Oral Iron Chela to Rs

8/11/2019 Oral Iron Chela to Rs

1/22

1

Review of Oral Iron Chelators

(Deferiprone and Deferasirox)

for the Treatment of Iron Overload in Pediatric Patients

D. Adam Algren, MD

Assistant Professor of Pediatrics and Emergency Medicine

Division of Pediatric Pharmacology and Medical Toxicology

Departments of Pediatrics and Emergency Medicine

Childrens Mercy Hospitals and Clinics/Truman Medical Center

University of Missouri-Kansas City School of Medicine


2/22

2

PROPOSAL

The World Health Organization Model List of Essential Medicines and ModelFormulary 2010 list deferoxamine (DFO) as the treatment of choice for both acute andchronic iron poisoning. The Model Formulary currently does not designate any orally

administered agents for the chelation of iron. It is proposed that deferasirox beconsidered the oral chelator of choice in the treatment of chronic iron overload.Deferasirox is widely available recent evidence support that it is both safe andefficacious.

INTRODUCTIONAcute iron poisoning and chronic iron overload result in significant morbidity

and mortality worldwide. Treatment of acute iron poisoning and chronic ironoverload can be challenging and care providers are often confronted with managementdilemmas. Oral iron supplements are commonly prescribed for patients with iron

deficiency anemia. The wide availability of iron supplements and iron-containingmultivitamins provide easy accessibility for both adults and children. The approach totreatment of acute iron toxicity involves providing adequate supportive care,optimizing hemodynamic status and antidotal therapy with IV deferoxamine, whenindicated.1 Early following an acute ingestion gastrointestinal (GI) decontaminationcan be potentially beneficial. Multiple options exist including: syrup of ipecac,gastric lavage, and whole bowel irrigation (WBI). Although definitive evidence thatGI decontamination decreases morbidity and mortality is lacking it is often consideredto be beneficial. The decision to initiate GI decontamination should be made on anindividual case basis. In addition to conventional GI decontamination other methodsto prevent absorption have been investigated. Likewise, several small studies have

investigated the use of other oral agent/chelators for the treatment of acute ironpoisoning.

Chronic iron overload associated with red cell disorders (i.e. sickle cell anemiaand thalassemia) and other myelodysplastic syndromes affect a significantly largernumber of individuals. The body does not have an efficient mechanism to excreteiron. Thus, in those patients requiring multiple transfusions iron accumulates and isdeposited into multiple organ systems. The long term consequences of chronic ironoverload include multiple organ dysfunction (heart, liver, and endocrine) and/orfailure.2-5

Therefore. iron chelation is necessary to prevent organ failure and decrease mortality.Deferoxamine was the first iron chelator introduced into clinical practice.

Although effective, there are significant challenges associated with its use that canresult in non-compliance. Deferiprone and deferasirox, oral iron chelators, areincreasingly available and evidence supports their use in the treatment of chronic ironoverload. A perfect oral iron chelator does not exist; although, both deferiprone anddeferasirox are effective they have differences including different pharmacokineticsand adverse effect profiles. These differences are both advantageous and/or

problematic. These advantages and disadvantages will be reviewed and arecommendation for a chelator of choice will be made based on these considerations.

This review will summarize the available evidence regarding:


3/22

3

a) Efficacy of deferoxamine in the treatment of chronic iron overload and thechallenges associated with its use.

b) Efficacy and safety of deferipronec) Efficacy and safety of deferasiroxd) Formulation, dosing recommendation, and cost comparison between deferiprone

and deferasirox.

LITERATURE REVIEWThe studies for this review were identified by performing a search of the

PubMed using the search terms: iron poisoning, iron toxicity, iron chelation,deferoxamine, deferiprone, and deferasirox. The dates included 1966-2010.The Cochrane Database for Systematic Reviews was also searched and pertinentreviews were identified.6-8 The bibliographies of selected articles were also reviewedto identify any relevant studies not found by the original literature search.

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

EFFICACY AND SAFETY

ACUTE IRON POISONING-Several different methods to prevent iron absorption following acute

ingestions have been investigated. GI decontamination involves removing thecompound from the GI tract prior to its absorption or administering an agent that iscapable of binding the compound so that it is not available for systemic absorption.

Syrup of ipecac traditionally had been recommended to induce vomiting inorder to facilitate removal of a substance from the GI tract. There is scant evidence tosupport or refute the use of ipecac and therefore a recent international positionstatement recommended against routine use of ipecac in the poisoned patient.9 Theavailable evidence does suggest that efficacy decreases dramatically beyond 30-60minutes following ingestion. The generalizability of these recommendations todeveloping nations is not clear. In locations with limited medical resources ipecacadministration may be the best GI decontamination option due to the fact that it is notresource or labor intensive.

Physical removal of iron from the stomach may also be accomplished bygastric lavage. There are no studies that specifically address its use in those withacute iron ingestions. A consensus position statement also does not endorse its

routine use in poisoned patients.10

Available evidence suggests that it is mosteffective if performed within 1 hour. Performing gastric lavage with different lavage


4/22

4

solutions has also been investigated. Intuitively it would make sense that lavagesolutions could complex with the iron to form insoluble iron compounds. Hypertonic

phosphate solutions were not effective quickly abandoned due to morbidity fromassociated electrolyte abnormalities that it induced.11-14 Although there is someevidence to support the efficacy of magnesium hydroxide to prevent absorption of

iron it is generally not recommended for several reasons.15-17

An un-realistically largevolume would have to be administered and patients would be at risk for developingelectrolyte abnormalities.

Activated charcoal has become the method of choice among healthcareproviders for GI decontamination. However, iron does not adsorb well to charcoaland therefore its use should be limited to those situations involving co-ingestants thatcharcoal is deemed necessary.18

Whole bowel irrigation consists of the administration of polyethylene glycolelectrolyte solution to promote intestinal evacuation prior to systemic absorption.WBI should be considered in cases of significant iron ingestion as there are limitedoptions for GI decontamination in iron poisoning.19 However, this procedure can be

labor intensive as it requires the ingestion of a large amount of polyethylene glycolsolution over a relatively brief time course. Although commonly recommended thereis limited evidence to support its use.

Several investigators have examined the utility of oral iron chelation in thesetting of an acute iron overdose. Animal studies initially suggested that oraldeferoxamine decreased iron absorption and could potentially be of benefit.20Subsequent investigations failed to confirm decreased absorption in deferoxaminetreated swine and dogs.21-23 The literature regarding the efficacy of oral DFO inhumans is limited. A small volunteer study that assessed its ability to bind iron failedto demonstrate decreased absorption.24 However, another volunteer study that used alarger dose of DFO was able to show decreased iron absorption.25 Clinical experiencewith oral DFO in overdose patients is limited. Early studies examining the efficacy ofDFO suggested that it likely does not prevent iron absorption and could in factcontribute to toxicity by facilitating production and absorption of the toxic metaboliteferrioxamine.22-23 The utility of other oral iron chelators for acute iron poisoning isunknown. A rat model administered oral deferiprone following administration of anLD50 dose of iron. Deferiprone decreased mortality in the treatment group,especially in those that received a follow up dose.26 There are no human studiesaddressing its use.

CHRONIC IRON OVERLOAD

Deferoxamine was introduced in the 1960s and was the first iron chelatorused for the treatment of chronic iron overload. Several of the studies addressed inthis review have combined the use of DFO with an oral chelator. Although it isadministered parenterally, a review of evidence supporting its use will provide

background regarding chelation therapy for chronic iron overload. Even though thereis significant clinical experience with DFO a majority of the literature is retrospectiveor observational.

DFO is derived from Streptomyces pilosus and is administered parenterallygiven its poor oral bioavailability.27 DFO has a short half life and must beadministered by intravenous (IV) or subcutaneous injections/infusions.28-29 IV and

subcutaneous administration were shown to be more efficacious at improving ironexcretion compared to intramuscular administration.30-32An intermittent subcutaneous


5/22


6/22

6

administration can adversely affect skeletal maturation and result in growthretardation.55 The cumbersome nature and complications associated with DFOtherapy pushed investigators to identify oral agents that would suitable for long-termchelation in those with chronic iron overload.

Deferiprone was initially introduced in Europe in the 1980s and was the first

oral chelator to be used for the treatment of iron overload (Table). It is a bidentatehydroxypyridone with a small molecular weight (139). Peak plasma levels occurwithin 1 hour. It forms a stable complex with iron that is then excreted in the urine.56It is metabolized by glucuronidation in the liver and has a relatively short half-life of47-134 minutes necessitating multiple daily dosing.57-58 Early animal datademonstrated good iron mobilization using deferiprone.59-60 The scientific dataregarding deferiprone is derived mostly from observational, retrospective, orcombination chelator studies. The lack of traditional safety and efficacy trialscomparing deferiprone to deferoxamine has prevented approval in the United States;however it is used in Europe (under specific conditions) and other countries.

Several decades of experience with deferiprone have been reported. Initial

studies demonstrated comparable amounts of iron excretion when deferiprone wascompared to deferoxamine.61-62 However, DFO appears to results in slightly highernet iron excretion as a result of fecal loss. Deferiprione results in more significantreduction in iron levels in those with a higher iron burden.63 It may not be as helpfulfor those less significant iron overload. However, this problem can be overcome byincreasing the amount of deferiprone administered from 75 to 100 mg/kg/day.63

Multiple studies have examined the deferiprones ability to lower serumferritin concentrations. These studies are mostly retrospective and observational andinclude both adult and pediatric patients. A majority of the trials followed patients forat least 1 year with several trails following patients for 3 or more years. The mostcommon dose administered in the trails was 75 mg/kg/day. The number of subjects ineach trial is small, typically numbering less than 40. However, several series with alarger number of subjects have been published.

The effectiveness of deferiprone was reported by Cohen and colleagues in a 4year observational trial.64 It included 187 patients with a mean age of 18 (range 10-41). Deferiprone was quite effective in lowering serum ferritin over the study period.In those patients with more severe iron overload the ferritin level dropped from 3661 1862 mcg/L to 2630 1708 mcg/L. Patients with lower initial ferritin levels hadless dramatic results. There were 47 patients that discontinued therapy as a result ofincreasing ferritin levels. The reasons for decreased effectiveness in this subset of

patients were not clear. They did not differ significantly from the study population

except they were less likely to have undergone splenectomy.

64

Goel and colleguesexamined their 3 year experience with deferiprone in 58 thalassemia patients (meanage 11.9 years).65 They demonstrated that those patients that entered the trial withhigher mean serum ferritin concentrations (mean 4745 1873 ng/ml) tended to havethe best response to therapy. Deferiprone was not uniformally successful in lowerferritin concentrations as 17 patients finished in the study with higher concentrations

A smaller study of 21 patients evaluated deferiprone in thalassemia patients.66The mean age of patients was 22 (range 7.5-31 years). Follow up at 3 yearsdemonstrated significant decreases in hepatic iron and serum ferritin concentrations.Although the mean serum ferritin decreased from 3975 766 mcg/L to 2546 381mcg/L those patients with more severe iron overload were only able to achieve ferritin

concentrations of 3273 568 mcg/L.66

Similarly, the same authors examineddeferiprone effectiveness in 18 patients treated for a mean of 4.6 years.67 The mean


7/22

7

age of the patients was 18.2 (range 10.5-23.7 years). Hepatic iron concentrationsremained elevated in 7 of18 patients. Five of these patients had biopsy documented

progression of liver fibrosis. Even though there was significant improvement inserum ferritin levels, 9 of17 patients had levels that remained greater than 2500mcg/L.67 More recent trials have assessed the efficacy of deferiprone in young

children. El Alfy and colleagues reviewed its use in 100 children (mean age 5.1 2.4years) with thalassemia or sickle cell disease.68 At the end of the 6 month treatment

period there was a significant drop in mean serum ferritin levels from 2532 1463ng/L to 2176 1144 ug/L (p


8/22

8

chelators. Given that combination therapy appeared to result in greater iron excretionand that deferiprone was associated with a higher incidence of adverse effects thereviewers concluded that deferiprone should be reserved for those patients in whomdeferoxamine therapy is contraindicated or inadequate.6

Deferiprone is associated with several adverse effects. The most concerning is

agranulocytosis. In clinical trials neutropenia has been reported in up to 5% withagranulocytosis typically reported in < 1%. Patients that develop agranulocytosistypically do so during the first year of therapy, but it has been reported up to 19months after deferiprone initiation.56,93 Combination therapy with deferoxamine andand/or an intact spleen place patients at higher risk.73 Neutropenia is typicallyreversible upon discontinuation of the drug, but can reoccur if deferiprone isreintroduced.94-95 It has yet to be elucidated if the neutropenia and agranulocytiosis isan idiosyncratic reaction or a dose-related direct myelotoxicty.56,93 Frequentmonitoring of white blood cell counts is recommended.96 Consideration should begiven to avoiding deferiprone in patients with myeloproliferative disorders.

Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain have

been reported in up to 33% of patients.94,97 These are usually mild and typically donot result in drug discontinuation. Elevations of liver transaminases have beenreported during deferiprone treatment. An early trial suggested that deferiprone wasassociated with progressive liver fibrosis.67 This was a small trial involving 19

patients of which 5 were considered to have progression of liver fibrosis. Subsequenttrials involving larger numbers of patients have not demonstrated liver toxicity.94,98-100Liver enzyme elevations tend to be mild and reversible. In a recent pediatric trial12% of patients experienced a mild elevation in ALT.68 Only 1 patient had anelevation greater than twice the upper limit of normal at 3 and 6 months. Deferipronewas continued in all patients without incident. The contribution of deferiprone toworsening liver disease is often difficult to determine because of the natural

progression associated with chronic iron overload. Other co-existing diseases, such ashepatitis, or other medications associated with hepatotoxicity contribute to thedifficulty of assigning culpability to deferiprone.

Arthralgias and arthritis have been associated with deferiprone. Although ithas been reported to occur in 30-40% of patients in some studies large trials havereported a much lower incidence of 4%.56,64,101-2 Large joint, such as the knees, aremore commonly affected. 50% of cases develop with the first year of therapy.Symptoms are typically mild and resolve with discontinuation.

Deferasirox is the most recent oral chelator to be used for the management ofchronic iron overload (Table). Unlike deferiprone, deferasirox was developed and

studied under more rigorous scientific scrutiny. Although there is less long-termoutcome data available, multiple studies have or are currently addressing its efficacyand safety.

Iron chelation occurs when 2 molecules of deferasirox bind to 1 molecule ofiron.103 Peak plasma concentrations occur within 1-2 hours of administration. It ishighly protein bound (99%) and is metabolized by the liver with subsequent fecalexcretion.104 The eliminations half life is 7-18 hours.105 This relatively longelimination facilitates once daily dosing. The tablets may be dissolved in water or

juice without altering the bioavailability.96

Initial data suggests that deferasirox has the capacity to gain access tointracellular iron similar to deferiprone. Laboratory and animal studies confirm its

ability to chelate cardiac iron.106-107

Recent data regarding deferasiroxs ability totreat cardiac iron overload initial human studies are promising. Multiple studies have


9/22

9

shown deferasirox is effective in decreasing cardiac iron burden; however, the resultsregarding if it is effective in removing cardiac iron in cases of severe iron overload areconflicting.108-110 More recently a large trial of 192 thalassemia patients investigatedthe efficacy of deferasirox in reducing cardiac iron overload as well as preventingcardiac iron accumulation.111 One third of the patients were less than 16 years old.

The mean deferasirox dose administered over the 1 year treatment period was 32.6mg/kg/day. A statistically significant decrease in cardiac iron, as demonstrated bycardiac magnetic resonance imaging, was observed. Deferasirox was also beneficialin preventing accumulation of cardiac iron.111

Deferasirox is effective in lowering serum ferritin levels and decreasingoverall iron burden. An early trial that evaluated the dose-response relationshipdemonstrated that 20mg/kg/day effectively chelated iron. However, net iron excretiononly occurred at a dose of 40 mg/kg/day.112 Yet, in another trial 20 mg/kg/daydecreased liver iron concentrations in 71 adult thalassemia patients.113 A larger trialcompared deferasirox (132 patients) to deferoxamine (63 patients) for the treatment ofiron overload in patients with sickle cell anemia. The median age of the deferasirox

treatment group was 15 years. At the end of 1 year deferasirox (10-30 mg/kg/day)was equivalent to deferoxamine in lowering liver iron concentrations.114 Likewise,Cappellini and colleagues assessed the efficacy of deferasirox versus deferoxamine in

pediatric thalassemia patients.115 The mean age of the 296 patients that receiveddeferasirox was 17 ( 9.4 years). The mean daily dose of deferasirox varied between6.2mg and 28.2mg depending on baseline liver iron concentrations. Across alltreatment groups noninferiority of deferasirox was not demonstrated. This was likelyrelated to underdosing of deferasirox in a significant number of patients. Furtheranalysis demonstrates that deferasirox was not inferior to deferoxamine in those

patients that received 20-30mg/kg/day. At the higher 30mg/kg/day dose a decrease inserum ferritin and liver iron concentrations were observed.115 Taher and colleaguesassessed the utility of deferasirox in heavily iron-overloaded thalassemia patients.116This was a prospective trial that followed 237 patients (162 were between 2 and 16years of age) for 1 year. A majority of patients completed the trial on 30 mg/kg/day.Deferasirox was effective and resulted in statistically significant decreases in liveriron concentrations and serum ferritin levels.116 Recently, the largest trial to dateassessing deferasirox was published. It was a 1 year, prospective study of 1,744

patients with transfusion-associated iron overload.117 The mean age of all patientswas 30.6 years (range 2-89 years). Similar to other trials the initial deferasirox dosevaried and dose adjustments occurred throughout the trial. At the conclusion of thestudy 51% of patient were receiving greater than 30 mg/kg/day and 39.6% were

receiving between 20-30 mg/kg/day. There was a statistically significant reduction inserum ferritin from baseline.117 Although a majority of deferasirox studies haveenrolled thalassemia patients it has shown efficacy in treatment of other conditionsassociated with iron overload.114,118

A Cochrane review addressed the use deferasirox for the treatment of ironoverload. In assessing its use in sickle cell anemia patients the reviewers concludedthat deferasirox was as effective as deferoxamine in reducing iron overload. 7 Theycautioned however that long-term outcome data does not exist and further study isneeded to assess its efficacy and safety. Although the same authors revieweddeferasirox use in patients with myelodysplastic syndromes they were not able toidentify any trials that met their inclusion criteria.8 Additionally, a review of

deferasirox for the treatment of thalassemia patients is currently in progress.


10/22

10

Deferasirox is generally well tolerated. Adverse effects associated with its useare for the most part mild and self-limiting. The development of adverse effectsseems to be idiosyncratic and not dose dependent.119 Gastrointestinal symptoms, suchas nausea, vomiting, and abdominal pain, as common and have been reported in up to1/3 of patients.96,111,116,117,120 These symptoms are often mild, self-resolving, and

typically do not necessitate discontinuing therapy. Skin rashs (maculopapular) areanother common adverse effect that is reported in up to 10% of patients.114-117,121Again, these rashes are mild and resolve with drug discontinuation.

The most concerning adverse effect is acute renal insufficiency. This has beenreported in up to 1/3 of patients in trials.111,113-116,121 Generally the elevations are mildand transient, however up to 10% of patients can have an increase greater than 33%above baseline117. These abnormalities almost always resolve following drugdiscontinuation.

A significant number of pediatric patients have been included in deferasiroxtrials to date.114,115,121 The adverse effect profile in children is similar to that seen inadults. Likewise, no effects on growth and sexual development have been reported to

date.

FORMULATION, DOSING, COST

Deferiprone is available as a 500mg tablet and an oral solution (100mg/0.4ml).The recommended dose is 75 mg/kg/day divided into 3 doses.122

Deferasirox is available in 125 mg, 250 mg, and 500 mg dissolvable oraltablets. The tablets are to be completely dissolved in water or juice and taken on anempty stomach.123 The recommended dose is 20-30 mg/kg/day given in a single dailydose. Subsequent dosing should be based on periodic serum ferritin monitoring.

A cost comparison between deferiprone and deferasirox has to account formultiple variables including: drug cost, laboratory monitoring cost, cost associatedwith treating adverse effects and/or worsening of underlying disease as a result ofnon-compliance. A true, unbiased cost comparison between deferiprone anddeferasirox has not been published. It has been estimated that the cost of treating achild with deferiprone could be twice the cost of deferoxamine. Whereas, thedeferasirox could cost 2-3 times as much as deferoxamine.124 Thus a rough pricingorder would be: deferasirox> deferiprone> deferoxamine. However, this could varyfrom country to country. Several recent reports suggest that deferasirox therapy ismore cost effective than traditional deferoxamine therapy.125,126


11/22

11

Table. Comparison of iron chelatorsProperty Deferoxamine Deferiprone Deferasirox

Chelator: ironbinding

1:1 3:1 2:1

Route ofadministration

Subcutaneous orintravenous

Oral Oral

Usual dosage 25-50 mg/kg perday

75 mg/kg per day 20-30 mg/kg perday

Schedule Administeredover 8-24 hours,5-7 days perweek

Three times a day Daily

Adverse effects Local reactionsOphthalmologic

AuditoryPulmonaryNeurologicInfectious

Agranuloctyosis/neutropeniaArthralgias/Arthritis

Gastrointestinaldisturbances

RenalInsufficiency

Advantages Long-term dataavailable

May be superior in removalof cardiac iron

Once dailyadministrationOnly oralchelator licensedfor use in US

Disadvantages ToxicityCompliance

problems

Not licensed for use inUnited States.

Frequent blood countmonitoring required

Long-term datalacking

Drug Cost $ $$ $$$

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


12/22

12

SUMMARY

Acute iron poisoning continues to occur resulting in morbidity and mortality.Treatment of acute iron poisoning should focus on providing supportive care andadministering deferoxamine parenterally. Oral iron chelators have not been widely

studied in human, acute iron poisoning and are therefore not recommended.Worldwide many individuals with red cell disorders and myelodysplasia

develop transfusion-associated chronic iron overload. Significant morbidity andmortality are associated with iron overload. Historically, deferoxamine was the onlyiron chelator available. Deferoxamine therapy is inconvenient, time-consuming, andassociated with undesirable adverse effects resulting in non-compliance. Over the lastcouple of decades significant evidence has emerged supporting the use of the oral ironchelators deferiprone and deferasirox. Although both are effective at decreasing iron

burden several characteristics favor deferasirox. The once daily dosing requirementfor Deferasirox permits relative ease of administration and would be expected to

positively contribute to treatment adherence. It also has a favorable adverse effectprofile when compared to deferiprone which requires frequent blood countmonitoring. Although more research and long-term follow up studies are needed for

both oral chelators it is proposed that deferasirox be considered the oral chelator ofchoice in pediatric patients with transfusion-associated chronic iron overload.


13/22

13

REFERENCES

1. Madiwale T, Liebelt E. Iron: Not a Benign Therapeutic Drug. Curr Op Pediatr.2006;18:174-9.

2. Cunningham MJ. Update on Thalassemia: Clinical Care and Complications.Hematol Oncol Clin North Am. 2010;24:215-27.

3. Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine Complications in Patientswith Thalassemia Major. Pediatr Endocrinol Rev. 2007;5:642-8.

4. Delvecchio M, Cavallo L. Growth and Endocrine Function in Thalassemia Majorin Childhood and Adolescence. J Endocrinol Invest. 2010;33:61-8.

5. Hershko C. Pathogenesis and Management of Iron Toxicity in Thalassemia. AnnNY Acad Sci. 2010;1202:1-9.

6. Roberts D, Brunskill S, Doree C, Williams S, Howard J, Hyde C. OralDeferiprone for Iron Chelation in People with Thalassemia. Cochrane Database SystRev. 2007;3:CD004839.

7. Meerpohl JJ, Antes G, Rcker G. Deferasirox for managing Transfusional IronOverload in People with Sickle Cell Disease. Cochrane Database Syst Rev.2010;4:CD007477.

8. Meerpohl JJ, Antes G, Rcker G. Deferasirox for Managing Iron Overload in

People in People with Myelodysplastic Syndome. Cochrane Database Syst Rev.2010;10:CD007461.

9. American Academy of Clinical Toxicology, European Association of PoisonControl Centres and Clinical Toxicologists. Position Paper: Ipecac Syrup. J ToxicolClin Toxicol. 2004;42:133-43.

10. American Academy of Clinical Toxicology, European Association of PoisonControl Centres and Clinical Toxicologists. Position Paper: Gastric Lavage. JToxicol Clin Toxicol. 2004;42:933-43.

11. Geffner ME, Opas LM. Phosphate Poisoning Complicating Treatment for IronIngestion. Am J Dis Child. 1980;134:509-10.

12. Bachrach L, Correa A, Levin R, Grossman M. Iron Poisoning: Complications ofHypertonic Phosphate Lavage Therapy. J Pediatr. 1979;94:147-9.

13. Dean BS, Krenzelok EP. In Vivo Effectiveness of Oral Complexation Agents inthe Management of Iron Poisoning. J Toxicol Clin Toxicol. 1987;25:221-30.14. Dean BS, Krenzelok EP. In Vivo Effectiveness of Oral Complexation Agents inthe Management of Iron Poisoniong. J Toxicol Clin Toxicol. 1987;25:221-230.


14/22

14

15. Corby DG, McCullen AH, Chadwick EW, Decker WJ. Effect of OrallyAdministered Magnesium Hydroxide in Experimental Iron Intoxication. J ToxicolClin Toxicol. 1985-1986;23:489-99.

16. Wallace KL, Curry SC, LoVecchio F, Raschke RA. Effect of Magnesium

Hydroxide on Iron Absorption Following Simulated Mild Iron Overdose in HumanSubjects. Acad Emerg Med. 1998;5:961-65.

17. Snyder BK, Clark RF. Effect of Magnesium Hydroxide Administration on IronAbsorption after a Supratherapeutic Dose of Ferrous Sulfate in Human Volunteers: ARandomized Controlled Trial. Ann Emerg Med. 1999;33:400-5.

18. American Academy of Clinical Toxicology, European Association of PoisonControl Centres and Clinical Toxicologists. Position Paper: Single-Dose ActivatedCharcoal. Clin Toxicol. 2005;43:61-87.

19. American Academy of Clinical Toxicology, European Association of PoisonControl Centres and Clinical Toxicologists. Position Paper: Whole Bowel Irrigation.J Toxicol Clin Toxicol. 2004;42:843-854.

20. Dean B, Oehme FW, Krenzelok E, Hines R. A Study of Iron Complexation in aSwine Model. Vet Hum Toxicol. 1988;30:313-5.

21. Dean BS, Oehme FW, Krenzelok EP, Griffith GR, Hines RH. Iron Complexationwith Oral Deferoxamine . Vet Hum Toxicol. 1996;38:96-8.

22. Whitten CF, Gibson GW, Good MH, Goodwin JF, Brough AJ. Studies in AcuteIron Poisoning. I. Deferrioxamine in the Treatment of Acute Iron Poisoning: ClinicalObservation, Experimental Studies, and Theoretical Considerations. Pediatrics.1965;36:322-35.

23. Whitten CF, Chen Y, Gibson GW. Studies in Acute Iron Poisoning. II. FurtherObservations on Deferrioxamine in the Treatment of Acute Experimental IronPoisoning. Pediatrics. 1966;38:102-110.

24. Jackson TW, Ling LJ, Washinton V. The Effect of Oral Deferoxamine on IronAbsorption in Humans. J Toxicol Clin Toxicol. 1995;33:325-9.

25. Gomez HF, McClafferty HH, Flory D, Brent J, Dart RC. Prevention ofGastrointestinal Iron Absorption by Chelation from an Orally Administered PremixedDereroxamine/Charcoal Slurry. Ann Emerg Med. 1997;30:587-592.

26. Berkovitch M, Livne A, Lushkov G, et al. The Efficacy of Oral Deferiprone inAcute Iron Poisoning. Am J Emerg Med. 2000;18:36-40.

27. Bannerman RM, Callender ST, Williams DL. Effect of Desferrioxamine andD.T.P.A in Iron Overload. Br Med J. 1962;2:1573-1577.

28. Lee P, Mohammed N, Marshall L, et al. Intravenous Infusion Pharmacokineticsof Deferoxamine in Thalassaemic Patients. Drug Metab Disp. 1993;21:640-4.


15/22

15

29. Porter JB. Deferoxamine Pharmacokinetics. Semin Hematol. 2001;38:(1 Suppl1):63-8.

30. Propper RD, Cooper B, Rufo RR, et al. Continuous Subcutaneous

Administration of Deseroxamine in Patients with Iron Overload. N Engl J Med.1977;297:418-23.

31. Propper RD, Shurin SB, Nathan DG. Reassessment of the use ofDesferrioxamine in Iron Overload. N Engl J Med. 1976;294:1421-1423.

32. Hussain MA, Green N, Flynn DM, Hussein S, Hoffbrand AV. SubcutaneousInfusion and Intramuscular Injection of Desferrioxamine in Patients withTransfusional Iron Overload. Lancet. 1976;2:1278-80.

33. Borgna-Pignatti C, Cohen A. Evaluation of a New Method of Administration of

the Iron Chelating Agent Deferoxamine. J Pediatr. 1997;130:86-88.

34. Smith RS. Iron Excretion in Thalassaemia Major After Administration ofChelating Agents. Br Med J. 1962;2:1577-80.

35. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in Medically TreatedPatients with Homozygous B-Thalassemia. N Engl J Med. 1994;331:574-8.

36. Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and Causes of Deathin Thalassaemia Major. Lancet. 1989;2:27-30.

37. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and Complicationsin Patients with Thalassemia Major Treated with Transfusion and Deferoxamine.Haematologica. 2004;89:1187-93.

38. Wolfe L, Oliveri N, Sallan D, et al. Prevention of Cardiac Disease bySubcutaneous Deferoxamine in Patients with Thalassemia Major. N Engl J Med.1985;312:1600-3.

39. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of Deferoxamine inPreventing Complications of Iron Overload in Patients with Thalassemia Major. N

Engl J Med. 1994;331:567-73.40. Cooper B, Bunn HF, Propper RD, Nathan DG, Rosenthal DS, Moloney WC.Treatment of Iron Overload in Adults with Continuous Parenteral Desferrioxamine.Am J Med. 1977;63:958-66.

41. Borgna-Pignatti C, Franchini M, Gandini G, Vassanelli A, De Gironcoli M, ApriliG. Subcutaneous Bolus Injection of Deferoxamine in Adult Patients Affected byOnco-hamatologic Diseases and Iron Overload. Haematologica. 1988;83:788-90.

42. Franchini M, Gandini G, de Gironcoli M, Vassanelli A, Borgna-Pignatti C, ApriliG. Safety and Efficacy of Subcutaneous Bolus Injection of Deferoxamine in Adult

Patients with Iron Overload. Blood. 2000;95:2776-9.


16/22

16

43. Cossu P, Toccafondi C, Vardeu F, et al. Iron Overload and DesferrioxamineChelation Therapy in Beta-thalassemia Intermedia. Eur J Pediatr. 1981;137:267-71.44. Di Gregorio F, Romeo MA, Pizzarelli G, Aiello G, Russo G. An Alternative toContinuous Subcutaneous Infusion of Desferrioxamine in Thalassaemic Patients. Br JHaematol. 1997;98:601-2.

45. Wali YA, Taqi A, Deghaidi A. Study of Intermittent Intravenous DeferrioxamineHigh-dose Therapy in Heavily Iron-loaded Children with Beat-thalassemia MajorPoorly Compliant to Subcutaneous Injections. Pediatr Hematol Oncol. 2004;21:453-60.

46. Davis BA, Porter JB. Long-term Outcomes of Continuous 24-hour DeferoxamineInfusions via Indwelling Intravenous Catheters in High-Risk Beta-Thalassemia.Blood. 2000;95:1229-36.

47. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term Chelation Therapy in

Thalassaemia Major: Effect on Liver Iron Concentration, Liver Histology, andClinical Progress. Br Med J. 1974;2:16-20.

48. Cohen A, Martin M, Schwartz E. Depletion of Excessive Liver Iron Stores withDesferrioxamine. Br J Haematol. 1984;58:369-73.

49. De Virgiliis S, Cossu P, Sanna G, et al. Iron Chelation in Transfusion-dependentThalassemia with Chronic Hepatitis. Acta Haematol. 1982;67:49-56.

50. Cohen A, Schwartz E. Excretion of Iron in Response to Deferoxamine in SickleCell Anemia. J Pediatr. 1978;92:659-62.

51. Kalpatthi R, Peters B, Holloman D, et al. Safety and Efficacy of High DoseIntravenous Desferoxamine for Reduction of Iron Overload Due to ChronicTransfusion in Sickle Cell Patients. Blood. 2008;112:abst 1430.

52. Silliman CC, Peterson VM, Mellman DL, et al. Iron Chelation by Deferoxaminein Sickle Cell Patients with Severe Transfusion-induced Hemsiderosis: ARandomized, Double-blind Study of the Dose-response Relationship. J Lab ClinMed. 1993;122:48-54.

53. Aydinok Y, Erermis S, Bukusoglu N, et al. Psychosocial Implications ofThalassemia Major. Pediatr Int. 2005;47:84-9.

54. Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and Costs ofNoncompliance with Iron Chelation Therapy in Patients with Transfusion-dependentThalassemia: a Literature Review. Transfusion. 2007;47:1919-29.

55. De Virgiliis S, Congia M, Frau F, et al. Deferoxamine-induced GrowthRetardation in Patients with Thalassemia Major. J Pediatr. 1988;113:661-9.

56. Piga A, Roggero S, Salussolia I, Massano D, Serra M, Longo F. Deferiprone.

Ann NY Acad Sci. 2010;1202:75-8.


17/22

17

57. Matsui D, et al. Relationship Between the Pharmacokinetics and Iron ExcretionPharmacodynamics of the New Oral Iron Chelator 1,2-dimethyl-3-hydroxypyrid-4-one in Patients with Thalassemia. Clin Pharmacol. 1991;50:294-98.

58. Kontoghiorghes GJ, Goddard JG, Bartlett AN, Sheppard L. Pharmacokinetic

Studies in Human with the Oral Iron Chelator 1,2-dimethyl-3-hydroxypyrid-4-one.Clin Pharm Ther. 1990;48:255-61.

59. Gale GR, Litchenberg WH, Smith AB, Singh PK, Campbell RA, Jones MM.Comparative Iron Mobilizing Actions of Deferoxamine, 1,2 Dimethyl-3-hydroxypyrid-4-one, and Pyridoxal Isonicotinoyl Hydrazone in Iron Hydroxamate-loaded Mice. Res Commun Chem Pathol Pharmacol. 1991;73:299-313.

60. Bergeron RJ, Streiff RR, Wiegand J, Luchetta G, Creary EA, Peter HH. AComparison of the Iron-chelating Properties of 1,2-dimethyl-3-hydroxypyrid-4-one,1,2-diethyl-3-hydroxypyrid-4-one, and Deferoxamine. Blood. 1992;79:1882-90.

61. Olivieri NF, Koren G, Hermann C, et al. Comparison of Oral Iron Chelator L1and Desferrioxamine in Iron-loaded Patients. Lancet. 1990;336:1275-9.

62. Collins AF, Fassos FF, Stobie S, et al. Iron-balance and Dose-response Studiesof the Oral Iron Chelator 1,2-dimethyl-3-hydroxypyrid-4-1 (L1) in Iron-loadedPatients with Sickle Cell Disease. Blood. 1994;83:2329-2333.

63. Cappellini MD, Musallam KM, taher AT. Overview of Iron Chelation Therapywith Desferrioxamine and Deferiprone. Hemoglobin. 2009;33:S58-S69.

64. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety andEffectiveness of Long-term Therapy with the Oral Iron Chelator Deferiprone. Blood.2003;102:1583-7.

65. Goel H, Girish KM, Phadke SP. Long-term Efficacy of Oral Deferiprone inManagement of Iron Overload in Beta Thalassemia Major. Hematology. 2008;13:77-82.

66. Olivieri NF, Brittenham GM, Matsui D, et al. Iron Chelation Therapy with OralDeferiprone in Patients with Thalassemia Major. N Engl J Med. 1995;332:918-22.

67. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term Safety andEffectiveness of Iron-chelation Therapy with Deferiprone for Thalassemia Major. NEngl J Med. 1998;339:417-23.

68. El Alfy M, Sari TT, Lee CL, Tricta F, El-Beshlawy A. The Safety, Tolerability,and Efficacy of a Liquid Formulation of Deferiprone in Young Children withTransfusional Iron Overload. J Pediatr Hematol Oncol. In Press.

69. Won SC, Han DK, Seo JJ, et al. Efficacy and Safety of Deferipron (Ferriprox),an Oral Iron-chelating Agent, in Pediatric Patients. Korean J Hematol. 2010;45:58-

61.


18/22

18

70. Al-Refaie FN, Wonke B, Hoffbrand AV, et al. Efficacy and Possible AdverseEffects of the Oral Iron Chelator 1,2-dimethyl-3-hydroxypyrid-4-1 (L1) inThalassemia Major. Blood. 1992;80:593-99.

71. Mazza P, Amurri B, Lazzari G, et al. Oral Iron Chelating Therapy: a Single

Center Interim Report on Deferipron (L1) in Thalasssemia. Haematologica.1998;83:496-501.

72. Del Vecchio GC, Crollo E, Schettini F, et al. Factors Influencing Effectivenessof Deferiprone in a Thalassemia Major Setting. Acta Hematol. 2000;104:99-102.

73. Maggio A, DAmico GD, Morabito A, et al. Deferiprone versus Deferoxamine inPatients with Thalassemia Major: a Randomized Clinical Trial. Blood Cell Mol Dis.2002;28:196-208.

74. Maggio A, Vitrano A, Capra M, et al. Long-term Sequential Deferiprone-

deeroxamine versus Deferiprone Alone for Thalassaemia Major Patients: aRandomized Clinical Trial. Br J Haematol. 2009;145:245-54.

75. Daar S, Pathare AV. Combined Therapy with Desferrioxamine and Deferipronein Beta Thalassemia Major Patients with Transfusional Iron Overload. Ann Hematol.2006;85:315-9.

76. Origa R, Bina P, Agus A. Combined Therapy with Deferiprone andDesferrioxamine in Thalassemia Major. Haematologia. 2005;90:1309-14.

77. Galanello R, Kattamis A, Piga A. A Prospective Randomized Controlled Trial onthe Safety and Efficacy of Alternating Deferoxamine and Deferiprone in theTreatment of Iron Overload in Patients with Thalassemia. Haematologia.2006;91:1241-1243.78. Kolnagou A, Kleanthous, Kontoghiorghes GJ. Reduction of Body Iron Stores to

Normal Range Levels in Thalassaemia by using a Deferiprone/deferoxamineCombination and their Maintenance thereafter by Deferiprone Monotherapy. Eur JHaematol. 2010;85:1-9.

79. Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation ofTotal Body Iron load with Very Intensive Combination Chelation Resverses Cardiac

and Endocrine Complications of Thalassaemia major. Br J Haematol. 2010;148:466-75.

80. Tsiapras D, Fragatou S, Farmaki K, et al. Effect of Combined Chelation Therapywith Deferipron and Deferoxamine of Left Ventricular Diastolic Function in AdultBeta-thalassemia Major Patients. Hemoglobin. 2010;34:210-20.

81. Tsironi M, Assimakopoulos G, Polonofi K, Rigaki K, Aessopos A. Effects ofCombined Deferiprone and Deferoxamine Chelation Therapy on Iron Load Indices inBeta-thalassemia. Hemoglobin. 2008;32:29-34.

82. Christofordis A, Haritandi A, Tsatra I, Tsitourides I, Karyda S, Athanassiou-Metaxa M. Four-year Evaluation of Myocardial and Liver Iron Assessed


19/22

19

Prospectively with Serial MRI Scans in Young Patients with Beta-thalassemia Major:Comparison Between Different Chelation Regimens. Eur J Haematol. 2007;78:52-7.

83. DAngelo E, Mirra N, Rocca A, Carnelli V. Combined Therapy withDesferrioxamine and Deferiprone: a New Protocol for Iron Chelation in Thalassemia.

J Pediatr Hematol Oncol. 2004;26:451-3.

84. Alymara V, Bourantas D, Chaidos A, et al. Effectiveness and Safety ofCombined Iron-chelation Therapy with Deferoxamine and Deferiprone. Hematol J.2004;5:475-9.

85. Aydinok Y, Ulger Z, Nart D, et al. A Randomized Controlled 1-year Study ofDaily Deferiprone Plus Twice Weekly Desferrioxamine Compared with DailyDeferiprone Monotherapy in Patients with Thalassemia Major. Haematologia.2007;92:1599-606.

86. Kolnagou A, Economides C, Eracleous E, Kontoghiorghes GJ. Long TermComparative Studies in Thalassemia Patients Treated with Deferoxamine or aDeferoxamine/deferiprone Combination. Identification of Effective ChelationTherapy Protocols. Hemoglobin. 2008;32:41-7.

87. Peng CT, Wu KH, Wu SF, et al. Deferiprone or Deferoxamine vs. CombinationTherapy in Patients with Beta-thalassemia major: a Case Study in Taiwan.Hemoglobin. 2006;30:125-30.

88. Kattamis A, Ladis V, Berdousi H, et al. Iron Chelation Treatment withCombined Therapy with Deferiprone and Deferioxamine: a 12-month Trial. BloodCells Mol Dis. 2006;36:21-5.89. Lai ME, Grady RW, Vacquer S, et al. Increased Survival and Reversion of Iron-induced Cardiac Disease in Patients with Thalassemia Major receiving IntensiveCombined Chelation Therapy as Compared to Desferoxamine Alone. Blood CellsMol Dis. 2010;45:136-9.

90. Pepe A, Meloni A, Capra M. Deferasirox, Deferiprone and DesferrioxamineTreatment in Thalassemia Major Patients: Cardiac Iron and Function ComparisonDetermined by Quantitative Magnetic Resonance Imaging. Haematologica. 2010Sep 30. In press.

91. Ricchi P, Ammirabile M, Spasiano A, et al. Combined Chelation Therapy inThalassemia Major with Deferiprone and Desferrioxamine: a Reterospective Study.Eur J Haematol. 2010;85:36-42.

92. Galanello R, Agus A, Campus S, Danjou F, Giardina PJ, Grady RW. CombinedIron Chelation Thearpy. Ann NY Acad Sci. 2010;1202:79-86.

93. Hoffbrand AV, Cohen A, Hershko C. Role of Deferiprone in Chelation Therapyfor Transfusional Iron Overload. Blood. 2003;102:17-24.

94. Ceci A, Baiardi P, Felisi M, et al. The Safety and Effectiveness of Deferiprone ina Large-scale 3-year Study in Italian Patients. Br J Haematol. 2002;118:330-6.


20/22

20

95. Al-Refaie FN, Wonke B, Hoffbrand AV. Deferiprone-associated Myelotoxicity.Eur J Haematol. 1994;53:298-301.

96. Cappellini MD, Piga A. Current Status in Iron Chelation in Hemoglobinopathies.Curr Mol Med. 2008;8:663-74.

97. Cohen AR, Galanello R, Piga A, DiPalma A, Vullo C, Tricta F. Safety Profile ofthe Oral Iron Chelator Deferiprone: a Multicenter Study. Br J Haematol.2000;108:305-312.

98. Hoffbrand AV, Al-Refaie F, Davis B, et al. Long-term Trial of Deferiprone in 51Transfusion-dependent Iron Overloaded Patients. Blood. 1998;91:295-300.

99. Wanless A, Sweeney G, Dhillon AP, et al. Lack of Progressive Hepatic FibrosisDuring Long-term Therapy with Deferiprone in Subjects with Transfusion-dependentBeta-thalassemia. Blood. 2002;100:1566-9.

100. Tondury P, Zimmerman A, Nielsen P, et al. Liver Iron and Fibrosis duringLong-term Treatment with Deferiprone in Swiss Thalassaemic Patients. Br JHaematol. 1998;101:413-5.

101. Al-Refaie FN, Hershko C, Hoffbrand AV, et al. Results of Long-termDeferiprone (L1) Therapy: a Report by the International Study Group on Oral IronChelators. Br J Haematol. 1995;91:224-9.102. Ceci A, Baiardi P, Felisi M, et al. The Safety and Effectiveness of Deferipronein a Large-scale 3-year Study in Italian Patients. Br J Haematol. 2002;118:330-6.

103. Kwiatkowski JL. Oral Iron Chelators. Pediatr Clin N Am. 2008;55:461-82.

104. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, Metabolism, andDisposition of Deferasirox in Beta-thalassemic Patients with Transfusion-dependentIron Overload who are at Pharmacokinetic Steady State. Drug Metab Dispos.2010;38:808-16.

105. Lindsey WT, Olin BR. Deferasirox for Transfusion-related Iron Overload: AClinical Review. Clin Ther. 2007;29:2154-66.

106. Glickstein H, El RB, Link G, et al. Action of Chelators in Iron-loaded CardiacCells. Accessibility to Intracellular Labile Iron and Functional Consequences. Blood.2006;108:3195-203.

107. Wood JC, Otto-Duessel M, Gonzalez I, et al. Deferasirox and Deferiproneremove Cardiac Iron in the Iron-overloaded Gerbil. Trans Res. 2006;148:272-80.

108. Wood JC, Glynos T, Thompson A, et al. Follow-up Report on the 2-yearCardiac Data from a Deferasirox Monotherapy Trial. Am J Hematol. 2010;85:818-9.

109. Wood JC, Kang BP, Thompson A, et al. The Effect of Deferasirox on Cardiac

Iron in Thalassemia Major: Impact of Total Body Iron Stores. Blood. 2010;116:537-43.


21/22

21

110. Pathare A, Taher A, Daar S. Deferasirox (Exjade) Significantly ImprovesCardiac T2* in Heavily Iron-Overlaoded Patients with beta-Thalassemia Major. AnnHematol. 2010;89:405-9.

111. Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of Deferasirox inReducing and Preventing Cardiac Iron Overload in B-thalassemia. Blood.2010;115:2364-71.

112. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and Safety ofICL670 in Iron-loaded Patients with Thalassemia: a Randomised, Double-blind,Placebo-controlled, Dose-escalation Trial. Lancet. 2003;361:1597-602.

113. Piga A, Galanello R, Forni GL, et al. Randomized Phase II Trial of Deferasirox(Exjade, ICL 670), a Once-daily, Orally Administered Iron Chelator, in Comparisonto Deferoxamine in Thalassemia Patients with Transfusional Iron Overload.

Haematologia. 2006;91:873-80.

114. Vichinsky E, Onyekwere O, Porter J, et al. A Randomised Comparison ofDeferasirox versus Deferoxamine for the Treatment of Transfusional Iron Overload inSickle Cell Disease. Br J Haematol. 2006;136:501-8.115. Cappellini MD, Cohen A, Piga A, et al. A Phase 3 Study of Deferasirox(ICL670), a Once-daily Oral Iron Chelator, in Patients with B-thalassemia. Blood.2006;107:3455-62.

116. Taher A, El-Beshlawy A, Elalfy M, et al. Efficacy and Safety of Deferasirox, anOral Iron Chelator, in Heavily Iron-Overloaded Patients with B-thalassemia: theESCALATOR Study. Eur J Haematol. 2009;82:458-65.

117. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring Iron Chelation by Ironintake and Serum Ferritin: the Prospective EPIC Study of Deferasirox in 1744 patientswith Transfusion-dependent Anemia. Haematologica. 2010;95:557-66.

118. Gattermann N, Finelli C, Porta MD, et al. Deferasirox in Iron-overloadedPatients with Transfusion-dependent Myelodysplastic Syndromes: Results from aLarge 1-year EPIC Study. Leuk Res. 2010;34:1143-50.

119. Taher A, Cappellini MD, Vichinsky E, et al. Efficacy and Safety of DeferasiroxDose of >30 mg/kg per d in Patients with Transfusion-dependent Anaemia and IronOverload. Br J Haematol. 2009;147:752-9.

120. Porter JB. DeferasiroxCurrent Knowledge and Future Challenges. Ann NYAcad Sci. 2010;1202:87-93.

121. Galanello R, Piga A, Forni GL, et al. Phase II Clinical Evaluation ofDeferasirox, a Once-daily Oral Chelating Agent, in Pediatric Patients with B-thalassemia major. Haematologia. 2006;91:1343-51.


22/22

122. Product Information: Ferriprox Apo Pharma. Ontario, Canada. Available at:http://www.ferriprox.com/aboutferriprox/default_intl.asp. Last accessed December12, 2010.

123. Product Information: EXJADE . Novartis. East Hanover, New Jersey, US.

Available at: http://www.us.exjade.com/patient/full-prescribing-information.jsp. Lastaccessed December 12, 2010.

124. Neufeld EJ. Oral Chelators Deferasirox and Deferiprone for Transfusional IronOverload in Thalassemia Major: New Data, New Questions. Blood. 2006;107:3436-41.

125. Imran F, Phatak P. Pharmacoeconomic Benefits of Deferasirox in theManagement of Iron Overload Syndomes. Expert Rev Pharmacoecon Outcomes Res.2009;9:297-304.

126. Tolley K, Oliver N, Miranda E, Migliaccio-Walle K, Bozkaya D, Li Q. CostEffectiveness of Deferasirox Compared to Desferrioxamine in the Treatment of IronOverload in Lower-risk, Transfusion-dependent Myelodysplastic Syndrome Patients.J Med Econ. 2010;13:559-70.

Documents

Oral Iron Chela to Rs