Deferiprone

Observational studies

Since the controversy about the safety of deferiprone [ ], its position as a therapeutic agent has been clarified [ ]. In the absence of iron storage, deferoxamine is undoubtedly toxic. However, it has been accepted, in spite of serious toxicity, because of the great need of an effective iron chelator for oral use [ ]. In this context, two studies are important, because they cast doubt on the efficacy of deferiprone [ , ]. In the first, a long-term study in 51 transfusion-dependent iron-overloaded patients, 19 withdrew because of adverse events: arthropathy (stiffness, crepitus, effusion; n = 5), gastrointestinal symptoms (severe nausea, anorexia, vomiting; n = 5), granulocytopenia (n = 3), renal insufficiency (n = 1), and tachycardia (n = 1) [ ]. In the second study, in 26 patients who continued to use the drug, there was generally no satisfactory reduction in iron stores. On the other hand, deferiprone caused fewer adverse effects and was more effective in patients who were previously well-chelated and had lower initial ferritin concentrations. Also, in the long run deferiprone did not adequately control the body iron burden. In addition, in this study the alarming suspicion was raised that deferiprone can paradoxically worsen hepatic fibrosis in patients with thalassemia major, based on hepatic biopsies in 19 patients [ ].

In contrast, studies in Italy and the USA have reached more positive conclusions. Of 187 patients with thalassemia who were unable or unwilling to use deferoxamine, 162 completed 1 year of treatment with deferiprone (75 mg/kg/day) [ ]. One patient developed agranulocytosis and another nine had various degrees of neutropenia (altogether 5%). Other reasons for withdrawal were nausea and vomiting (n = 4; total frequency 24% of patients), thrombocytopenia below 100 × 10 ⁹ /l (n = 2), and a fall in serum alanine transaminase (n = 2). Arthralgia developed in 11 patients (6%). In 29 patients who had not adhered well to deferoxamine and who took deferiprone (70 mg/kg/day) with a minimum follow-up of 1 year, adverse effects were pain in the knees in three patients, reversible neutropenia in one, and gastric intolerance in one [ ]. A repeat liver biopsy in 20 patients showed a reduction in the grade of liver siderosis and of iron content in seven. Worsening of hepatic fibrosis was not mentioned.

In 11 Greek patients who took deferiprone 75–100 mg/kg/day for 6 months, there were no serious adverse events of any kind [ ].

In a Lebanese study in 17 patients, mainly with thalassemia major, there were no serious adverse reactions to deferiprone 50–75 mg/kg/day [ ]. Joint pain, stiffness, or swelling occurred in six patients; the symptoms were severe in two and mild in four patients. Seven patients had nausea, especially in the first month of treatment, and two had a reduced appetite. Headache developed in four patients. Mouth ulcers, sore throat, bitter taste, and fatigue occurred in single cases. In one patient there was a weakly positive ANF after 6 months. There were no cases of granulocytopenia and in none of the patients did adverse reactions require drug withdrawal. The authors suggested that environmental or hereditary factors might have influenced the results.

In a large-scale program for the controlled use of deferiprone, established in 1997 by the Italian Ministry of Health, 86 centers collected information about 532 patients [ ]. In 187 patients, 269 events led to interruption of treatment, often transient. Permanent withdrawal because of adverse events occurred in 47 patients (8.9%). Reasons for withdrawal of treatment in 64 patients included non-compliance (n = 30), a serum ferritin concentration above 4000 ng/ml (n = 14), and a ferritin concentration below 500 ng/ml (n = 3). The most common adverse events were mild to severe granulocytopenia (4.3%), arthralgia (3.9%), gastrointestinal discomfort (3.2%), including nausea, vomiting, and abdominal pain, and transient increases in alanine transaminase activity (2.8%); however, the alanine transaminase results were not clearly presented in the report. Adverse events that were not established as adverse effects were urticaria, erythema, dermatitis, fever, flu-like symptoms, and “infectious episodes”; the authors did not comment on these.

In an open trial in 13 patients with Friedreich’s ataxia aged 14–23 years, deferiprone 20–30 mg/kg/day for 6 months removed accumulated iron from a specific brain area (detected using MRI scanning) and produced significant neurological improvement compared with age-matched controls [ ]. Four patients withdrew because of adverse events, two because of musculoskeletal pain, one because of Guillain–Barré syndrome, and one because of reversible agranulocytosis. Guillain–Barré syndrome is not an established adverse effect of deferiprone. During the study there was a clear reduction in body iron, as shown by reductions in serum iron, ferritin, and hemoglobin concentrations. It is not clear for how long deferiprone can be continued safely in Friedreich’s ataxia and whether iron supplements are beneficial.

Patients with hemoglobin H disease present with anemia of the thalassemia intermedia type. Although transfusions are rarely needed, these patients often acquire iron overload, presumably owing to increased dietary absorption secondary to ineffective erythropoiesis, and diabetes and liver and heart failure can ensue. In 16 patients with hemoglobin H disease whose serum ferritin concentrations were above 900 μg/l deferiprone reduced serum ferritin and cardiac iron content in 12 [ ]. Treatment began with 50 mg/kg/day and was slowly increased to 75 mg/kg/day in most patients. All passed reddish urine, especially during the early phase of treatment. There was mild to significant arthralgia in 10 of the 16 patients, usually affecting the large joints (knees, shoulders, hips). One patient had a persistent gastrointestinal upset, which did not respond to lowering the dose and required permanent withdrawal. Two patients complained of loss of appetite in the initial period, but another had increased appetite and gained 4 kg.

In 61 patients deferiprone was more efficacious than deferoxamine in improving asymptomatic cardiac siderosis [ ]. Oral deferiprone (n = 29) was started at 75 mg/kg/day and was subsequently increased to 100 mg, while for deferoxamine (n = 32) the prescribed dose was 35 mg/kg/day. Of those who took deferiprone two withdrew, both because of liver enzymes (unrelated in at least one). The adverse effects pattern of these treatments were different. While gastrointestinal upsets were most common in deferiprone users (n = 19), they did not occur in deferoxamine users, in whom infusion site reactions were frequent (n = 12). Nine patients who used deferiprone reported increased appetite. Mild or moderate arthropathy occurred in 28% of those who used deferiprone and in 19% of those who used deferoxamine. Transient mild neutropenia occurred in one patient and did not necessitate withdrawal.

In a retrospective study in 45 hepatitis C positive patients with thalassemia deferiprone 75 mg/kg/day for 23–60 months was not associated with worsening of hepatic fibrosis or injury [ ]. In another study liver biopsies were assessed in 17 patients with thalassemia using deferiprone 75 mg/kg/day for a mean period of 39 months, including 11 with positive hepatitis C serology [ ]. In these patients liver histology was compared with previous samples. There were no changes in fibrotic scores in 15 patients, while two had slight worsening.

Of 88 patients in Taiwan using deferiprone 75–80 mg/kg/day for beta-thalassemia, one had mild and transient neutropenia and two had arthropathy; deferiprone was continued in these patients [ ].

Comparative studies

Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone 75 mg/kg/day and 40 received subcutaneous deferoxamine 20–50 mg/kg/day on 5 days a week; the patients were followed for 2 years [ ]. All those who took deferiprone did so because deferoxamine had not been suitable, due to either non-compliance or adverse reactions. One of those taking deferiprone withdrew for unknown reasons (and was excluded from the study). Deferiprone was commonly associated with orange discoloration of the urine. Six patients complained of joint pains, mainly in large joints (moderate to severe in two and mild in four), not requiring drug withdrawal. Seven patients reported nausea, four had headaches, two rashes, and two fatigue. Abdominal discomfort, mouth ulcers, and sore throat each occurred in one patient. Although two patients had transient falls in neutrophil count (to 1.3 × 10 ⁹ and 1.44 × 10 ⁹ /l), presumably secondary to a viral infection, there were no cases of agranulocytosis.

Cardiovascular

Since circulating deferiprone-iron complexes can easily dissociate, deferiprone can redistribute iron in the body [ ]. Although this might theoretically lead to the precipitation or aggravation of heart failure [ ], no such cases have as yet been reported.