dosing schedule proposed forfurther studies and recommended by the manufacturer. Ap-proximately 84% of the dose is excreted in the feces, withonly approximately 8% elimination through the urine.12,15

This would suggest that no dose adjustments would beneeded for patients with mild-to-moderate renal insuffi-ciency. The clearance of the drug at steady-state is between0.103 and 0.144 L/h/kg.14

Clinical Trials

In a Phase I study, deferasirox was studied in 24 malepatients with transfusion-dependent β-thalassemia, using a2-period, randomized, double-blind, placebo-controlledparallel-group design.14 All patients had previously re-ceived a mean daily dose of deferoxamine 20–50 mg/kgfor at least 4 weeks prior to screening. Patients receivedsingle oral doses ranging from 2.5 to 80 mg/kg to investi-gate the drug’s safety, tolerability, and pharmacokinetics.After an initial 16 day run-in period, patients were ran-domized to 1 of 3 study groups; each group received a sin-gle low dose of deferasirox followed by a higher dose 7weeks later. Within each treatment period, 2 patients ineach group received placebo. Between treatment periods,patients were permitted to return to their usual transfusionand deferoxamine therapy.

Group 1 started with 2.5 mg/kg, which was increased to20 mg/kg, group 2 started with 5 mg/kg and was increasedto 40 mg/kg, and group 3 started with 10 mg/kg, whichwas increased to 80 mg/kg. Efficacy was measured by uri-nary iron excretion. Safety assessments included physicalexamination, electrocardiogram (ECG), vital signs, au-diometry, clinical laboratory evaluations, and adverseevent monitoring, and took place up to 10 days after pa-tients received the drug.14


HE VanOrden and TM Hagemann



The urinary excretion of deferasirox and its iron com-plex was less than 0.1% of the dose given. The drug waswell tolerated, and adverse events were considered mild.Nausea and diarrhea were noted in 3 of 8 patients in the 80mg/kg dose group. There were 6 reports of headache (1 inthe placebo group, 4 in the 2.5 mg/kg group, 1 in the 20mg/kg group). There were single reports of joint pain, ver-tigo, and influenza, which were not dose related and werenot considered to be drug related.14

Twenty-four patients over 16 years of age with β-thal-assemia and iron overload were enrolled in a randomized,placebo-controlled, double-blind, dose escalation studycompleted over 12 days.12 All patients had serum ferritinlevels between 1000 and 8000 ng/mL at baseline and hadundergone liver biopsy within 3 months of enrollment.Three patients were not randomized due to issues thatarose on the first day of the study: 1 patient had a delayedhemolytic reaction to a transfusion and 2 patients had cen-tral line infections. Twenty-one patients were randomizedto 1 of 3 groups: 10, 20, or 40 mg/kg once daily. In eachcohort, 5 patients received deferasirox and 2 receivedplacebo. Patients consumed a diet with a prescribed ironcontent for the 12 days of the study. There was no differ-ence in patient demographics at baseline with respect toage and weight.

All doses of deferasirox resulted in a positive net ironexcretion as measured by atomic absorption spectrometryof dietary, urine, and fecal iron and calculated net iron ex-cretion. There was a dose-related increase in net iron ex-cretion, with iron balance achieved with 20 mg/kg daily.However, this was a very small sample size and a shortcourse of administration. Skin rash was reported in 4 pa-tients receiving 20 and 40 mg/kg. Nine patients discontin-ued the study secondary to serious adverse events not sus-pected to be caused by the study drug including fever andhypotension, transfusion reaction, retinal infarct, centralline infection, elevated QT interval with hypocalcemia andhypoparathyroidism, and rash. All patients were receivingstudy drug except the patient exhibiting fever and hypoten-sion. Of the 4 cases of rash, 3 were deemed to be related tothe study drug. The rash was erythematous and macu-lopapular; involved the trunk, arms, and legs; and tendedto occur 8–10 days after starting the 40 mg/kg dose. Therewas no incidence of respiratory or hemodynamic compro-mise in conjunction with development of the rash. Otheradverse effects included increased transient transaminases(n = 1), diarrhea (n = 4), moderate nausea (n = 1), and mildabdominal pain (n = 1), and were seen in the groups re-ceiving 20 and 40 mg/kg. The authors concluded that netiron excretion with deferasirox 20 mg/kg would preventnet iron accumulation equivalent to 0.3–0.5 mg/kg/day inmost patients receiving transfusions of packed red bloodcells 12–15 mL/kg/month. The 20 mg/kg dose wasdeemed to be the most safe and effective in this study.12

In a Phase II study conducted over 1 year, 71 β-thal-assemia patients with transfusional iron overload were ran-domized to receive either deferasirox 10 or 20 mg/kg giv-en once daily or deferoxamine 40 mg/kg/day given subcu-taneously 5 days a week.21 Liver iron content (LIC) wasmeasured by SQUID every 3 months, and patients weremonitored for any changes in hepatic, renal, cardiac, ocu-lar, and audiometric parameters. Total body iron elimina-tion rate was based on a calculation of the volume of redblood cells transfused and the change in total body ironstores extrapolated from the LIC. Preliminary results on 63patients after 6 months of therapy showed that the range oftotal body iron elimination in deferasirox patients (7.7–28.5 mg/day) was similar to what was seen in the deferox-amine patients in the study, as well as values reported inthe literature for deferoxamine. In the deferasirox 10mg/kg group, LIC decreased from baseline in 11 patients,demonstrated no change in 5 patients, and increased frombaseline in 6 patients. For patients receiving deferasirox 20mg/kg, LIC decreased from baseline in 12 patients, did notchange in 8 patients, and increased in 1 patient. In the de-feroxamine 40 mg/kg/day group, LIC decreased frombaseline in 11 patients, did not change in 7 patients, and in-creased in 2 patients. The mean ± SD absolute change was–0.6 ± 1.61 for deferasirox 10 mg/kg, –1.5 ± 2.24 for de-ferasirox 20 mg/kg, and –1.3 ± 1.8 for deferoxamine 40mg/kg. Intermittent, mild nausea was the only adverse ef-fect reported, and it was seen more often in the 20 mg/kgdeferasirox group.

Deferasirox was evaluated in 184 patients with varioustransfusion-dependent anemias (85 β-thalassemia, 47myelodysplastic syndrome, 30 Diamond–Blackfan syn-drome, 22 other anemias, excluding sickle cell) in an open-label, noncomparative, multicenter study over 1 year.22

This study included pediatric patients (n = 35) between 2and 16 years of age (19% of all pts.). LIC was assessed viaSQUID in 35% of the patients. Doses of deferasirox 5, 10,20, and 30 mg/kg were assigned based on LIC at baseline.There was a dose-dependent decreased effect on LIC, withoverall success rates of 56.4% (95% CI 48.8 to 63.9).There was a statistically significant decrease in LIC of 4.7± 8.6 mg/g dw in patients with β-thalassemia and 3.7 mg/gdw in all patients with other anemias (p < 0.001). A signif-icant decrease in LIC was seen in all patients with a base-line LIC of more than 7 mg/g dw treated with either 20 or30 mg/kg; there was a dose-dependent decrease of ferritinin all groups. The number of blood transfusions was alsosimilar across all groups.

The most frequent adverse effects were mild transientgastrointestinal disturbances (~76%) and skin rash(~10%). There were no cases of severe renal impairmentor failure; however, increases of serum creatinine 33%above baseline on 2 or more consecutive visits were ob-




served in 40% of patients overall, most frequently in dosesabove 30 mg/kg/day in those with rare anemias. The au-thors noted that serum creatinine levels stayed within thenormal range despite the increases seen. Two patients, bothin the 30 mg/kg dose group, were discontinued from thestudy based on increased serum creatinine. No cases ofagranulocytosis were reported in the patients with β-thal-assemia. The study drug was discontinued in 10% of pa-tients due to adverse event or death, mostly secondary tocomplications of the underlying disease state (5 deaths inthe other anemias group). Two patients older than 50 yearswere discontinued from the study secondary to continuedincreases in serum creatinine and 1 was discontinued sec-ondary to diarrhea. There were no reports of arthropathy,growth failure, or bone changes. Overall, deferasirox ex-hibited dose-dependent effects, which produced statistical-ly significant decreases in LIC. Doses of 20 and 30 mg/kgproduced stable or decreasing LIC over 1 year of therapy,while doses of 5 and 10 mg/kg were too low to producethis effect.22

The efficacy and safety of deferasirox were evaluated inan open-label, multicenter, Phase II trial in 47 patients withmyelodysplastic syndrome and iron overload.23 Patientsranged in age from 20 to 81 years (mean 65.1) and re-ceived 5, 10, 20, or 30 mg/kg depending on their baselineLIC, which was not reported. Overall, a dose-dependentdecrease in LIC of 5.7 ± 6.3 mg/g dw (mean ± SD) wasseen, as well as a dose-dependent decrease in serum fer-ritin (overall decrease of 267.6 ± 2053.1 µg/L). The medi-an number of transfusions per patient was 14 (range 6–26)over the year of the study. There were no cases of drug-in-duced neutropenia or arthralgia reported. Most adverseevents were mild/moderate and involved transient, mildgastrointestinal disturbances. There were 4 deaths, all ofwhich were related to the underlying diseases. Two pa-tients discontinued the study secondary to drug-relatedevents, including mild emesis and mild increases in serumcreatinine levels.

Cappellini et al.24 compared once-daily oral deferasiroxwith subcutaneous infusion of deferoxamine in a 1 year,open-label, multicenter, Phase III study in 586 patientswith β-thalassemia and transfusional hemosiderosis. Thestudy investigated the hypothesis that deferasirox was non-inferior to deferoxamine, based on the primary endpoint ofmaintenance or reduction of baseline LIC. Patients wererandomized 1:1, and LIC was used to assign the dose of ei-ther agent. Patients with LIC of 2–3 mg/g dw received ei-ther deferasirox 5 mg/kg or deferoxamine 20–30 mg/kg(group 1). Patients with LIC between 3 and 7 mg/g dwwere randomized to receive deferasirox 10 mg/kg or defer-oxamine 25–35 mg/kg (group 2). Patients with baselineLIC of 7–14 mg/g dw received either deferasirox 20mg/kg or deferoxamine 35–50 mg/kg (group 3), and those

with LIC greater than 14 mg/g dw received either de-ferasirox 30 mg/kg or 50 mg/kg or more of deferoxamine(group 4). LIC was measured by liver biopsy (84% of pa-tients) or by magnetic susceptometry using SQUID. Fifty-one percent of the patients in this study were 16 years ofage or younger (range 2–53).

The absolute reduction in LIC for all patients was –2.4± 8.2 (deferasirox) and –2.9 ± 5.4 (deferoxamine), whichwere each statistically significant from baseline (p <0.001). However, all groups with baseline LIC less than 7mg/g dw showed marked differences in each group at theend of 1 year (LIC 4 ± 3.8 with deferasirox, 0.13 ± 2.2with deferoxamine). Dosing by LIC category in the treat-ment arms was disproportionate, which affected the non-inferiority analysis. There was a less than twofold differ-ence in the average daily dose of deferoxamine betweenthe highest and lowest dosing categories compared with afivefold difference in the deferasirox dosing categories,which means that patients with baseline LICs less than 7mg/g dw received lower doses of deferasirox (5–10 mg/kg),while those in the deferoxamine comparator arm receivedcorrespondingly higher doses of deferoxamine. Successcriteria after 1 year of treatment were defined by an LICfrom 1 to less than 7 mg/g dw for patients with a baselineLIC of 10 mg/g dw or less, and a decrease by 3 mg/g dwor more for patients who had an LIC of 10 mg/g dw orhigher at baseline.24

Overall success rates were 52.9% with deferasirox and66.4% with deferoxamine. Non-inferiority was achieved inpatients with LICs of 7 mg/g dw or higher. Changes in LICfrom baseline to end of study (EOS) were significant anddose-dependent for both treatments. Deferasirox doses of20 and 30 mg/kg produced stable or decreasing LIC levelsover 1 year (p < 0.001). Dose-dependent increases in LICwere found in patients receiving deferasirox 5 and 10mg/kg. There was a dose-dependent effect on ferritin forboth treatment arms, which paralleled the changes in LIC.Serum ferritin levels at baseline and EOS, respectively, forgroup 1 were 1532 and 2532 µg/L for deferasirox and1232 and 836 µg/L for deferoxamine. In group 2, ferritinlevels were 1881 µg/L at baseline and 2543 µg/L at EOSfor deferasirox, and 1469 µg/L at baseline and 1518 µg/Lat EOS for deferoxamine. For group 3, ferritin baselineand EOS levels, respectively, were 1954 and 2032 µg/Lfor deferasirox and 2041 and 1845 µg/L for deferoxamine.Group 4 had serum ferritin levels of 3318 µg/L at baselineand 2069 µg/L at EOS for deferasirox and 2542 µg/L atbaseline and 1920 µg/L at EOS for deferoxamine. Overall,deferasirox doses of 5 and 10 mg/kg led to increasingserum ferritin levels over time, 20 mg/kg doses led to sta-ble ferritin levels, and doses of 30 mg/kg led to decreasedferritin levels. The number of blood transfusions was simi-lar in both groups.24





Of note, during the New Drug Application hearings, thevalidity of SQUID was questioned in this study24; the LICsmeasured by SQUID in this trial were found to have variedsubstantially among the study institutions. SQUID wasfound to have underestimated LIC by a factor of 2 com-pared with LIC measured by liver biopsy.25 Novartis askedthat patients whose LIC had been measured by SQUID(16%) be excluded from the efficacy analysis for FDA ap-proval. The rationale was that the initial deferasirox dosewas based on LIC and, because SQUID measurement un-derestimated the LIC measured by biopsy, patients whosedose was determined on this basis were apparently under-dosed.

Generally, deferasirox was well tolerated, with the mostcommon adverse effects presenting as mild, transient gas-trointestinal disturbances and skin rashes. There were nofindings of agranulocytosis, arthropathy, growth failure,bone changes, or sensorineural toxicity. Four deaths (1with deferasirox, 3 with deferoxamine) were consideredunrelated to the study drugs. Three patients in the de-ferasirox arm discontinued therapy due to moderate in-creases in transaminase levels in association with increasedserum ferritin levels. Once-daily oral deferasirox taken formore than 1 year had a statistically significant decrease inLIC similar to that seen with the use of deferoxamine; thiseffect was dose-dependent, with a better response in pa-tients taking 20 and 30 mg/kg.24

Several ongoing studies are evaluating the use of de-ferasirox for iron overload in sickle cell disease and myelo-dysplastic syndrome. Data are not yet available from thesestudies.

Adverse Drug Reactions and Drug Interactions

From all trials to date, the most commonly reported ad-verse effects with deferasirox were transient, includingnausea (10%), vomiting (9%), abdominal pain (14%), diar-rhea (12%), and skin rash (8%).12,14,19,21-24,26 These effectsrarely caused discontinuation of the study drug. Skin rashwas usually erythematous and maculopapular and tendedto occur about 1 week after starting high-dose therapy (40mg/kg).12 Some mild increases in serum creatinine levelswere observed; these appear to be dose-related. In patientswith β-thalassemia, 3% overall had serum creatinine val-ues that increased more than 33% above baseline but werestill within normal range. In patients who exhibited theseserum creatinine elevations, the daily dose was decreasedby 10 mg/kg. In patients with rare anemias, such as Black-fan–Diamond syndrome, this percentage increased to 16%.However, no cases of moderate-to-severe renal impair-ment or renal failure have been observed in any of the tri-als to date. Also of note, there have been no cases of agran-ulocytosis, an effect that is associated with deferoxamine,seen in any patient who has taken deferasirox in any of the

trials to date. This is a chronic therapy, and long-term fol-low-up of patients receiving deferasirox will be importantto assess adverse effects that may occur with long-termuse. Studies are planned to evaluate duration of use longerthan 1 year.

Drug-induced hepatitis confirmed by liver biopsy lead-ing to drug discontinuation has been seen in 2 patients inone clinical trial.24 In this study, 25 additional patients hadincreased alanine aminotransferase (ALT) levels more than5 times the upper limit of normal at 2 or more post-base-line visits. Two patients were discontinued from the studydue to increased ALT levels. The increases in transaminas-es did not appear to be dose related. Liver function testsshould be performed monthly during deferasirox treatmentand dose adjustments should be considered for patientswith persistent or severe elevations.15

Both ocular and auditory function were assessed in clin-ical trials; disturbances, including high-frequency hearingloss, lens opacities, cataracts, and elevations in intraocularpressure, were reported at less than a 1% incidence overall.Ophthalmic and auditory tests are recommended beforestarting treatment and at yearly intervals. If abnormalitiesare found on examination, dose reduction or discontinua-tion should be considered.15

In healthy volunteers, deferasirox has shown no effecton the pharmacokinetics of digoxin.15 It is unknown at thistime what the potential effects of digoxin on deferasiroxpharmacokinetics may be, as this has not been studied. Po-tential interactions with hydroxyurea, vitamin C, or alu-minum-containing antacids have not been evaluated. De-ferasirox has a lower affinity for aluminum than for iron; itis recommended to avoid concomitant use of deferasiroxwith aluminum-containing antacids. To date, the only es-tablished contraindication to deferasirox is prior hypersen-sitivity to the drug.15

Special Populations

Deferasirox has not been studied in women who arepregnant or breast-feeding, or in pediatric patients youngerthan 2 years.

Thirty patients 65 years of age and older have been in-cluded in clinical trials of deferasirox, with the majority (n= 27) having myelodysplastic syndrome. Caution shouldbe used in patients older than 65 years due to a greater fre-quency of decreases in hepatic, renal, or cardiac function.15

Deferasirox has been studied in pediatric patients 2years of age and older with β-thalassemia. In an open-la-bel, 48 week, multicenter study of 40 pediatric patients, pa-tients were stratified by age into 2 groups: those aged from2 to less than 12 years of age, labeled “children,” and those12–17 years of age, labeled “adolescents” (mean age forall patients: 10.4 y).26 All patients initially received de-ferasirox 10 mg/kg, and the dose was increased after 12




weeks if indicated by increases in LIC and serum ferritinlevels. Safety was monitored by assessing adverse effects,hematology, blood and urine chemistry, vital signs, ECG,ophthalmology and auditory tests, and growth parameters.LIC was measured at baseline and at 4, 12, 24, 36, and 48weeks by SQUID.

While dose increases were allowed after week 12, only21 patients (14 children, 7 adolescents) required an in-crease. Three patients had dose increases before week 20,3 had increases between weeks 20 and 24, and the remain-ing patients had dose increases after 34 weeks. Only 1 sub-ject required a dose increase to 30 mg/kg. Serum ferritintrends were similar in all patients. The amount of iron re-moved by deferasirox at the doses used (10–20 mg/kg)was too low to counterbalance iron intake, which wasclose to the upper limit of standard transfusion requirementsin β-thalassemia (0.46 mg/kg). Iron intake was marginallygreater than calculated iron excretion. Deferasirox was welltolerated, with mild, transient nausea reported in 2 adoles-cents and skin rash reported in 2 children, 1 of which led tostudy drug discontinuation. One patient exhibited increasedtransaminase levels, which normalized after dose interrup-tion and did not recur with continuation of the study drug.There were no reports of agranulocytosis, thrombocytope-nia, arthralgia, increases in serum creatinine, or growth ab-normalities. This study used lower doses compared withprevious data in adults, and the dose used (10 mg/kg) wastoo low to maintain a negative iron balance.26

This initial starting dose for pediatric patients 2 years orolder is 20 mg/kg/day, and dose modifications are the sameas for adult patients.

Dosage and Administration

Deferasirox is an orally active iron chelator provided as125, 250, and 500 mg tablets that are to be dispersed innoncarbonated water, orange juice, or apple juice, and in-gested orally once daily. Doses less than 1 g should be dis-persed in 3.5 ounces of liquid and doses more than 1 gshould be dispersed in 7 ounces of liquid. Dispersion of thetablet typically takes approximately 3 minutes of manualstirring. After the suspension is swallowed, any remainingresidue should be resuspended in a small volume of liquidand swallowed. Deferasirox should be taken on an emptystomach 30 minutes before eating.15

The recommended starting dose is 20 mg/kg and shouldbe rounded to the nearest available tablet strength. It is rec-ommended that therapy begin when a patient has evidenceof chronic iron overload, such as transfusion of approxi-mately 100 mL/kg of packed red blood cells and a serumferritin level higher than 1000 µg/L. Serum ferritin shouldbe monitored monthly, and the dose of deferasirox shouldbe adjusted every 3–6 months as needed. Dose adjust-ments should be made in increments of 5–10 mg/kg. If

serum ferritin is consistently less than 500 µg/L after start-ing therapy, interruption of therapy should be considered.Doses of deferasirox greater than 30 mg/kg/day should beused with caution.15

Summary

Deferasirox is a new drug within a class of agents thatcan now be given orally for the treatment of transfusion-re-lated iron overload in patients 2 years of age and olderwith chronic anemias that require multiple transfusions overlong periods of time. Current data show deferasirox to be aseffective as the current treatment of choice, subcutaneous de-feroxamine administered over 8–12 hours, 5–7 days perweek. Adverse effects are relatively mild and transient andare most likely to include nausea, abdominal pain, diarrhea,and skin rash. There are no cases reported to date of any de-velopment of agranulocytosis with the use of deferasirox. Be-cause deferasirox is administered once daily in an oral for-mulation, patient adherence to this therapy may be improvedover that with use of long subcutaneous infusions.

Further studies are ongoing to assess the use of de-ferasirox in sickle cell disease patients and myelodysplas-tic syndrome patients with chronic iron overload. To date,no data exist on the effects of deferasirox in pregnancy,lactation, hepatic insufficiency, or renal insufficiency. De-ferasirox should be avoided with aluminum-containingantacids. Other drug interactions have not been studied.

Deferasirox represents a significant advancement in thetreatment of chronic iron overload and could help manypatients who are unable to comply with the current stan-dard of care.

Heidi E VanOrden PharmD, Senior Clinical Pharmacist, Centerfor Cancer and Blood Disorders, Children’s Medical Center of Dallas,Dallas, TXTracy M Hagemann PharmD, Associate Professor, Departmentof Pharmacy: Clinical and Administrative Sciences, College of Phar-macy, University of Oklahoma, Oklahoma City, OK Reprints: Dr. Hagemann, Department of Pharmacy: Clinical andAdministrative Sciences, College of Pharmacy, University of Okla-homa, 1110 N. Stonewall Ave., Oklahoma City, OK 73117-1223, fax405/271-6430, [email protected]

References

1. Porter JB. Practical management of iron overload. Br J Haematol 2001;115:239-52.

2. Kushner JP, Porter JP, Oliveri NF. Secondary iron overload. Hematology(Am Soc Hematol Educ Program) 2001:47-61.

3. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complicationsof beta-thalassemia major in North America. Blood 2004;104:34-9.

4. deVirgiliis S, Sanna G, Cornacchia G, et al. Serum ferritin, liver ironstores, and liver histology in children with thalassemia. Arch Dis Child1980;55:43-5.

5. Lo L, Singer ST. Thalassemia: current approach to an old disease. PediatrClin North Am 2002;49:1165-91.

6. Porter JB, Davis BA. Monitoring chelation therapy to achieve optimaloutcome in the treatment of beta-thalassemia. Best Pract Res ClinHaematol 2002;15:329-68.






The Annals of Pharmacotherapy n 2006 June, Volume 40 n 1117www.theannals.com

7. Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibilitymeasurement of human iron stores. N Engl J Med 1982;307:1671-5.

8. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment ofthalassemia. Blood 1997;89:739-61.

9. Olivieri NF. The beta-thalassemias. N Engl J Med 1999;341:99-109.10. Committee for Orphan Medicinal Products. Public summary of positive

opinion for orphan designation of 4-(3,5-bis-(hydroxyl-phenyl)-1,2,4)tri-azol-1-yl)-benzoic acid for the treatment of chronic iron overload requir-ing chelation therapy. London: European Medicines Agency, 2003 Jan 8.

11. Nick H, Wong A, Acklin P, et al. ICL670A: preclinical profile. Adv ExpMed Biol 2002;509:185-203.

12. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safetyof ICL670 in iron-loaded patients with thalassaemia: a randomized, dou-ble-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361:1597-602.

13. National Horizon Scanning Center. Deferasirox (ICL670) for iron over-load. Jan 2005. www.pcpoh.bham.ac.uk/publichealth/horizon (accessed2005 Jun 20).

14. Galanello R, Piga A, Alberti D, et al. Safety, tolerability, and pharma-cokinetics of ICL670, a new orally active iron-chelating agent in patientswith transfusion-dependent iron overload due to β-thalassemia. J ClinPharmacol 2003;43:565-72.

15. Package insert. Exjade (deferasirox). East Hanover, NJ: Novartis Phar-maceuticals, November 2005.

16. Barton JC. Deferasirox (Novartis). Curr Opin Investig Drugs 2005;6:327-35.

17. Hershko C, Konijin AM, Nick HP, et al. ICL670: a new synthetic oralchelator: evaluation in hypertransfused rats with selective radioironprobes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood 2001;97:1115-22.

18. Sergejew T, Forgiarini P, Schnebli HP. Chelator-induced iron excretion iniron-overloaded marmosets. Br J Haematol 2000;110:985-92.

19. Cappellini M. Iron-chelating therapy with the new oral agent ICL670(Exjade). Best Pract Res Clin Haematol 2005;18:289-98.

20. Novartis media release. Novartis files Exjade new drug applications fortreatment of chronic iron overload due to blood transfusions. May 3,2005. www.novartis.com (accessed 2005 May 14).

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EXTRACTO

OBJETIVO: Revisar la literatura disponible sobre la farmacología,farmacocinética, eficacia, toxicología, efectos adversos, interacciones dedrogas, y guías de dosificación para deferasirox, un producto en estudiosfase III.

FUENTES DE INFORMACIÓN: Los revisores buscaron en las bases de datosde estudios en el idioma inglés utilizado el motor de búsqueda deartículos MEDLINE (entre 1966 hasta abril de 2006), ExtractosFarmacéuticos Internacionales (del 1970 hasta abril de 2006), y la basede datos de la biblioteca Cochrane. Los términos claves usados en labúsqueda incluyeron quelación de hierro, quelación, sobrecarga dehierro, deferasirox, y ICL670.

SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Los datos sobre laeficacia, toxicología, efectos adversos, y farmacocinética se obtuvo deestudios clínicos aleatorio. Otra información se obtuvo de estudios nopublicados pero en disponibles como extractos (n = 4) con datosdisponibles sobre deferasirox del manufacturero.

SÍNTESIS: Deferasirox es un quelante de hierro oral. En los estudiosclínicos deferasirox demostró eficacia al tratar sobrecarga de hierro enpacientes con β-talasemia con dosis entre 20 y 30 mg/kg día. Se haestudiado en pacientes mayores de 2 años y aparenta ser seguro. Losefectos adversos mas comúnmente reportados son nausea, malestargastrointestinal, y sarpullido y estos son de leves y transitorios. Noexisten informes de reacciones adversas serias en estudios hasta elmomento.

CONCLUSIONES: Deferasirox representa una nueva estrateguia en elmanagejo de sobrecarga crónica de hierro en pacientes con anemiacrónica que requieren transfusiones de sangre. La literatura disponiblesugiere que deferasirox es tan segura y efectiva como la terapia estándaren dosis de of 20–30 mg/kg/day for β-talasemia. Se recomiendan másinvestigaciones para confirmar su eficacia en otras enfermedadescrónicas que requieren transfusiones.

Jorge R Miranda-Massari

RÉSUMÉ

OBJECTIF: Revoir la littérature disponible sur la pharmacologie, lapharmacocinétique, l’efficacité, la toxicologie, les effets secondaires, lesinteractions médicamenteuses, et les recommandations posologiques dudeferasirox, un médicament en phase III d’investigation.

SOURCE DE L’INFORMATION: Une recherche informatisée sur les banquesde données MEDLINE (1966–avril 2006), InternationalPharmaceutical Abstracts (1970–avril 2006), et la Cochrane LibraryDatabase a été effectuée. Les mots clés de recherche incluent: ironchelation, chelation, iron overload; deferasirox, et ICL670.

SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les données sur l’efficacité,la toxicité, les effets secondaires, et la pharmacocinétique furentobtenues à partir des études randomisées ouvertes ou à double-insu. Desinformations supplémentaires furent obtenues d’études publiées sousforme d’abrégé (n = 4) ainsi que du manufacturier.

RÉSUMÉ: Le deferasirox est un chélateur de fer actif par voie orale. Dansles études cliniques, le deferasirox a été démontré efficace dans letraitement de la surcharge de fer chez les patients avec β-thalassémie àdes doses de 20 et 30 mg/kg. Il a été étudié chez les patients âgés de plusde 2 ans et semble sécuritaire. Les effets secondaires les plus fréquentsétaient légers et impliquaient des nausées transitoires, des désordresgastrointestinaux, et un rash cutané. Aucun rapport d’effets secondairessérieux n’existe à ce jour.

CONCLUSIONS: Le déferasirox représente une nouvelle approche dans letraitement de la surcharge chronique en fer chez des patients souffrantd’anémie chronique et requerrant des transfusions sanguines. Lalittérature suggère que le deferasirox est sécuritaire et aussi efficace quele traitement standard à des doses de 20 à 30 mg/kg/jour pour la β-thalassémie. Des études supplémentaires seront nécessaires pourconfirmer l’efficacité auprès d’autres maladies requerrant régulièrementdes transfusions sanguines

Marc M Perreault



deferasirox--an oral agent for chronic iron overload

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