Deferiprone

Hosp Pharm 2012;47(2):1291362012 ! Thomas Land Publishers, Inc.www.thomasland.comdoi: 10.1310/hpj4702-129

Formulary Drug ReviewsDeferiprone

Dennis J. Cada, PharmD, FASHP, FASCP (Editor)p; Terri L. Levien, PharmD;and Danial E. Baker, PharmD, FASHP, FASCP

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documentedmonographs on drugs that are newly released or are in late phase 3 trials. The monographs aretargeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-pagesummary monographs on agents that are useful for agendas and pharmacy/nursing in-services. Acomprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is alsoprovided each month. With a subscription, the monographs are sent in print and are also availableon-line. Monographs can be customized to meet the needs of a facility. Subscribers to The For-mulary Monograph Service also receive access to a pharmacy bulletin board, The FormularyInformation Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy arediscussed on The F.I.X.Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in thiscolumn. For more information about The Formulary Monograph Service or The F.I.X., call TheFormulary at 800-322-4349. The February 2012 monograph topics are on rivaroxaban in non-valvular atrial fibrillation, zolpidem tartrate sublingual, aflibercept, glucarpidase, and mipomersen.The DUE/MUE is on zolpidem.

Generic Name: DEFERIPRONE

Proprietary Name: Ferriprox (ApoPharma)

Approval Rating: 1S

Therapeutic Class: Detoxification Agents; IronChelators

Similar Drugs: Deferasirox, Deferoxamine

Sound- or Look-AlikeNames: Deferasirox, Deferoxamine,

Ferrlecit

INDICATIONSDeferiprone is indicated for the treatment of trans-

fusional iron overload due to thalassemia syndromeswhen current chelation therapy is inadequate.1

Several forms of severe anemia require regular redblood cell transfusion, including beta-thalassemia, sickle-cell disease, Diamond-Blackfan anemia, and myelodys-plastic syndrome. With repeated transfusions, patients

accumulate iron, resulting in the formation of hemosid-erins (insoluble ferritin) in tissues. Hemosiderin forma-tion can result in congestive heart failure and death if leftuntreated. The long-term consequences of iron toxicityalso include cirrhosis and endocrine disorders. Iron che-lators are used to mobilize the iron deposits by forminga soluble complex between the chelator and iron thatcan be excreted in the urine and/or feces.2 The US Foodand Drug Administration (FDA)approved indicationsfor the available iron chelators are compared in Table1. Deferiprone labeling includes a statement that safetyand effectiveness have not been established for thetreatment of transfusional iron overload associated withchronic anemias other than thalassemia syndromes.1

CLINICAL PHARMACOLOGYDeferoxamine, a parenteral iron chelator with 1:1

stoichiometry for iron, is highly effective and has fewtoxic effects. Although it has been shown to preventiron-induced heart disease and extend life, it is ad-ministered as an intravenous (IV) or slow subcutaneousinfusion over a period of 8 to 12 hours, 5 to 7 times

*Executive Editor, The Formulary; Clinical Associate Professor of Pharmacotherapy, Drug Information Center, WashingtonState University, Spokane, Washington; Director, Drug Information Center, and Professor of Pharmacy Practice, College ofPharmacy, Washington State University Spokane, PO Box 1495, Spokane, Washington 99210-1495. The authors indicate norelationships that could be perceived as a conflict of interest.

Hospital Pharmacy 129

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a week, resulting in less than optimal adherence bymany patients.5 Deferiprone, with 3:1 stoichiometryfor iron, is a less efficient iron chelator than deferox-amine. In addition, it is quickly converted to an in-active form by glucuronidation and is an effectivechelator only for a relatively short period of time afteroral administration.5 It is administered orally, has anadverse effect profile that differs from that of defer-oxamine, and has been studied in conjunction withdeferoxamine.

Table 1 compares the pharmacology of deferox-amine, deferiprone, and deferasirox. Deferiprone hasa lower binding affinity for copper, aluminum, andzinc than for iron.1

Studies have not been conducted to assess therelationship between the deferiprone dose and theamount of iron eliminated from the body.1

PHARMACOKINETICSDeferiprone is rapidly absorbed from the upper

gastrointestinal (GI) tract following oral administra-tion, appearing in the blood within 5 to 10 minutes ofadministration. Peak serum concentrations occurwithin approximately 1 hour under fasting conditionsand in up to 2 hours in the fed state. Administrationwith food also resulted in a 38% increase in the peakconcentration and a 10% increase in exposure; how-ever, deferiprone may be administered with or withoutfood.1,6

The deferiprone elimination half-life is 1.9 hours.1,6

Deferiprone is metabolized primarily via UDG glu-

curonosyltransferase (UGT) 1A6. The major metabo-lite, 3-O-glucuronide, lacks iron-binding capability.1

More than 90% of the dose is eliminated from plasmawithin 5 to 6 hours after ingestion.1 Deferiprone-chelated iron is detected rapidly following oral de-feriprone administration, with peak values observedin 60 to 120 minutes.6

COMPARATIVE EFFICACYThe FDA-approved indication, treatment of

patients with transfusion-dependent iron overload inwhom previous iron chelation therapy has failed or isconsidered inadequate because of poor tolerance, isbased on a pooled analysis from several studies. Datafrom 236 patients were analyzed. A 20% reduction inserum ferritin was achieved in 50% of patients (95%confidence interval [CI], 43-57). An increase in cardiacMRI T2p (pronounced T2 star) from a mean atbaseline of 11.8 ms to a mean of 15.1 ms was observedafter approximately 1 year of treatment; the clinicalsignificance of this observation is not known.1

Current guidelines for the management of thal-assemia major recommend initiation of deferoxaminetherapy as soon as transfusions have deposited enoughiron to cause tissue damage (after the first 10 to 20transfusions or when the ferritin level rises above1,000 mcg/L). Only deferoxamine, the first availableiron chelator used in the treatment of iron overload inthalassemia, has been proven to improve survival.European and US labeling recommends use of defer-iprone only as a second-line therapy in patients in

Table 1. Comparison of US Food and Drug Administration (FDA)approved iron chelation agents1-4

Deferasirox Deferiprone Deferoxamine

Brand name (manufacturer) Exjade (Novartis) Ferriprox (ApoPharma) Desferal (Novartis)

Pharmacology Tridentate molecule; 2:1stoichiometry for iron

Bidentate molecule; 3:1stoichiometry for iron

Hexadentatemolecule; 1:1stoichiometry for iron

Route of administration Oral Oral IV

Indications

Treatment of chronic ironoverload due to bloodtransfusions

Patients 2 yearsand older


Treatment of transfusional ironoverload due to thalassemiasyndromes when currentchelation therapy is inadequate

Adults

Treatment of acute ironintoxication


Note: IV5 intravenous.

130 Volume 47, February 2012

Formulary Drug Reviews

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whom deferoxamine is contraindicated or inadequate.Guidelines suggest combined regimens may be usefulwhenmonotherapy is inadequate, particularly in patientswith very high levels of heart iron or cardiac dysfunc-tion.1,7 In a Cochrane review of 10 studies involving 398patients with thalassemia, the authors concluded therewas no reason to change current treatment recom-mendations that suggest deferiprone be used when de-feroxamine is contraindicated or inadequate. Althoughseveral studies compared deferiprone with deferoxa-mine, none reported long-term outcomes such as mor-tality or end-organ damage. Pronounced differences inthe baseline characteristics in the included studiesand the individual study endpoints precluded pooling ofthe study results.8 An additional meta-analysis of ran-domized studies of iron chelation therapies revealeda high level of bias and poor study quality amongstudies of iron chelation agents in patients with thalas-semia. No one agent was observed to be more effectivethan the others. Ejection fraction was higher aftercombined therapy with deferoxamine and deferiprone orsequential deferoxamine/deferiprone therapy comparedwith any individual agent. Liver iron concentration wasalso reduced to a greater extent with deferiprone plusdeferoxamine. Myocardial iron did not differ betweenregimens.9 Several additional studies have demonstratedenhanced effects on serum ferritin with combined orsequential regimens of deferoxamine and deferipronecompared with deferoxamine or deferiprone mono-therapy.10-14

In a randomized study comparing deferiprone 75mg/kg/day and deferoxamine 50 mg/kg/day for 1 yearin 144 patients with thalassemia major and serumferritin between 1,500 and 3,000 ng/mL, serum ferritinwas reduced to a similar extent in the 2 treatmentgroups. Reductions in liver and heart iron contentmeasured by magnetic resonance and liver fibrosisscores and heart function assessed by ultrasound alsodid not differ between groups.15 In another random-ized controlled trial comparing deferoxamine mono-therapy, deferiprone monotherapy, sequential therapywith deferiprone and deferoxamine, and combinedtherapy with deferiprone and deferoxamine in 265patients with thalassemia major, deferoxamine mon-otherapy was associated with an increased risk ofdeath. Increased mortality in the deferoxamine grouprelative to the other treatment groups was primarilyrelated to heart damage.16 Improved cardiac disease-free survival with deferiprone compared with defer-oxamine was also noted in a retrospective analysis ofpatients treated with either agent for at least 4 years ina single center.17

A potential benefit with deferiprone was suggestedin patients with myocardial iron overload, although anadvantage relative to other therapies has not beenproven. In a prospective randomized, controlled trialcomparing deferiprone with deferoxamine in 61patients with thalassemia major who had previouslybeen maintained on subcutaneous deferoxamine,myocardial siderosis (myocardial T2p) was improvedto a greater extent with deferiprone (27% vs 13%, P5.023). Left ventricular ejection fraction, right ventric-ular ejection fraction, and end-systolic volume werealso increased to a greater extent with deferiprone.Changes in liver iron and serum ferritin were similarbetween treatments.18,19 In another cohort of patientswith thalassemia major treated with iron chelatormonotherapy for at least 1 year and identified througha registry, myocardial T2p was higher in the defer-iprone-treated patients than in those treated with de-ferasirox or deferoxamine (P 5 .0001). Higher leftventricular ejection fractions were observed in thedeferiprone- and deferoxamine-treated patients com-pared with the deferasirox group. Liver iron concen-trations were lower in the deferoxamine group thanin the deferiprone or deferasirox groups.20 Similarobservations were noted from patients in a singlecenter treated with deferiprone for 3 years or controlstreated with deferoxamine who were matched for age,sex, and current ferritin concentration. The defer-iprone group had lower myocardial iron and higherejection fractions than the deferoxamine controls. Ex-cess myocardial iron (T2p less than 20 ms) was lesscommon in the deferiprone group (27% vs 67%, P5.025), as was severe iron overload (T2p less than 10ms; 7% vs 37%, P 5 .04).21 Additional studies havereported additional improvements in myocardial T2pwith the addition of deferiprone therapy to deferox-amine therapy.22

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONSContraindications

Deferiprone is contraindicated in patients withhypersensitivity to deferiprone or any of the productingredients.1 The contraindications, warnings, andprecautions for each of the iron chelators are sum-marized in Table 2.

Warnings and PrecautionsDeferiprone labeling includes a black box warning

regarding the risk of agranulocytosis, which occurred in1.7% of patients treated with deferiprone in clinicaltrials. Neutropenia can precede the development ofagranulocytosis. The absolute neutrophil count (ANC)



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Table 2. Contraindications, warnings, and precautions of iron chelating agents1,3,4

Deferasirox Deferiprone Deferoxamine

Contraindications

Hypersensitivity X X X

CrCl , 40 mL/min or serumcreatinine . 2 times ULN

X

Severe renal disease or anuria X

Poor performance status andhigh risk MDS or advancedmalignancies

X

Platelet count , 50 3 109/L X

Black box warnings

Agranulocytosis X

Infection risk X

Renal failure X

Hepatic failure X

GI hemorrhage X

Warnings and precautions

Infection X X

Fetal risk X

May cause renal impairment X X

May cause hepatic impairment X

GI hemorrhage X

Cytopenias (eg, agranulocytosis,neutropenia, thrombocytopenia)

X

Hypersensitivity reactions X

Infusion reactions X

Elderly patients X

Special senses X X

Growth retardation X

Respiratory distress syndrome X

Vitamin C X

Aluminum overload X

Special populations

Hepatic impairment Avoid in severe impairment;reduced starting dose in moderateimpairment; monitor closely

Not evaluated; caution Not evaluated

Renal impairment Caution; increase monitoringfrequency

Not evaluated; caution Avoid in severe renaldisease or anuria

Pediatric No unique precautions Not established No unique precautions

Elderly Monitor closely; greaterfrequency of decreased hepatic,renal, or cardiac function

Not established; cautiousdose selection advised

Caution; increased riskof eye disorders

Pregnancy Category C D C

Breast-feeding Discontinue drug orbreast-feeding

Discontinue drug orbreast-feeding

Caution

Note: GI5 gastrointestinal; CrCl5 creatinine clearance; MDS5myelodysplastic syndrome; ULN5 upper limit of normal.



should be measured prior to starting therapy withdeferiprone and weekly while on therapy. Therapyshould be interrupted if neutropenia develops (ANCless than 1.5 3 109/L). Therapy with deferiproneshould not be resumed in patients developing agranu-locytosis or neutropenia unless the potential benefitsoutweigh the potential risks. If infection occurs whileon deferiprone, therapy should be interrupted and theANC monitored more frequently.1

A cardiac QT study has not been conducted withdeferiprone. Patients with a history of QT pro-longation developed torsades de pointes during ther-apy with deferiprone. Caution is advised with the useof deferiprone in patients who may be at increased riskof QT prolongation, including those with congestiveheart failure, bradycardia, diuretic use, cardiac hy-pertrophy, hypokalemia, or hypomagnesemia.1

Caution is advised with the use of deferiprone inpatients with renal or hepatic impairment, because nostudies have been conducted specifically evaluating thesafety or efficacy of deferiprone in these conditions.1

Increased serum alanine aminotransferase (ALT)values have been observed in 7.5% of patients treatedwith deferiprone in clinical trials. ALT values shouldbe monitored monthly during therapy.1 Worseninghepatic fibrosis caused a long delay in the new ap-plication for approval in the United States; this isa controversial observation that was seen in 1 studybut not in other, larger studies.15,23-26 The approvedproduct labeling does not contain any cautions re-lated to worsening hepatic fibrosis.1

Decreased plasma zinc concentrations have beenobserved during deferiprone therapy. Plasma zincconcentrations should be monitored and supplemen-tation provided if deficiency occurs.1

The approved labeling states the safety and ef-fectiveness of deferiprone have not been established inpediatric patients.1 Six-month-long treatment witha deferiprone oral solution (Apotex, Canada) has beendescribed in 99 children 1 to 10 years of age (mean,5.1 years of age) with thalassemia syndromes treatedin 4 thalassemia treatment centers located in Indonesia,Malaysia, and Egypt. The oral solution was noted tobe bioequivalent to the tablet formulation. Therapywas initiated at a dosage of 50 mg/kg/day and couldbe increased to a maximum dosage of 100 mg/kg/day.The observed adverse event profile was similar tothat observed with deferiprone in adults. Signifi-cant reductions in mean serum ferritin level wereobserved.27

Deferiprone is in Pregnancy Category D; it cancause fetal harm. Women of childbearing potential

should be advised to avoid pregnancy while receivingdeferiprone. In animal studies, deferiprone was asso-ciated with embryofetal death and malformations.1

It is not known whether deferiprone is excreted inhuman milk. Deferiprone use should be avoided inbreast-feeding women.1

ADVERSE REACTIONSThe most common adverse reactions reported

during deferiprone therapy, occurring in at least 5% ofpatients, have included chromaturia (14.6%), nausea(12.6%), abdominal pain/discomfort (10.4%), vomiting(9.8%), arthralgia (9.8%), increased ALT (7.5%), andneutropenia (6.2%).1

DRUG INTERACTIONSAvoid concomitant use of deferiprone with other

drugs known to be associated with neutropenia oragranulocytosis. If concomitant use is unavoidable,ANC should be closely monitored.1

Deferiprone administration should be separatedfrom administration of mineral supplements or med-ications containing polyvalent cations (eg, iron, alu-minum, zinc) by at least 4 hours.1

Deferiprone is primarily eliminated via metabo-lism via UGT 1A6. Caution is advised if deferiprone iscoadministered with UGT 1A6 inhibitors (eg, sily-marin); studies have not been conducted with defer-iprone and UGT 1A6 inhibitors.1

RECOMMENDED MONITORINGSerum ferritin concentration should be monitored

every 2 to 3 months to assess the effects of deferiproneon body iron stores. ANC should be measured prior toinitiation of therapy and monitored weekly while ontherapy. Serum ALT should be monitored monthlyduring deferiprone therapy. Plasma zinc should also bemonitored, with zinc supplementation provided in theevent of deficiency.1

DOSINGThe recommended initial dosage of deferiprone is

25 mg/kg orally 3 times daily. The maximum dosage is33 mg/kg 3 times daily. Dose adjustments should beindividualized based on the patients response andtherapeutic goals (maintenance or reduction of bodyiron burden). The prescribed dose should be roundedto the nearest 250 mg (half of a tablet).1

PRODUCT AVAILABILITY AND STORAGEDeferiprone received FDA approval on October

14, 2011. It is available as 500mg scored tablets and is



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supplied in bottles of 100 tablets. Deferiprone shouldbe stored at controlled room temperature (20" to 25"C[68" to 77"F]); excursions are permitted between 15"and 30"C (59" and 86"F). Store out of the reach andsight of children.1

CONCLUSIONDeferiprone is an oral iron chelator that lowers

serum ferritin and hepatic and cardiac iron stores inpatients with thalassemiamajor and transfusion-relatediron overload. Because of a lack of outcome studies, useshould be limited to second-line therapy. Additionalstudies are necessary to establish a cardiac benefit rel-ative to other iron chelation therapies.

REFERENCES1. Ferriprox [package insert]. Rockville, MD: ApoPharmaUSA Inc; October 2011.

2. Hershko C. Pathogenesis and management of iron toxicityin thalassemia. Ann NY Acad Sci. 2010;1202:1-9.

3. Exjade [package insert]. East Hanover, NJ: NovartisPharmaceuticals; August 2011.

4. Desferal [package insert]. East Hanover, NJ: NovartisPharmaceuticals; September 2008.

5. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effec-tiveness and safety of ICL670 in iron-loaded patients withthalassaemia: a randomised, double-blind, placebo-controlled,dose-escalation trial. Lancet. 2003;361(9369):1597-1602.

6. Limenta LMG, Jirasomprasert T, Jittangprasert P, et al.Pharmacokinetics of deferiprone in patients with b-thalassae-mia: impact of splenectomy and iron status. Clin Pharmaco-kinet. 2011;50(1):41-50.

7. Cappellini MD, Cohen A, Eleftheriou A, Piga A, Porter J,Taher A, eds. Guidelines for the Clinical Management ofThalassaemia. 2nd ed. Cyprus: Thalassaemia InternationalFoundation; November 2008. http://www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition.EN.pdf. Accessed October17, 2011.

8. Roberts DJ, Brunskill S, Doree C, Williams S, Howard J,Hyde C. Oral deferiprone for iron chelation in people withthalassaemia. Cochrane Database Syst Rev. 2007;(3):CD004839.10.1002/14651858.CD004839.pub2.

9. Maggio A, Filosa A, Vitrano A, et al. Iron chelation ther-apy in thalassemia major: a systematic review with meta-analysis of 1520 patients included on randomized clinical trials.Blood Cells Mol Dis. 2011;47(3):166-175.

10. Pantalone GR, Maggio A, Vitrano A, et al. Sequential al-ternating deferiprone and deferoxamine treatment comparedto deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in b-thalassemiamajor patients. Hemoglobin. 2011;35(3):206-216.

11. Zareifar S, Jabbari A, Cohan N, Haghpanah S. Efficacy ofcombined desferrioxamine and deferiprone versus single des-

ferrioxamine therapy in patients with major thalassemia. ArchIran Med. 2009;12(5):488-491.

12. Maggio A, Vitrano A, Capra M, et al. Long-term sequentialdeferiprone-deferoxamine versus deferiprone alone for thalas-saemia major patients: a randomized clinical trial. Br J Hae-matol. 2009;145(2):245-254.

13. Aydinok Y, Ulger Z, Nart D, et al. A randomized con-trolled 1-year study of daily deferiprone plus twice weeklydesferrioxamine compared with daily deferiprone mono-therapy in patients with thalassemia major. Haematologica.2007;92(12):1599-1606.

14. Galanello R, Kattamis A, Piga A, et al. A prospectiverandomized controlled trial on the safety and efficacy of al-ternating deferoxamine and deferiprone in the treatment ofiron overload in patients with thalassemia. Haematologica.2006;91(9):1241-1243.

15. Maggio A, DAmico G, Morabito A, et al. Deferiproneversus deferoxamine in patients with thalassemia major:a randomized clinical trial. Blood Cells Mol Dis. 2002;28(2):196-208.

16. Maggio A, Vitrano A, Capra M, et al. Improving survivalwith deferiprone treatment in patients with thalassemia major:a prospective multicenter randomised clinical trial under theauspices of the Italian Society for Thalassemia and Hemoglo-binopathies. Blood Cells Mol Dis. 2009;42(3):247-251.

17. Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparativeeffects of deferiprone and deferoxamine on survival and car-diac disease in patients with thalassemia major: a retrospectiveanalysis. Haematologica. 2003;88(5):489-496.

18. Pennell DJ, Berdoukas V, Karagiorga M, et al. Random-ized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardialsiderosis. Blood. 2006;107(9):3738-3744.

19. Smith GC, Alpendurada F, Carpenter JP, et al. Effect ofdeferiprone or deferoxamine on right ventricular function inthalassemia major patients with myocardial iron overload.J Cardiovasc Magn Reson. 2011;13:34.

20. Pepe A, Meloni A, Capra M, et al. Deferasirox, defer-iprone and desferrioxamine treatment in thalassemia majorpatients: cardiac iron and function comparison determinedby quantitative magnetic resonance imaging. Haematologica.2011;96(1):41-47.

21. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM,Pennell DJ. Comparison of effects of oral deferiprone andsubcutaneous desferrioxamine on myocardial iron concen-trations and ventricular function in beta-thalassaemia. Lancet.2002;360(9332):516-520.

22. Tanner MA, Galanello R, Dessi C, et al. A randomized,placebo-controlled, double-blind trial of the effect of combinedtherapy with deferoxamine and deferiprone on myocardialiron in thalassemia major using cardiovascular magnetic res-onance. Circulation. 2007;115(14):1876-1884.

23. Savulescu J. Thalassaemia major: the murky story of de-feriprone [editorial]. BMJ. 2004;328(7436):358-359.



24. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-termsafety and effectiveness of iron-chelation therapy with deferipronefor thalassemia major. N Engl J Med. 1998;339(7):417-423.

25. Wanless IR, Sweeney G, Dhillon AP, et al. Lack of pro-gressive hepatic fibrosis during long-term therapy with defer-iprone in subjects with transfusion-dependent beta-thalassemia[published correction appears in Blood. 2003;101(7):2460].Blood. 2002;100(5):1566-1569.

26. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F.Safety and effectiveness of long-term therapy with the oral ironchelator deferiprone. Blood. 2003;102(5):1583-1587.

27. ElAlfy MS, Sari TT, Lee CL, Tricta F, El-Beshlawy A. Thesafety, tolerability, and efficacy of a liquid formulation of de-feriprone in young children with transfusional iron overload[published correction appears in J Pediatr Hematol Oncol. 2011;33(7):572]. J Pediatr Hematol Oncol. 2010;32(8):601-605. g



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