DRUG AND PROFILE REPORTS

Deferasirox: a guide to its use in transfusional chronic ironoverload

Adapted from Drugs 2007; 67 (15): 2211-30[1] associated with improvements in both myocardial ironload and in labile plasma iron.[1]

What is the rationale for developingthe drug? Who should receive the drug?Individuals with various anaemic conditions (including Deferasirox is approved for the treatment of

β-thalassaemia, sickle cell disease and myelodysplastic transfusional iron overload in both paediatric and adultsyndrome) require lifelong regular blood transfusions.[1]

populations.[4,5] Table I presents a summary of the dosageBecause the body does not actively excrete iron, excessive and administration, recommended monitoring andiron from transfusions can quickly accumulate to toxic pharmacokinetics of deferasirox.levels (e.g. within a few years), leading to organ Dosage adjustments of deferasirox should depend ondysfunction of the liver, heart, pituitary or pancreas and, patient response, serum ferritin trends, goal of therapyeventually, early death.[1]

(e.g. to maintain or to reduce body iron levels) and serumFor the last ≈40 years, deferoxamine has been the creatinine levels.[4,5] Temporary interruption of treatment

standard treatment for transfusional chronic iron overload, may be required if serum ferritin levels are consistentlywith beneficial effects on body iron levels, iron-overload <500 μg/L.complications and lifespan in adequately treated patients.[2]

Are there any important warnings?However, the burdensome administration (subcutaneousinfusion for ≥8 hours, 5–7 days per week) affects In postmarketing surveillance, there have been reportscompliance and leads to inadequate chelation in up to 50% of hepatic or renal failure, some with a fatal outcome, inof patients.[1] Deferiprone, an oral three-times daily patients treated with deferasirox.[4,5,9] Serum creatininechelator, demonstrated effective reduction of iron should be monitored,[4,9] particularly in patients who are atoverload,[3] but has had limited availability in the EU and increased risk of complications, have pre-existing renalis not approved in the US because of its association with conditions, are elderly, have co-morbid conditions or areneutropenia.[1]

receiving medicinal products that depress renal function.[9]

Deferasirox (Exjade®),1 the most recently approved Dosage reduction and/or temporary discontinuation mayiron chelator, is easily administered (i.e. orally once be required in patients who develop elevated serumdaily),[4,5] and is a valuable new option in the management creatinine.[4,9] Liver function should be monitoredof transfusional chronic iron overload.[1]

regularly and treatment with deferasirox should bemodified or interrupted if there are unexplained, persistentHow does the drug work?or progressive increases in serum transaminase levels.[9]

Deferasirox is a tridentate iron chelator with highaffinity for iron as Fe3+ and chelates at a ratio of 2 : 1(deferasirox : iron).[4,5] Deferasirox has minimal affinityfor other divalent metal ions such as zinc or copper, withno reported clinically significant reductions in plasma zincor copper levels.[1]

In a phase III trial,[6] ≈70% of patients receivingdeferasirox 20–30 mg/kg/day (the approved regimen)achieved net iron excretion or maintained iron balance.Those patients not achieving a beneficial effect withdeferasirox received lower dosages (i.e. <20 mg/kg/day).Data from smaller trials[1] also indicate that deferasiroxdosages of <20 mg/kg/day are unlikely to maintain netiron balance or result in net iron excretion. Preliminarydata indicate that deferasirox treatment of ≈1 year is

Adis EvaluationKey points in the overall evaluation of oral deferasirox intransfusional chronic iron overload

Clinical benefits

Maintains or reduces body iron, liver iron concentrations andserum ferritin levelsMay be preferred over deferoxamine treatmentMay result in greater life-long compliance, leading tolong-term benefitsClinically manageable tolerability profile

Potential limitations

Long-term efficacy and tolerability not establishedLack of data in patients with anaemias other thanβ-thalassaemia or with renal or severe hepatic impairmentLong-term pharmacoeconomic analyses would be of benefit

1 The use of trade names is for product identification purposes only and does not imply endorsement.

1172-0360/08/0002-001/$48.00 © 2008 Adis Data Information BV. All rights reserved.

2

Table I. Features and properties of oral deferasirox (Exjade®) in the treatment of patients (pts) withtransfusional chronic iron overload (including pts with β-thalassaemia, sickle cell disease,myeodysplastic syndrome and other rare chronic anaemias)[4,5,7,8]a

Indications in the EU

Pts aged ≥6 y with transfusional chronic iron overload due to β-thalassaemia major and requiring ≥7 mL/kg/mo of packed red bloodcells (PRBC)Pts aged 2–5 y with transfusional chronic iron overload due to other anaemias or β-thalassaemia major but with infrequent bloodtransfusion (<7 mL/kg/mo of PRBC) and who have contraindications to, or inadequate chelation from, subcutaneous deferoxamine

Indication in the US

Pts with any form of transfusional chronic iron overload aged ≥2 y

Dosage and administration

Initial and maintenance dosage EU: 10–30 mg/kg once dailyb

US: 20 mg/kg once daily

Dosage titration and adjustments Increments of 5–10 mg/kg/d at intervals of 3–6 mo

Maximum dosage 30 mg/kg once daily

Timing At approximately the same time each day, on an empty stomach 30 min prior to food

Preparation Tablets should be dispersed in water, or orange or apple juice

Availability

125, 250 or 500 mg tablets for oral suspension

Monitoring requirements

Serum ferritin, creatinine clearance, serum creatinine, proteinuria, liver function, blood counts

Pharmacokinetic profile (at steady state after multiple dosages of 20 mg/kg/d in patients with β-thalassaemia)

Bioavailability 70%

Time to steady state 3 d

Mean peak plasma concentration (Cmax) 95–107 μmol/L

Median time to Cmax 1–2 h

Mean area under the plasma time- 1001–1279 μmol • h/Lconcentration curve from time zero to 24 h

Plasma protein binding ≈99%

Apparent volume of distribution 14.37 L

Metabolism Primarily by hepatic glucuronidation with biliary excretion of metabolites

Primary route of elimination Faecal (83%)

Mean elimination half-life 8.6–9.8 h

Most frequent adverse events in clinical trials

Nausea, vomiting, abdominal pain, constipation, diarrhoea, skin rash

a Local prescribing information should be consulted for further information.

b Dosage is dependent on aim of therapy: 10 mg/kg/d is appropriate if body iron reduction is not required and receiving <7 mL/kg/mo ofPRBC; 30 mg/kg/d is appropriate if requiring body iron reduction and receiving >14 mL/kg/mo of PRBC.

Patients should also have regular monitoring of blood liver iron concentrations and serum ferritin levels. Thecounts and treatment should be interrupted in patients who underlying anaemic condition was predominantly β-develop unexplained cytopenia.[9] thalassaemia;[6,7,10] other conditions included sickle cell

disease,[11] myelodysplastic syndrome[10] or other rareAre there any important drug interactions?chronic anaemias.[10] Data from these trials are

At therapeutic dosages, deferasirox does not induce orsummarized in table II.

inhibit cytochrome P450 enzymes.[1] ConcomitantNoninferiority of deferasirox over deferoxamine wasadministration of deferasirox with aluminium-containing

not achieved in the phase III trial in patients with β-antacids, vitamin C doses of >200 mg or other ironthalassaemia.[6] However, noninferiority was established inchelators is not recommended.[4,5]

a predefined subgroup analysis comparing the effect ofWhat is the efficacy of the drug? deferasirox 20–30 mg/kg/day with that of deferoxamine

41–51 mg/kg/day on liver iron concentration. Data fromIn clinical trials with a duration of ≈1 year, deferasirox20–30 mg/kg/day was effective in reducing or maintaining all trials indicate that only deferasirox dosages of ≥20 mg/

Drugs Ther Perspect 2008; Vol. 24, No. 2

Table II. Efficacy of oral deferasirox (DFX) in patients (pts) with transfusional chronic iron overload. In threetrials,[6,7,11] initial dosages of either study drug were dependent on baseline liver iron concentration (LIC);pts with baseline LIC of 2–3, >3–7, >7–14 or >14 mg Fe/g dry weight (dw) received DFX 5, 10, 20 or 30 mg/kg/d orally once daily or deferoxamine (DFO) 20–30, 25–35, 35–50 or ≥50 mg/kg/d administered over8–12 h by subcutaneous infusion for 5[6,11] or 7[11] days each week. In the remaining trial,[7] study drugdosages were predefined and not based on baseline LIC; DFO was administered over 5 consecutive dayseach weekStudy (duration; wk) Underlying disorder Pts age Regimen (mg/kg/d) Success/response Mean change from

(y) [no. of pts] ratea (% of pts) baseline LIC (mg Fe/g dw)

Randomized, open-label comparisons with DFO

Cappellini et al.[6] (52) β-Thalassaemia ≥2 DFX 5–30 [276] 52.9b –2.4

DFO 20 to ≥50 [277] 66.4b –2.9

Piga et al.[7] (48) β-Thalassaemia ≥18 DFX 10 [24] 45.8 –0.4

DFX 20 [24] 72.7 –2.1

DFO 40 [23] 76.2 –2.0

Vichinsky et al.[11] (52) Sickle cell disease ≥2 DFX 5–30 [132] –3.0**

DFO 20 to ≥50 [63] –2.8*

Noncomparative trial

Porter et al.[10] (52) Various anaemiasc ≥2 DFX 5–30 [184] 56.4 –4.2**

a Success was defined as the proportion of pts achieving LIC maintenance and/or reductions at study end to 1 to <7 mg Fe/g dw (ifbaseline LIC <10 mg Fe/g dw)[6,10] or LIC reduction of ≥3 mg Fe/g dw at study end (if baseline LIC ≥10 mg Fe/g dw); response wasdefined as a >10% reduction in LIC.[7]

b Primary endpoint. Noninferiority of DFX over DFO was established in pts receiving DFX ≥20 mg/kg/d or DFO ≥41 mg/kg/d.

c β-Thalassaemia, myelodysplastic syndrome, Diamond-Blackfan anaemia and other anaemias.

* p < 0.05, ** p < 0.001 vs baseline.

kg/day have a beneficial effect on liver iron concentration disease or myelodysplastic syndrome.[1] Incremental(table II). quality-adjusted life years gained with deferasirox relative

to deferoxamine in patients with β-thalassaemia wereSerum ferritin levels were maintained with deferasiroxmainly attributed to patient preference for an oral iron20 mg/kg/day and were reduced with deferasirox 30 mg/chelator.[1]kg/day (mean changes from baseline were –36 and

–926 μg/L, respectively).[6] The corresponding dosages ofWhat are its adverse effects?deferoxamine reduced serum ferritin by 364 (41 mg/kg/

day) and 1003 μg/L (51 mg/kg/day). Extension studies In ≈1-year clinical trials, deferasirox was associated(<4 years duration) also reported maintenance or reduction with a clinically manageable tolerability profile.[1] Mostserum ferritin levels with deferasirox 20 or 30 mg/kg/ adverse events were of mild severity and usually resolvedday.[1]

spontaneously. The most common treatment-relatedadverse events in deferasirox recipients wereIs it preferred over standard treatment?gastrointestinal (nausea, vomiting, abdominal pain,

In preliminary data, patients with β-thalassaemia or constipation and diarrhoea) and skin rash. These adversesickle cell disease reported greater satisfaction and events, as well as increased serum creatinine, were doseconvenience and less time lost to treatment with related and, in some cases, required dosage interruptionsdeferasirox relative to with deferoxamine.[1] After or reductions. The most frequently reported adverse events52 weeks of treatment, 84% and 86% of deferasirox in the phase III trial[6] are presented in figure 1.recipients were willing to continue treatment, compared Elevated serum creatinine levels may develop duringwith only 11% and 14% of deferoxamine recipients.[1]

treatment with deferasirox, although the relationshipbetween the rate of iron excretion and increase in serum

Is the drug cost effective? creatinine levels requires further study.[4] Most increasesin serum creatinine levels resolve spontaneously or withPharmacoeconomic analyses conducted from a US ordose reduction or interruption.[1]UK healthcare payer perspective suggest that deferasirox

is a cost-effective treatment relative to branded or generic Elevated serum creatinine was reported in 36%[11] anddeferoxamine in patients with β-thalassaemia, sickle cell 38%[6] of deferasirox recipients in clinical trials. Although

1172-0360/08/0002-003/$48.00 © 2008 Adis Data Information BV. All rights reserved.

4

may be of particular importance in the management ofpatients who are currently adequately treated withdeferoxamine.[14]

References1. Yang LPH, Keam SJ, Keating GM. Deferasirox: a review of its

use in the management of transfusional chronic iron overload[published erratum appears in Drugs 2007; 67 (16): 2333]. Drugs2007; 67 (15): 2211-30

2. Roberts DJ, Rees D, Howard J, et al. Desferrioxamine mesylate formanaging transfusional iron overload in people with transfusion-dependent thalassaemia. Cochrane Database System Rev 2005; (4):CD004450

3. Roberts DJ, Brunskill SJ, Doree C, et al. Oral deferiprone for ironchelation in people with thalassaemia. Cochrane Database SystemRev 2007 Jul 18; (3): CD004839

4. European Medicines Agency. Exjade: summary of product charac-teristics [online]. Available from URL: http://www.emea.europa.eu[Accessed 2007 Dec 17]

5. Exjade® (deferasirox tablets for oral suspension): US prescribinginformation. East Hanover, New Jersey: Novartis Pharmaceuticals

0 5 10 15 20 25

Pyrexia

Headache

Abdominal pain

Cough

Nasopharyngitis

Diarrohea

Creatinine increase1

Influenza

Nausea

Pharyngolaryngeal pain

Vomiting

Respiratory tract infection

Bronchitis

Rash

Pharyngitis

Back pain

Incidence (% of pts)

DFX (n = 296)DFO (n = 290)

θ

Fig. 1. Tolerability of oral deferasirox (DFX) or subcutaneousdeferoxamine (DFO) in patients (pts) with transfusional chronic ironoverload due to β-thalassaemia. Adverse events with ≥8% incidencein either treatment arm in a 48-wk, randomized, open-label, phase IIItrial[6] reported in the US prescribing information.[5] Pts received DFXonce daily or DFO infused over 8–12 h for 5–7 days each week.1 Includes ‘blood creatinine increased’ and ‘blood creatinineabnormal’. Corporation, 2007 Apr

6. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study ofdeferasirox (ICL670), a once-daily oral iron chelator, in patientselevated serum creatinine levels generally remained withinwith β-thalassemia. Blood 2006 May 1; 107 (9): 3455-62the normal range,[6,12] one trial[10] reported increased serum

7. Piga A, Galanello R, Forni GL, et al. Randomized phase II trial ofcreatinine levels to >33% of baseline in 40% ofdeferasirox (Exjade®, ICL670), a once-daily, orally-administered

deferasirox recipients. Deferasirox was also associated iron chelator, in comparison to deferoxamine in thalassemia pa-tients with transfusional iron overload. Haematologica 2006 Jul; 91with increased ALT levels in some patients.[1]

(7): 873-80Postmarketing cases (some with fatalities) of renal

8. Galanello R, Piga A, Alberti D, et al. Safety, tolerability, andfailure, hepatic failure or cytopenia have been reported in pharmacokinetics of ICL670, a new orally active iron-chelating

agent in patients with transfusion-dependent iron overload due todeferasirox recipients, most of whom had significant co-beta-thalassemia. J Clin Pharmacol 2003 Jun; 43 (6): 565-72morbidities.[9]

9. Important information about Exjade (deferasirox) tablets for oralsuspension [online]. Available from URL: http://www.fda.gov [Ac-cessed 2007 Dec 17]What is the current positioning of

10. Porter J, Vichinsky E, Rose C, et al. A phase II study with ICL670the drug?(Exjade®), a once-daily oral iron chelator, in patients with varioustransfusion-dependent anemias and iron overload [abstract no.3193]. Blood 2004 Nov 16; 104 (11 Pt 1): 872a. Plus posterThe benefits of iron chelation therapy in the treatmentpresented at the 46th Annual Meeting and Exposition of the Amer-of patients with transfusional chronic iron overload areican Society of Hematology; 2004 Dec 4-7; San Diego (CA)

undisputed.[13] Accumulated excess iron must be slowly11. Vichinsky E, Onyekwere O, Porter J, et al. A randomised compari-

removed to avoid toxicity due to over chelation;[13]son of deferasirox versus deferoxamine for the treatment of trans-fusional iron overload in sickle cell disease. Br J Haematol 2007therefore, early initiation of chelation therapy is desired.Feb; 136 (3): 501-8Despite its efficacy, subcutaneous deferoxamine is often

12. Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluationassociated with noncompliance.[1]

of deferasirox, a once-daily oral chelating agent, in pediatric pa-tients with β-thalassemia major. Haematologica 2006 Oct; 91 (10):Oral deferasirox provides an easily administered and1343-51effective alternative in an area with few treatment options.

13. Kushner JP, Porter JP, Olivieri NF. Secondary iron overload.However, as most patients require lifelong chelationHematology Am Soc Hematol Educ Program 2001: 47-61

therapy, it should be noted that the long-term efficacy14. Neufeld EJ. Oral chelators deferasirox and deferiprone for transfu-

(prevention of iron overload-related complications and sional iron overload in thalassemia major: new data, new ques-death) and safety of deferasirox are not established. This tions. Blood 2006 May 1; 107 (9): 3436-41

Drugs Ther Perspect 2008; Vol. 24, No. 2