Deferiprone is an oral iron chelating agent used to treat transfusion related, chronic iron overload. Deferiprone has been linked to a low rate of transient serum aminotransferase elevations during therapy and to rare instances of clinically apparent liver injury.
Deferiprone (de fer’ i prone) is an orally available iron chelating agent that binds iron with a high affinity and zinc and copper to a lesser extent. In clinical trials in patients with transfusion related iron overload, deferiprone therapy lowered both circulating and tissue (cardiac, liver) iron levels and maintained reduced iron concentrations in patients previously treated long term with subcutaneous infusions of deferoxamine. Deferiprone was approved for use in Europe in 1994, but was not approved in the United States until 2011. Current indications are restricted to patients with transfusion related iron overload due to thalassemic syndromes. Deferiprone is available in tablets of 500 mg under the brand name Ferriprox. The recommended initial dose is 25 to 33 mg/kg three times daily. Side effects can include nausea, abdominal pain, arthralgias and neutropenia (6%). Severe adverse events include agranulocytosis (1% to 2%) and infections. Weekly monitoring of white blood cell counts is recommended.
In large clinical trials, elevations in serum aminotransferase levels occurred in 7.5% of patients treated with deferiprone and led to drug discontinuation in ~1%. In many situations, it was unclear whether the ALT elevations were due to deferiprone therapy as opposed to spontaneous worsening of an underlying chronic hepatitis B or C, which is common in patients with transfusion related iron overload. Furthermore, there have been very few reports of clinically apparent liver injury attributed to deferiprone therapy and the clinical features of hepatic injury from deferiprone (latency to onset, pattern of serum enzyme elevations, clinical symptoms and laboratory findings, subsequent course) have not been defined.
Iron overload itself can cause liver injury and result in significant fibrosis and even cirrhosis. By decreasing hepatic iron stores, deferiprone and other iron chelators should improve liver disease and prevent progression of fibrosis. In a controversial open label study of deferiprone therapy for up to 4 years in 19 patients with thalassemia and iron overload, progression of fibrosis was found in 5 of 12 subjects who underwent repeat liver biopsy after an average of 4 years, compared to none of 12 subjects who were separately followed while being treated with deferoxamine. Several subsequent studies, however, failed to show fibrosis progression in subjects with thalassemia and iron overload treated with deferiprone, particularly among those without concurrent hepatitis C.
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations during deferiprone therapy is not known. Deferiprone is metabolized in the liver largely by glucuronidation to a more water soluble complex with subsequent urinary excretion.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. Deferiprone has not been implicated in cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There does not appear to be cross reactivity in risk for hepatic injury between deferiprone and other iron chelators including deferoxamine and deferasirox.
Drug Class: Hematological Agents; Chelating
Agents, Iron Chelators
Other Drugs in the Subclass, Iron Chelators: Deferasirox, Deferoxamine
REPRESENTATIVE TRADE NAMES
Deferiprone – Ferriprox®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 6 August 2014
Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999. (Review of hepatotoxicity published in 1999 before the availability of deferiprone).
Byrns MC, Penning TM. Treatment of metal exposure. Environmental toxicology: carcinogens and heavy metals. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1872-6. (Textbook of pharmacology and therapeutics).
Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, McClelland RA, et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med 1995; 332: 918-22. PubMed Citation (Among 21 patients with beta thalassemia and iron overload treated with oral deferiprone for an average of 3 years, serum ferritin and liver iron concentrations decreased; ALT levels decreased in most patients, but fluctuated significantly in one patient who was positive for anti-HCV).
Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McClelland RA, Burt AD, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998; 339: 417-23. PubMed Citation (Among 19 patients with thalassemia major and iron overload who were treated with deferiprone for an average of 4.6 years, repeat liver biopsies showed progression of fibrosis in 5 of 14 patients with available liver histology; in contrast, no progression of histologic fibrosis was found in 12 separately studied subjects who had been treated with deferoxamine infusions).
Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 2000; 108: 305-12. PubMed Citation (Among 187 patients with beta thalassemia and iron overload treated with deferiprone for at least one year, neutropenia arose at a rate of 5.4 and agranulocytosis at 0.6 per 100 patient years; ALT elevations [
≥2 times ULN] were frequent even before therapy [23%] and 85% of patients had anti-HCV).
Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, Galanello R, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002; 118: 330-6. PubMed Citation (Among 532 patients with thalassemia enrolled into a program to distribute deferiprone, neutropenia occurred at a rate of 2.1 and agranulocytosis at 0.4 per 100 patient years after 5-13 months of therapy and ALT elevations occurred in 15 patients [2.8%], 5 of whom discontinued therapy for this reason).
Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003; 102: 1583-7. PubMed Citation (Among 187 patients with thalassemia and iron overload treated with deferiprone for up to 4 years, agranulocytosis occurred in 0.2 and neutropenia in 2.8 per 100 patient years; ALT fluctuated with no consistent change or pattern, 1 patient stopped therapy for ALT elevations and 1 for hepatitis, but no patient developed evidence of end stage liver disease).
Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 2002; 100: 1566-9. PubMed Citation (Independent reading of liver biopsies by 3 pathologists from 56 patients with iron overload taken before and after deferiprone therapy scored fibrosis as decreasing slightly in 11 without hepatitis C [Ishak fibrosis scores decreasing from 1.12 to 0.97] and rising slightly among 45 with hepatitis C [1.91 and 2.04], neither change being statistically significant).
Wu SF, Peng CT, Wu KH, Tsai CH. Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients. Hemoglobin 2006; 30: 215-8. PubMed Citation (Among 17 patients with thalassemia and iron overload treated with deferiprone for an average of 3.3 years, overall fibrosis scores did not change, but they increased in 2 patients one of whom had hepatitis C).
Ha SY, Chik KW, Ling SC, Lee AC, Luk CW, Lam CW, Ng IO, et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Hemoglobin 2006; 30: 263-74. PubMed Citation (Among 26 patients treated with deferiprone with or without deferoxamine, 6 [23%] had fluctuating ALT elevations which resolved with stopping deferiprone, but did not always recur with restarting; liver biopsies in 18 patients showed slightly increased fibrosis in 4, but decreased or resolution of fibrosis in an equal number).
Jamuar SS, Lai AH. Safety and efficacy of iron chelation therapy with deferiprone in patients with transfusion-dependent thalassemia. Ther Adv Hematol 2012; 3: 299-307. PubMed Citation (Review of safety and efficacy of deferiprone mentions that "transaminitis" occurs in up to 60% of treated subjects, but is nonprogressive and usually resolves spontaneously without routine need for discontinuation).
Viprakasit V, Nuchprayoon I, Chuansumrit A, Torcharus K, Pongtanakul B, Laothamatas J, Srichairatanakool S, et al. Deferiprone
(GPO-L-ONE(®)) monotherapy reduces iron overload in transfusion-dependent thalassemias: 1-year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO-L-ONE; A001) from Thailand. Am J Hematol 2013; 88: 251-60. PubMed Citation (Among 73 children with severe thalassemia major treated with deferiprone for at least one year, serum ferritin levels did not change overall, but did decrease in those with initially very high levels; elevations in ALT occurred in 16% which led to stopping therapy in 6 patients).
Xia S, Zhang W, Huang L, Jiang H. Comparative efficacy and safety of deferoxamine, deferiprone and deferasirox on severe thalassemia: a meta-analysis of 16 randomized controlled trials. PLoS One 2013; 8: e82662. PubMed Citation (Systematic review and metaanalysis of 16 publications comparing iron chelating agents found differences in myocardial content, but not "live iron" concentrations with different therapies, and that the combination of deferoxamine and deferiprone had "higher risk" than deferoxamine).
Calvaruso G, Vitrano A, Di Maggio R, Ballas S, Steinberg MH, Rigano P, Sacco M, et al.; The Investigators of the Multicenter Randomized Clinical Trial of Deferiprone versus Deferoxamine in Sickle-Cell-Disease. Deferiprone versus deferoxamine in sickle cell disease: results from a 5-year long-term Italian multi-center randomized clinical trial. Blood Cells Mol Dis 2014 May 7. [Epub ahead of print] PubMed Citation (Among 60 patients with sickle cell disease and iron overload treated with deferiprone or deferoxamine for up to 5 years, serum ferritin levels decreased in both groups to a similar extent, and "liver damage" [increase twice the normal value] occurred in 10% of deferiprone, but none of deferoxamine treated subjects).
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