A Record Of 1320 Suspect, Deferasirox-Related, Patient Deaths Reported In 2009: Insufficient Toxicity Testing, Low Efficacy And Lack Of Transparency May Endanger The Lives Of Iron Loaded Patients

REFERENCES

• Nick H. Letter to the Editor. Iron chelation therapy in hereditary hemochromatosis and thalassemia intermedia: regulatory and non regulatory mechanisms of increased iron absorption [Kontoghiorghes GJ, Spyrou A, Kolganou A. Hemoglobin. 2010;34(3);251–264.] Hemoglobin. 2011;35(2):175–179.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ. Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin Drug Saf. 2007;6(3):236–239.
   Web of Science ®Google Scholar
• Kontoghiorghes GJ. Ethical issues and risk/benefit assessment on iron chelation therapy: Advances with deferiprone/deferoxamine combination and concerns on deferasirox’s safety, efficacy and costs. Hemoglobin. 2008;32(1–2):1–15.
   PubMed Web of Science ®Google Scholar
• Maggio A. Light and shadows in the iron chelation treatment of haematological diseases. Br J Haematol. 2007;138(3):407–421.
   PubMed Web of Science ®Google Scholar
• Anonymous. Deferasirox: for iron overload: only a third-line option. Prescrire Int. 2007;16(91):196.
   Google Scholar
• Angelucci E, Barosi G, Camaschella C, . Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008;93(5):741–752.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ. Response to the Letter to the Editor: Transparency and access to full information for the fatal or serious toxicity risks, low efficacy and high price of deferasirox, could increase the prospect of improved iron chelation therapy worldwide. Hemoglobin. 2008;32(6):608–615.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ, Kolnagou A. Molecular factors and mechanisms affecting iron and other metal excretion or absorption in health and disease. The role of natural and synthetic chelators. Curr Med Chem. 2005;12(23):2695–2709.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ, Spyrou A, Kolganou A. Iron chelation therapy in hereditary hemochromatosis and thalassemia intermedia: regulatory and non regulatory mechanisms of increased iron absorption. Hemoglobin. 2010;34(3);251–264.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ. Chelators affecting iron absorption in mice. Arzneimittelforschung. 1990;40(12):1332–1335.
   PubMed Web of Science ®Google Scholar
• Stobie S, Tyberg J, Matsui D, . Comparison of the pharmacokinetics of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in healthy volunteers, with and without co-administration of ferrous sulfate, to thalassemia patients. Int J Clin Pharmacol Ther Toxicol. 1993;31(12):602–605.
   PubMedGoogle Scholar
• Dresow B, Fischer R, Nielsen P, Gabbe EE, Piga A. Effect of oral iron chelator L1 in iron absorption in man. Ann NY Acad Sci. 1998;850:466–468.
   PubMed Web of Science ®Google Scholar
• Gomez HF, McClafferty HH, Flory D, Brent J, Dart RC. Prevention of gastrointestinal iron absorption by chelation from an orally administered premixed deferoxamine/charcoal slurry. Ann Emerg Med. 1997;30(5):587–592.
   PubMed Web of Science ®Google Scholar
• Nick H, Wong A, Acklin P, . ICL670A: preclinical profile. Adv Exp Med Biol. 2002;509:185–203.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ. Do we need more iron chelating drugs? Lancet 2003;362(9382):495–496.
   PubMed Web of Science ®Google Scholar
• Bruin GJ, Faller T, Wiegand H, . Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. Drug Metab Dispos. 2008;36(12):2523–2538.
   PubMed Web of Science ®Google Scholar
• Anonymous. Exjade (deferasirox) tablets for oral suspension. Prescribing information. Novartis Pharmaceutical Corporation USA (NDA 21–882). October, 2006; 1–12. Changes to the warnings and adverse reactions sections (www.fda.gov) 2006 and 2007.
   Google Scholar
• Kontoghiorghes GJ, Barr J, Baillod RA. Studies of aluminium mobilisation in renal dialysis patients using the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Arzneimittelforschung. 1994;44(4): 522–526.
   PubMedGoogle Scholar
• Kontoghiorghes GJ, Sheppard L, Barr J, Baillod R. Aluminium mobilisation in renal dialysis patients using the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Drugs Today (Barc).1992;28 (Suppl. A):183–187.
   Google Scholar
• Liu P, Yao YN, Wu SD, Dong HJ, Feng GC, Yuan XY. The efficacy of deferiprone on tissues aluminum removal and copper, zinc, manganese level in rabbits. J Inorg Biochem. 2005;99(8):1733–1737.
   PubMed Web of Science ®Google Scholar
• Malluche HH, Smith AJ, Abreo K, Faugere MC. The use of deferoxamine in the management of aluminium accumulation in bone in patients with renal failure. N Engl J Med. 1984;311(3):140–144.
   PubMed Web of Science ®Google Scholar
• Djaldetti M, Fishman P, Notti I, Bessler H. The effect of tetracycline administration on iron absorption in mice. Biomedicine. 1981;35(5):150–152.
   PubMedGoogle Scholar
• Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289–295.
   PubMed Web of Science ®Google Scholar
• Shakeri-Nejad K, Stahlmann R. Drug interactions during therapy with three major groups of antimicrobial agents. Expert Opin Pharmacother. 2006;7(6):639–651.
   PubMed Web of Science ®Google Scholar
• Sandberg AS, Brune M, Carlsson NG, Hallberg L, Skoglund E, Rossander-Hulthén L. Inositol phosphates with different numbers of phosphate groups influence iron absorption in humans. Am J Clin Nutr. 1999;70(2):240–246.
   PubMed Web of Science ®Google Scholar
• Rossander-Hultén L, Brune M, Sandström B, Lönnerdal B, Hallberg L. Competitive inhibition of iron absorption by manganese and zinc in humans. Am J Clin Nutr. 1991;54(1):152–156.
   PubMed Web of Science ®Google Scholar
• Tuntawiroon M, Sritongkul N, Brune M, . Dose-dependent inhibitory effect of phenolic compounds in foods on nonheme-iron absorption in men. Am J Clin Nutr. 1991;53(2):554–557.
   PubMed Web of Science ®Google Scholar
• Glahn RP, Wortley GM, South PK, Miller DD. Inhibition of iron uptake by phytic acid, tannic acid, and ZnCl2: studies using an in vitro digestion/Caco-2 cell model. J Agric Food Chem. 2002;50(2):390–395.
   PubMed Web of Science ®Google Scholar
• Kontoghiorghes GJ. Introduction of higher doses of deferasirox: better efficacy but not effective iron removal from the heart and increased risks of serious toxicities. Expert Opin Drug Saf. 2010;9(4):633–641.
   PubMed Web of Science ®Google Scholar
• Anonymous. Fatal adverse drug events. ISMP Medication Safety Alert. 2010;15(12):1–3.
   Google Scholar
• Kontoghiorghes GJ, Kolnagou A, Peng CT, Shah SV, Aessopos A. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf. 2010;9(2):201–206.
   PubMed Web of Science ®Google Scholar
• Vlachaki E, Chatzinikolaou K, Bekiari E, Klonizakis F, Tsapas A. Is deferasirox implicated in multiple organ failure in a patient with homozygous β-thalassemia? Angiology. 2011; (Epub ahead of print).
   Google Scholar
• Phatak P, Brissot P, Wurster M, . A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology. 2010; (Epub ahead of print) doi: 10.1002/hep.23879.
   Google Scholar
• Kontoghiorghes GJ, Eracleous E, Economides Ch, Kolnagou A. Advances in iron overload therapies. Prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NAll and their combinations. Curr Med Chem. 2005;12(23):2663–2681.
   PubMed Web of Science ®Google Scholar
• Kolnagou A, Economides Ch, Eracleous E, Kontoghiorghes GJ. Long-term comparative studies in thalassemia patients treated with deferoxamine or deferoxamine/deferiprone combination. Identification of effective chelation therapy protocols. Hemoglobin. 2008;32(1-2):41–47.
   Google Scholar
• Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Reduction of body iron stores to normal range levels in thalassaemia by using a deferiprone/deferoxamine combination and their maintenance thereafter by deferiprone monotherapy. Eur J Haematol. 2010;85(5):430–438.
   PubMed Web of Science ®Google Scholar
• Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010;148(3):466–475.
   PubMed Web of Science ®Google Scholar
• Tefler P, Goen PG, Christou S, . Survival of medically treated thalassaemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica. 2006;91(9):1187–1192.
   PubMed Web of Science ®Google Scholar
• Pennell DJ, Porter JB, Cappellini MD, . Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia. Blood. 2010;115(12):2364–2371.
   PubMed Web of Science ®Google Scholar
• Wood JC, Kang BP, Thompson A, . The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood. 2010;116(4):537–543.
   PubMed Web of Science ®Google Scholar
• Pepe A, Meloni A, Capra M, . Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica. 2011;96(1):41–47.
   PubMed Web of Science ®Google Scholar
• Wood JC, Glynos T, Thompson A, . Relationship between LPI, LIC, and cardiac response in a deferasirox monotherapy trial. Haematologica. 2011; (Epub ahead of print).
   Google Scholar
• Kontoghiorghes GJ. A new era in iron chelation therapy: the design of optimal, individually adjusted iron chelation therapies for the complete removal of iron overload in thalassemia and other chronically transfused patients. Hemoglobin. 2009;33(5):332–338.
   PubMed Web of Science ®Google Scholar