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In This Article
 »  Abstract
 » Introduction
 »  Significance of ...
 »  Brief Descriptio...
 »  Effect and Toler...
 »  Previous Studies...
 » Conclusion
 »  References
 »  Article Tables

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EDUCATIONAL FORUM
Year : 2020  |  Volume : 52  |  Issue : 6  |  Page : 514-519
 

Effectiveness and tolerability of twice daily dosing of deferasirox in unresponsive and intolerant transfusion-dependent beta-thalassemia patients: A narrative review


1 Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
2 Department of Paediatrics, JSS Medical College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India

Date of Submission06-Jun-2019
Date of Decision19-Dec-2019
Date of Acceptance04-Jan-2021
Date of Web Publication19-Feb-2021

Correspondence Address:
Dr. George Mathew Panachiyil
Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru - 570 015, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_333_19

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 » Abstract 


Chronic iron overload in beta-thalassemia patients after continuous blood transfusions has caused notable morbidity and mortality in these patients. The once-a-day oral iron chelator, deferasirox has established efficacy and bearable safety in adults and pediatric thalassemia patients. It is now extensively used for the management of transfusional hemosiderosis. However, a number of studies have revealed a few patients continued to be none respondent or intolerant toward the once-a-day regimen of deferasirox even after the administration of maximum dose recommended by the World Health Organization. In the literature, there were three studies showing the boon of twice in a day dosing of deferasirox among transfusional-dependent beta thalassemia patients. Therefore, a nonsystematic review was conducted on above three studies to ascertain the enhanced effectiveness and tolerability of twice per day regimen of deferasirox with the same total dose as that of once daily regimen of deferasirox in unresponsive or intolerant transfusion-dependent beta-thalassemia (TDT) patients. All the above studies concluded that the twice per day regimen of deferasirox was more efficacious and tolerable among TDT patients when compared to the once-a-day regimen with the same total daily dose. Although there was a significant good results from these studies, there is a need to conduct either muticenter study or randomized control study in a larger number of patients for the better confirmation of the results as all the above studies were conducted in the small number of TDT patients.


Keywords: Beta-thalassemia, deferasirox, iron chelation therapy, twice daily dosing


How to cite this article:
Babu T, Panachiyil GM, Sebastian J, Ravi MD. Effectiveness and tolerability of twice daily dosing of deferasirox in unresponsive and intolerant transfusion-dependent beta-thalassemia patients: A narrative review. Indian J Pharmacol 2020;52:514-9

How to cite this URL:
Babu T, Panachiyil GM, Sebastian J, Ravi MD. Effectiveness and tolerability of twice daily dosing of deferasirox in unresponsive and intolerant transfusion-dependent beta-thalassemia patients: A narrative review. Indian J Pharmacol [serial online] 2020 [cited 2021 Feb 26];52:514-9. Available from: https://www.ijp-online.com/text.asp?2020/52/6/514/309727





 » Introduction Top


Burden of thalassemia

Beta-thalassemias are a group of blood disorders with an autosomal recessive inheritance give rise to decreased or absent beta-globin subunit synthesis of hemoglobin that brings about variable results ranging from severe anemia to clinically asymptomatic individuals.[1],[2],[3] This disorder has complex physiopathology and disturbs multiple organ systems.[1] The clinical signs of beta-thalassemia and the burdens of its management reduce the health-related quality of life of the affected individuals.[4] Globally, it is estimated that around 56,000 conceptions could result in a major thalassemia disorder and approximately 30,000 of these thalassemia disorders are beta-thalassemia major.[3] Beta thalassemia is a worldwide disease which is more predominant in Asia, the Middle East, and Mediterranean countries.[2] A greater number of these thalassemia babies are being born in medium and low-income nations.[3] In India, the beta-thalassemia presents a significant magnitude of the health burden with an approximated 100,000 beta-thalassemia syndrome patients.[3]


 » Significance of Iron Chelation Therapy Top


Historically, the beta-thalassemia genotype was categorized into beta-thalassemia major, beta-thalassemia intermediate, or beta-thalassemia minor. However, of late, the categorization was changed and now they are classified as transfusion dependent beta-thalassemia (TDT) patients and Non-transfusion dependent beta thalassemia (NTDT) patients based on their blood transfusion requirements to improve practical therapy considerations.[1]

Beta-thalassemia patients are managed symptomatically with regular blood transfusions (once in every 2–5 weeks) as there is a reduction in red blood cell (RBC) formation or soar in damaging of cell with this disorder.[5] There is the introduction of 200–250 mg of elemental iron with each unit of transfused RBCs and the iron overloading starts after nearly ten to 20 transfusions.[6] Iron overload arises when there is a build-up of iron in various organs, and serum ferritin is more than 1000 mcg/L.[7] The iron overload resulting from the timely blood transfusions is the culprit of the disease process in thalassemia patients that can lead to organ injury and collapse.[8] In thalassemia patients, treatment with iron-chelating agents have demonstrated significant decline in organ damage due to iron overload and enhance survival rate.[9] Of late, there are three iron-chelating agents available on the market for the management of iron burdens such as deferoxamine, deferasirox, and deferiprone.[10] In case, if iron accumulation in these organs is not optimally treated from early childhood with iron chelation therapy can lead to the emergence of clinical morbidities.[11] Timely blood transfusions, iron chelation therapy, and patient response are the three main factors that govern various iron overloading complications. Hence, determining the particular age of incidence for the development of these complications is difficult.[11]

Iron-chelating agent reduces the iron burden by creating a complex with iron, thereby increasing the iron excretion and reducing its deposition in tissues. As a result, long-term complications due to iron deposition in tissues can be prevented or postponed, and hence, iron chelation therapy helps to retain safe iron levels for the patients.[6],[12] These patients require safe and effective iron chelation therapy as our body has a restricted physiologic mechanism to eliminate iron.[8] Primarily, the iron chelators bind to labile iron molecules with low molecular weight, so at any time only a minor portion of human body iron is accessible for chelation.[2] Therefore, the treatment with an iron-chelating agent is maximum effective if its activity exists throughout the day.[2]


 » Brief Description of an Iron-Chelating Agent Deferasirox Top


Deferasirox is a tridentate orally active iron-chelating agent that was determined in the year 1990s at Novartis Pharmaceuticals through the computer technology.[13] The deferasirox binds with ferric iron (2:1 ratio) to form iron deferasirox-ferric iron complex and the binding capacity depends upon its affinity and selectivity for the ferric iron.[14] In adults and pediatric thalassemia patients, deferasirox has established good efficacy and acceptable safety as iron chelator.[8]

Iron chelation therapy is instigated only if there is indication of chronic iron overload (transfusion of 100 ml/kg of packed RBCs or more and level of serum ferritin is stagnated at greater than 1000 mcg/L). The starting dose of deferasirox is 20 mg/kg/day, and it can be changed every 3–6 months by 5–10 mg/kg/day up to 40 mg/kg/day based on the patient's response and treatment target.[15],[16]

The half-life of deferasirox is 8–16 h that enable once-daily dosing of the drug.[8] As per the recommendation the deferasirox is given on an empty stomach by means of a suspension made with water or apple juice.[9] The deferasirox has high protein-binding capacity (approximately 99%), and it mainly binds to blood albumin. The apparent volume of distribution (Vd) of deferasirox is 14.37 ± 2.69 L (adults).[17] The time needed to achieve maximum plasma concentration is 1–4 h post dose.[17] The metabolism is hepatic through glucuronidation by UGT1A1 (primarily) and UGT1A3; minor oxidation by CYP450; undergoes enterohepatic recirculation and the excretion is through the fecal route (84%), with a far less in the urine (8%).[15] The summary of the properties of deferasirox is listed in [Table 1].[15]
Table 1: Properties of Deferasirox

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There is a requirement for the constant checking of thalassemia patients in terms of heart, endocrine organs, liver, and kidney functions.[18] Optimization of iron chelation therapy is important to attain good results in transfusion-dependent thalassemia patients.[9] Confirming good deferasirox adherence and avoiding and treating adverse effects are the key plans in optimizing the management with deferasirox.[9]


 » Effect and Tolerability of Twice in one-Day Dosing of Deferasirox in Unresponsive/Intolerant Transfusion-Dependent Beta-thalassemia Patients Top


Currently, a number of studies (nonclinical trial setting) revealed that a portion of patients could not attain acceptable iron balance even after receiving 30 mg/kg/day or greater dose. This category of thalassemia patients was defined as inadequate responders.[19] Besides, intolerant patients developed adverse events due to deferasirox at the therapeutic dose.[20] If adverse events are treated by reducing the deferasirox dose or interfering management, retaining the negative iron balance for these patients in the course of their timely blood transfusions will be difficult due to the poor iron chelation.[20] However, almost all the patients prefer to stay on deferasirox therapy because of the ease in taking this drug.[20] In an earlier study, it was revealed that deferasirox half-life could possibly reduce to 7 h in a number of patients, and as a result, the drugs total effective time of coverage in the body may be affected.[20],[21] Furthermore, some deferasirox-induced adverse effects may be dose related and connected to the peak drug levels.[20] Inter-individual variations in pharmacokinetic and pharmacodynamics of deferasirox were noted, predominantly in patients who received the maximum recommended deferasirox dose of 40 mg/kg/day.[22]

Splitting the once-a-day dosing of deferasirox to two times a day dosage without changing the total daily dose is beneficial for beta-thalassemia patients reliant on timely blood transfusion (unresponsive or intolerant with single daily deferasirox dosing) due to the improvement in the iron chelation and tolerability as twice in a day dosage regimen of deferasirox possess various pharmacokinetic advantages over the once-a-day regimen[20] and the advantages are: First, the peak concentrations are lower and may be related to reduced intolerance. Second, the trough concentrations are greater and thus improve the bioavailability of deferasirox in unresponsive thalassemia patients ensuring a better clinical efficacy.[23] Otto-Duessel et al. explained the above pharmacokinetic advantages in a gerbil model, and this study had described that poor response toward deferasirox therapy was may be due to the drugs low systemic exposure.[24]


 » Previous Studies on Twice Daily Dosing of Deferasirox Top


There were a total of three studies conducted previously among the TDT patients related to the increased effectiveness and tolerability of twice in a day dosing of deferasirox [Table 2].[20],[25],[26],[27]
Table 2: Previous studies on twice daily dosing of deferasirox

Click here to view


Chang et al. conducted the first retrospective study among TDT patients (unresponsive or intolerant to once per day deferasirox treatment) and were managed by two times a day deferasirox dosing with the same deferasirox daily dosage as of the once-a-day therapy. The TDT patients who were not responding to once-a-day dosing of deferasirox with dosages more than 30 mg/kg/day were described as those who presented with escalating serum ferritin levels for 180 consecutive days, with at least one level more than 2500 ng/dl and the intolerant patients were those who experienced adverse events due to deferasirox therapy at therapeutic doses. Unresponsive patients were incorporated in the effectiveness analysis after the management with two times in a day dosing of deferasirox for a minimum of 6 months. The intolerant patients were analyzed for the tolerability of twice per day dosing in the absence of a predetermined follow-up time interval. Serum ferritin, liver enzymes, pancreatic enzymes, and serum creatinine levels were the laboratory parameters checked in the included patients on a monthly basis and any adverse drug reactions due to deferasirox therapy were documented at each follow-up and were graded. In this study, iron chelation effectiveness was estimated on the basis of monthly variations in the serum ferritin levels. Furthermore, the tolerability of twice daily deferasirox dosing was found out by comparison made between the severity of adverse events related with once daily and the twice-daily deferasirox treatment. Only 18 beta-thalassemia patients satisfied the criteria for the inclusion in the study. Significant statistical median reduction in the serum ferritin levels was observed in 11 nonresponsive patients after 180 days of twice-a-day deferasirox treatment. Furthermore, among the seven intolerant patients, five patients had experienced comparatively less severe adverse events or no adverse events due to deferasirox therapy. Twelve patients that were 11 from the unresponsive group and 1 from the intolerant group administered with continuous twice daily deferasirox for 6 months presented a mild rise in serum creatinine levels. The authors concluded that the twice per day dosing of deferasirox with the equivalent deferasirox daily dosage as of the once-a-day therapy is efficacious in iron chelation among poor responders and also increases tolerability among intolerant patients with once-daily dosing of deferasirox.[20],[25]

In the retrospective-prospective study conducted by Salehifar et al. made a comparison between the effectiveness and tolerability of deferasirox twice in a day dosing with the single daily dosage. Patients aged 2 or more than 2 years and administered with only deferasirox (once daily dosing) for a minimum of 6 months were included in the study. The baseline serum ferritin level and the baseline deferasirox dose taken in this study were the last serum ferritin level before the start of the study and the mean deferasirox per day dose from the past 180 days. Complete blood count with differential, serum ferritin, creatinine, aspartate aminotransferase, and alanine aminotransferase (ALT) levels were estimated in the study patients for the assessment of the efficacy and safety of deferasirox. Twenty-one transfusion-dependent patients were enrolled in the study, and there was a significant reduction for mean ferritin level from 1814 ± 922 ng/ml to 1472 ± 907 ng/ml in the patients. Moreover, there were no major variations in the other laboratory parameters when compared to baseline values. The conclusion made from this study was that dividing the once-a-day dosing of deferasirox to two times in 1 day dosing resulted in more reduction in serum ferritin levels with reference to the initial serum ferritin level without causing any hepatic or renal adverse effects.[26]

A prospective cohort study was conducted by Gumruk et al., and in that study, they made a comparison between the effectiveness of the iron chelation therapy and tolerability of deferasirox among the TDT patients who were on deferasirox at a maximum dose of 40 mg/kg/day. The patients prescribed with deferasirox once daily dosing at a median dose of 40 mg/kg/day for at least 6 months were only included in the study. The maximum recommended dose of deferasirox was given to the patients because of serum ferritin levels more than 1500 ng/ml and in addition to the ferritin values, moderate-to-severe iron deposition was detected in cardiac or liver tissues in the study patients. The included patient's once daily deferasirox therapy was changed to twice in a day therapy with the same deferasirox daily dosage as of the once-a-day therapy and monitored for a median time interval of seven months. Serum ferritin, ALT, creatinine levels, and T2* magnetic resonance imaging of the heart and liver were measured at the starting of the two times per day regimen and at the finish of the follow-up period. Twice per day deferasirox dosing showed a statistically significant decline in serum ferritin levels when compared to once daily, and also, there was no significant difference (P > 0.05) in the ALT and serum creatinine levels for the early and follow-up values. Deferasirox dosage adjustment or its discontinuation was not done in any of the patients with twice in a day dosing. Two of the patients had deferasirox-related nausea during the once daily therapy; however, after changing to a two times a day regimen, none of the patients reported nausea. Patient's satisfaction survey was done in the end of the study that showed five patients preferred the use of twice daily regimen due to free of nausea adverse effect or more decrease in the serum ferritin levels when compared to once daily regimen. However, three patients preferred once daily regimen because of less frequency of the drug use, and two patients stated that they had not experienced any difference in terms of satisfaction. The authors concluded that twice in a day dose of deferasirox at higher doses was better tolerated by the patients when compared to once-a-day deferasirox at higher doses and caused a significant reduction in the ferritin levels of already high iron overload patients.[27]

In addition to the above studies which all were conducted in the TDT patients, there was also a retrospective-prospective study conducted by Pongtanakul and Viprakasit among the transfusion-dependent beta- and alpha-thalassemia patients. In this study, deferasirox administration schedule was changed from once per day regimen to two times in a day regimen, and the authors concluded that twice per day deferasirox was revealed to be effective in patients with deferasirox intolerance.[19]


 » Conclusion Top


All the above studies concluded that the twice in a day regimen of deferasirox was more effective and tolerable among TDT patients when compared to the once-a-day regimen with the same total daily dose. Although there was a significant good results from these studies, there is a need to conduct either muti-center study or randomized control study in a larger number of patients for the better confirmation of the results as all the above studies were conducted in the small number of TDT patients.

Key Notes

  • Splitting the single daily dosing of deferasirox to two times a day dosage without changing the total daily dose is beneficial for transfusion-dependent beta thalassemia patients (unresponsive or intolerant with once-a-day deferasirox dosing) due to the improvement in the iron chelation and tolerability as twice in a day dosage regimen of deferasirox possess various pharmacokinetic advantages over the once-a-day regimen
  • Twice daily deferasirox treatment can improve the effective time coverage of deferasirox in unresponsive thalassemia patients ensuring a better clinical efficacy
  • The intolerance and some adverse effects of once daily deferasirox regimen may be dose dependent and connected to the peak drug levels. Twice daily deferasirox regimen was revealed to be effective in reducing the intolerance and adverse effects as the peak drug concentrations are lower in this case when compared to once daily deferasirox regimen.


Acknowledgment

The authors would like to thank the staffs and the students of Department of Pediatrics and Clinical Pharmacy, JSS Hospital, Mysore, India, for their support and encouragement.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Taher AT, Cappellini MD. How I manage medical complications of β-thalassemia in adults. Blood 2018;132:1781-91.  Back to cited text no. 1
    
2.
Cappellini MD, Porter JB, Viprakasit V, Taher AT. A paradigm shift on beta-thalassaemia treatment: How will we manage this old disease with new therapies? Blood Rev 2018;32:300-11.  Back to cited text no. 2
    
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Mevada ST, Al Saadoon M, Zachariah M, Al Rawas AH, Wali Y. Impact of burden of thalassemia major on health-related quality of life in Omani children. J Pediatr Hematol Oncol 2016;38:384-8.  Back to cited text no. 4
    
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Osborne V, Davies M, Layton D, Shakir SA. Utilisation and safety of deferasirox: Results from an observational cohort study in England. Drug Saf 2018;41:267-75.  Back to cited text no. 5
    
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Chalmers AW, Shammo JM. Evaluation of a new tablet formulation of deferasirox to reduce chronic iron overload after long-term blood transfusions. Ther Clin Risk Manag 2016;12:201-8.  Back to cited text no. 6
    
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Mobarra N, Shanaki M, Ehteram H, Nasiri H, Sahmani M, Saeidi M, Goudarzi M, Pourkarim H, Azad M. A review on iron chelators in treatment of iron overload syndromes. Int J Hematol Oncol Stem Cell Res 2016;10:239.  Back to cited text no. 7
    
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Jaiswal S, Hishikar R, Khandwal O, Agarwal M, Joshi U, Halwai A, et al. Efficacy of deferasirox as an oral iron chelator in paediatric thalassaemia patients. J Clin Diagn Res 2017;11:FC01.  Back to cited text no. 8
    
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Kattamis A, Aydinok Y, Taher A. Optimising management of deferasirox therapy for patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes. Eur J Haematol 2018;101:272-82.  Back to cited text no. 9
    
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Vlachodimitropoulou Koumoutsea E, Garbowski M, Porter J. Synergistic intracellular iron chelation combinations: Mechanisms and conditions for optimizing iron mobilization. Br J Haematol 2015;170:874-83.  Back to cited text no. 10
    
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Saliba AN, Harb AR, Taher AT. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions. J Blood Med. 2015;6:197-209.  Back to cited text no. 11
    
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Ko BS, Chang MC, Chiou TJ, Chang TK, Chen YC, Lin SF, et al. Long-term safety and efficacy of deferasirox in patients with myelodysplastic syndrome, aplastic anemia and other rare anemia in Taiwan. Hematology 2019;24:247-54.  Back to cited text no. 12
    
13.
Hoffman R, Benz EJ, Heslop H, Silberstein LE, Weitz J, Anastasi J. Hematology: Basic Principles and Practice E-Book. 7th ed.. Philadelphia, PA: Elsevier Health Sciences; 2017. p. 557-8.  Back to cited text no. 13
    
14.
Novartis Pharmaceuticals Corporation. Highlights of Prescribing Information: JADENU®. New Jersey, US: Novartis; 2015. Available from: http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf. [Last accessed on 2016 Jan 07].  Back to cited text no. 14
    
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16.
Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). 3rd ed. Nicosia, Cyprus: Thalassaemia International Federation; 2014. p. 42-98.  Back to cited text no. 16
    
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Allegra S, Cusato J, De Francia S, Pirro E, Massano D, Piga A, et al. Deferasirox pharmacokinetic evaluation in β-thalassaemia paediatric patients. J Pharm Pharmacol 2017;69:525-8.  Back to cited text no. 17
    
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Al-Khabori M, Bhandari S, Al-Huneini M, Al-Farsi K, Panjwani V, Daar S. Side effects of deferasirox iron chelation in patients with beta thalassemia major or intermedia. Oman Med J 2013;28:121.  Back to cited text no. 18
    
19.
Pongtanakul B, Viprakasit V. Twice daily deferasirox significantly improves clinical efficacy in transfusion dependent thalassaemias who were inadequate responders to standard once daily dose. Blood Cells Mol Dis 2013;2:96-7.  Back to cited text no. 19
    
20.
Chang HH, Lu MY, Liao YM, Lin PC, Yang YL, Lin DT, et al. Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent β-thalassemia. Pediatr Blood Cancer 2011;56:420-4.  Back to cited text no. 20
    
21.
Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A, et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006;91:873-80.  Back to cited text no. 21
    
22.
Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Séchaud R, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361:1597-602.  Back to cited text no. 22
    
23.
Lu MY, Wang N, Wu WH, Lai CW, Kuo PH, Chiang PH, et al. Simultaneous determination of plasma deferasirox and deferasirox-iron complex using an HPLC-UV system and pharmacokinetics of deferasirox in patients with β-thalassemia major: Once-daily versus twice-daily administration. Clin Ther 2015;37:1751-60.  Back to cited text no. 23
    
24.
Otto-Duessel M, Aguilar M, Nick H, Moats R, Wood JC. Comparison of twice-daily vs once-daily deferasirox dosing in a gerbil model of iron cardiomyopathy. Exp Hematol 2007;35:1069-73.  Back to cited text no. 24
    
25.
Musallam KM. Managing unresponsiveness or intolerance to deferasirox therapy: A tale of two doses. Expert Rev Hematol 2011;4:411-4.  Back to cited text no. 25
    
26.
Salehifar E, Karami H, Kosaryan M, Masoudi H, Aliasgharian A, Mousavi M, et al. Efficacy of oral deferasirox by twice-daily dosing in patients with transfusion-dependent beta thalassemia. J Mazandaran Univ Med Sci 2015;25:1-8.  Back to cited text no. 26
    
27.
Gumruk F, Unal S, Bayhan T, Hazirolan T, Tuncer AM, Cetin M. Twice daily use of deferasirox is more effective in decreasing serum ferritin. Blood 2014;124:2675.  Back to cited text no. 27
    



 
 
    Tables

  [Table 1], [Table 2]



 

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