Deferoxamine

Uses

Deferoxamine is used in the treatment of acute iron poisoning and in iron storage diseases, notably beta-thalassemia [ ]. The usual regimen is 40 mg/kg/day as a subcutaneous infusion over 10–12 hours, starting at an early age (3 years). During erythrocyte transfusion, deferoxamine 300 mg/kg can be given intravenously over 24 hours. Ascorbic acid (vitamin C) 100 mg/day can also be given orally to facilitate mobilization of stored iron. With such a regimen the duration and quality of life in thalassemia can be greatly improved [ , ]. Another indication for deferoxamine is aluminium storage in patients on hemodialysis.

Iron chelation treatment has dramatically improved the prognosis of patients with beta-thalassemia [ ]. Parenteral deferoxamine reduces tissue iron stores, prevents iron-induced organ damage, and reduces morbidity and mortality. However, the burden of prolonged subcutaneous portable pump infusions, adverse reactions, patient non-compliance, and high cost are limiting factors, which have stimulated the development of orally active compounds. Combinations of chemically different types of chelators, which have different iron-carrying capacities and access different iron compartments, may work synergistically and result in increased efficacy, whereas lower doses of individual drugs may be less toxic [ ]. Examples are parenteral deferoxamine with oral deferiprone or 2,3-dihydroxybenzoic acid (2,3-DHB), or oral deferiprone with oral N,N′-bis(2-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HDEB). Iron bound to a “shuttle,” an oral agent that mobilizes tissue iron, is exchanged in the blood stream with a “sink,” such as parenteral deferoxamine, and excreted via the kidneys, while the shuttle is reused. Combinations of different iron chelators can enhance iron excretion, target specific iron compartments, minimize adverse effects, increase treatment options, improve adherence to therapy, and facilitate individualization of therapy. Increasing understanding of the kinetics of iron metabolism, iron overload, and the complexity of chelation should further improve therapeutic strategies.

General adverse effects and adverse reactions

Deferoxamine is only used parenterally. It is more toxic when used in patients with a low iron burden. After subcutaneous infusion many patients have some local irritation and swelling. Rapid intravenous injection can be followed by flushing, wheals, tachycardia, hypotension, acute adult respiratory distress, and renal insufficiency; shock or convulsions can also occur. Headache, blurred vision, dysuria, diarrhea, and leg or hand cramps have been reported. Intramuscular injection can be painful. Hypersensitivity reactions occasionally occur, with rash, fever, and edema; anaphylactic shock has been encountered [ , ]. As a test dose in patients with aluminium storage disease, a low dose (500 mg in 100 ml of 0.9% saline) is usually effective and safe [ ]. At the higher doses used in treatment, nausea, itching, dizziness, or more serious reactions can occur. When deferoxamine is given early in childhood, osteopathy and growth impairment can occur.

Withholding iron is an important protection strategy of the body against microbial and neoplastic cells, and cellular iron depletion plays a prominent role in cell-mediated immune defence [ ]. The use of deferoxamine is associated with an increased risk of life-threatening opportunistic infections, notably yersiniosis and mucormycosis; such infections can affect various organ systems and pose diagnostic problems. Hypersensitivity reactions can occur but are infrequent. Rare cases of anaphylactic shock, thrombocytopenia, and bone marrow failure have been described. Tumor-inducing effects have not been reported. Deferoxamine is teratogenic in animals.

Observational studies

In a 39-year-old woman with primary hemochromatosis and poor tolerance of phlebotomy, excellent results were obtained from deferoxamine 1 g intramuscularly five times a week for 3 months [ ]. Although deferoxamine is not usually recommended in hereditary hemochromatosis, and the use of chelators is limited, iron chelators can be beneficial in combination with phlebotomy in a subset of these patients.

In a retrospective study in 14 children with various hematological disorders (mean age 11 years, range 4–17, transfusional iron overload was treated with deferoxamine in a “weekend very-high dose” regimen [ ]. A single course was defined as 720 mg/kg in 48 hours (in isotonic saline 960 ml/day) by continuous intravenous infusion. The mean duration of treatment was 18 months. In one patient treatment was stopped because of the occurrence of transient paresthesia during the third infusion; presumably the dose of deferoxamine had been unnecessarily high. Another patient complained of muscle cramps in the legs towards the end of the infusion, which did not prevent continued treatment. Two patients with pre-existent hearing impairment had no worsening of symptoms.

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 for 2 years, and 40 received subcutaneous deferoxamine 20–50 mg/kg/day on 5 days a week [ ]. Those who received deferoxamine had done so for 4–24 years and were followed for 2 years. Infusion site reactions occurred in 34 patients, including pain, tenderness, itching, burning, erythema, swelling, induration, and lipodystrophy. Five patients had disturbances of vision and hearing, three had growth retardation. Six patients had increased heart rates, four had dizziness, and one had leg cramps.

In 61 randomized patients who had previously been treated for a long time with deferoxamine, a comparison was made between deferiprone and deferoxamine in improving asymptomatic cardiac siderosis; deferiprone was more efficacious [ ]. Oral deferiprone (n = 29) was started at 75 mg/kg/day and was then increased to 100 mg/kg/day; the dose of deferoxamine (n = 32) was 35 mg/kg/day. Two of those given deferiprone withdrew because of raised liver enzymes (unrelated in at least one); three of those given deferoxamine withdrew, because of deterioration of cardiac function in one and personal reasons in two). The adverse effects patterns of these treatments were different. Gastrointestinal upsets were most common with deferiprone and did not happen with deferoxamine. In 12 patients deferoxamine caused infusion site reactions and mild or moderate arthropathy occurred in 19%.

Cardiovascular

Although rarely described, hypotension can be a significant problem in patients receiving deferoxamine, especially when it is given too rapidly by intravenous injection [ ]; it is possibly due to histamine release [ ]. Dose reduction alleviates the hypotension. Anaphylactic shock has only rarely been reported [ ].

In a single report, soft-tissue swelling around the elbow and localized mild pitting edema were thought to have been induced by deferoxamine [ ]. Although the clinical features suggested a deep-vein thrombosis, this was ruled out by a phlebogram.

In iron storage disease, ascorbic acid should be given only after adequate serum concentrations of deferoxamine have been attained, in order to prevent serious cardiac arrhythmia [ ]. Opportunistic fungal infections associated with deferoxamine may also involve the heart muscle and usually have a fatal outcome [ ].

There was severe phlebitis in cancer patients receiving deferoxamine (50 mg/kg/day by intravenous infusion over 72 hours) and iron sorbitol citrate in an attempt to enhance doxorubicin activity [ ]. Dilution of the drug in large volumes of saline did not prevent this adverse effect.

Respiratory

Deferoxamine by continuous infusion can cause life-threatening acute adult respiratory distress syndrome, with respiratory failure, hypoxia, pulmonary edema, low pulmonary compliance, and a reduced pulmonary capillary wedge pressure [ , ]. Respiratory distress can start 32–72 hours after the infusion. Lung biopsy shows diffuse abnormalities with alveolar damage, interstitial fibrosis, and inflammatory infiltration with lymphocytes, eosinophils, mast cells, and some erythrocytes. It is therefore recommended that deferoxamine should not be given as a continuous infusion for more than 24 hours [ ]. Although the mechanism is unknown, it has been suggested that deferoxamine causes lung damage by paradoxically increasing the production of free radicals, as a result of extended exposure of the lungs to ferrioxamine [ ]. However, others have emphasized that pulmonary endothelial cells are sensitive to macrophage-generated oxidants, and have proposed that in chelating, intracellular iron deferoxamine may acutely reduce the synthesis of catalase and heme, and that readily available extracellular heme subsequently enters cells, is broken down, and releases iron in the presence of low concentrations of catalase, which catalyses oxidant damage [ ].

• In one patient, pulmonary symptoms occurred after 7 days of continuous deferoxamine infusion (dyspnea, tachypnea, tachycardia, pleuritic chest pain, and fever) and were diagnosed as pulmonary microemboli [ ].

Respiratory distress and interstitial infiltrates have also been reported in children receiving deferoxamine for iron poisoning or refractory cancers [ , ].

Lung damage was attributed to high doses of deferoxamine in 17 patients with beta-thalassemia major who were given 33 courses by continuous intravenous infusion of 10 days duration in doses up to 10 mg/kg/hour [ ]. Respiratory dysfunction developed in two girls given the highest doses (aged 11 and 15 years). The symptoms were dyspnea, tachypnea, tachycardia, and low-grade fever. Arterial blood gas measurements showed hypoxemia and hypercapnia. Chest X-rays showed bilateral interstitial infiltrates. In one patient, mechanical ventilation was needed for 2 weeks and it took 8 months before pulmonary function returned to normal. In both patients deferoxamine was reintroduced later on without relapse.

The lungs can also be involved in deferoxamine-associated infections, such as systemic mucormycosis, which often runs a fatal course [ , , , ].

• Pneumonia during treatment with high doses of deferoxamine (2–2.5 g by continuous infusion) in a patient with thalassemia major was found to be caused by Pneumocystis jirovecii [ ].

Nervous system

The use of deferoxamine to reduce aluminium overload in hemodialysis patients can exacerbate aluminium encephalopathy and precipitate dialysis dementia [ ]. Confusion, disorientation, agitation, aggression, abnormal behavior, speech arrest, myoclonus, hallucinations, and seizures can occur. Some patients are very sensitive to this effect, and a test dose of deferoxamine is advisable in order to ascertain whether aluminium is excessively mobilized [ ].

Deferoxamine can modify the electroencephalogram, with progressive slowing and bilateral paroxysms [ ].

Nausea and vomiting often develop in patients with rheumatoid arthritis after 4–12 days of treatment with deferoxamine, presumably as a result of chelation of iron from the central nervous system [ ]. Two patients who took the phenothiazine derivative prochlorperazine during treatment of rheumatoid arthritis with deferoxamine lost consciousness for 48–72 hours, possibly because this combination of drugs removed essential iron from the nervous system [ ].

Headache, loss of vision, disturbed consciousness, and various other neurological symptoms can be alarming signs of deferoxamine-associated systemic mucormycosis with cerebral involvement, a condition that is usually fatal [ ].

Sensorimotor neurotoxicity, with paresthesia, areflexia, reduced vibration and position sense, muscle weakness of the arms, and concomitant disturbances of vision and hearing, has been described in two thalassemia patients during the intravenous administration of high dosages of deferoxamine (120 mg/kg/day) [ ].

Neurophysiological evaluation of 40 patients with beta-thalassemia major showed abnormal findings in brain-stem-evoked potentials: auditory (25%), visual (15%), and somatosensory (7.5%); some had abnormal nerve conduction velocity (25%) and 15% had involvement of multiple neural pathways [ ]. Subclinical involvement of the auditory pathway was statistically associated with a higher mean daily dose of deferoxamine and a longer duration of treatment. Abnormalities of the somatosensory pathways were related to old age, a long duration of deferoxamine use, and low serum copper concentrations. Multiple neural pathway involvement was related to the duration of treatment. However, deferoxamine is only partly responsible for the subclinical abnormalities of neural pathways often found in patients with beta-thalassemia major.

Sensory systems

The reported frequency of sensorineural toxicity of deferoxamine varies. Some degree of visual and auditory toxicity can occur in about one-third of patients [ ], and impairment of vision and hearing can occur simultaneously [ ].

• A 25-year-old woman with beta-thalassemia, who had received subcutaneous deferoxamine 2 g/day (50 mg/kg) for 7 days a week for 3 years, developed visual loss. Her best-corrected visual acuity was 20/60 bilaterally. Automated perimetry showed bilateral central scotomata, and a Farnsworth Panel D-15 test showed an irregular pattern of errors. There were no lens opacities, and fundoscopy and fluorescein angiography were normal. Audiometry showed a bilateral high-frequency sensorineural deficit. Two days after withdrawal of deferoxamine and oral administration of zinc sulfate 20 mg/day, the central scotomata disappeared and her color vision and audiographic abnormalities reversed completely. The serum ferritin concentration was 656 ng/ml.

Since the serum ferritin concentration was relatively low, the original dose of deferoxamine may have been too high. Although zinc concentrations were not measured before treatment, the rapid and complete improvement in 48 hours after starting zinc sulfate suggested that deferoxamine-induced zinc deficiency may also have played a role.

Mineral balance

The administration of deferoxamine to dialysis patients in order to chelate aluminium is often associated with asymptomatic hypocalcemia, which can in turn aggravate hyperparathyroidism [ ]. Deferoxamine-induced hypocalcemia can be corrected with supplements of vitamin D and calcium carbonate.

• In an 8-month-old child the administration of deferoxamine for chelation of aluminium, which had accumulated as a result of total parenteral nutrition, caused sustained hypocalcemia without concomitant hypercalciuria [ ].

Presumably, the reduced calcium concentrations in this case reflected bone regeneration following the disappearance of aluminium from the bone.